@article{pezzanite_chow_dow_goodrich_gilbertie_schnabel_2023, title={Antimicrobial Properties of Equine Stromal Cells and Platelets and Future Directions}, volume={39}, ISSN={["1558-4224"]}, DOI={10.1016/j.cveq.2023.06.005}, abstractNote={Increasing antimicrobial resistance in veterinary practice has driven the investigation of novel therapeutic strategies including regenerative and biologic therapies to treat bacterial infection. Integration of biological approaches such as platelet lysate and mesenchymal stromal cell (MSC) therapy may represent adjunctive treatment strategies for bacterial infections that minimize systemic side effects and local tissue toxicity associated with traditional antibiotics and that are not subject to antibiotic resistance. In this review, we will discuss mechanisms by which biological therapies exert antimicrobial effects, as well as potential applications and challenges in clinical implementation in equine practice.}, number={3}, journal={VETERINARY CLINICS OF NORTH AMERICA-EQUINE PRACTICE}, author={Pezzanite, Lynn M. and Chow, Lyndah and Dow, Steven W. and Goodrich, Laurie R. and Gilbertie, Jessica M. and Schnabel, Lauren V}, year={2023}, month={Dec}, pages={565–578} }
 @article{schnabel_2023, title={Considerations for the Use of Biologic and Regenerative Therapies in Equine Practice}, volume={39}, ISSN={["1558-4224"]}, DOI={10.1016/j.cveq.2023.07.001}, number={3}, journal={VETERINARY CLINICS OF NORTH AMERICA-EQUINE PRACTICE}, author={Schnabel, Lauren V.}, year={2023}, month={Dec}, pages={XIII-XIV} }
 @article{smith_berglund_robertson_schnabel_mcmullen_gilger_oh_2023, title={Effect of gentamicin on CD3+T-lymphocyte proliferation for treatment of equine recurrent uveitis: An in vitro study}, volume={4}, ISSN={["1463-5224"]}, url={https://doi.org/10.1111/vop.13098}, DOI={10.1111/vop.13098}, abstractNote={Abstract Objective The objective of the study was to determine the effect of gentamicin on CD3+ T‐lymphocyte proliferation and cell viability using an in vitro cell culture model as a means of investigating the mechanism of action of low‐dose intravitreal gentamicin injection. Animals Studied Three adult horses with no evidence of ophthalmic or systemic disease. Procedure Peripheral blood lymphocytes were treated with gentamicin at concentrations 37.5 μg/mL, 112.5 μg/mL, 187 μg/mL, 375 μg/mL, or 750 μg/mL then stimulated to proliferate with concanavalin A (ConA). 4′,6‐diamidino‐2‐phenylindole (DAPI) and carboxyfluoroscein succinimidyl ester (CSFE) were used as markers of cell viability and cell proliferation, respectively. Following 5‐day culture, live cell counts and CSFE fluorescent intensity data were collected via automated cell count and flow cytometry. The experimental design was duplicated using preservative‐free gentamicin and a proprietary brand formulation. Statistical analysis was performed using two‐way ANOVA with Tukey's multiple comparison test. Results No statistically significant comparisons in CD3+ T‐lymphocyte live cell counts and geometric mean fluorescent intensity of CSFE were identified between gentamicin concentrations or formulations. Conclusions Gentamicin had no effect on equine peripheral blood CD3+ T‐lymphocyte cell viability and proliferation in concentrations ranging from “safe” to “retinotoxic” in relation to intravitreal injection volumes. Low‐dose intravitreal gentamicin may not suppress the Th1‐ and Th17‐mediated immune response.}, journal={VETERINARY OPHTHALMOLOGY}, author={Smith, Hannah L. and Berglund, Alix K. and Robertson, James B. and Schnabel, Lauren V. and McMullen, Richard J. and Gilger, Brian C. and Oh, Annie}, year={2023}, month={Apr} }
 @article{koch_schnabel_reynolds_berry_2023, title={Pneumatic compression therapy using the EQ Press accelerates lymphatic flow in healthy equine forelimbs as determined by lymphoscintigraphy}, volume={84}, ISSN={["1943-5681"]}, DOI={10.2460/ajvr.22.12.0214}, abstractNote={Abstract OBJECTIVE Limb lymphedema in horses can be debilitating and painful. Pneumatic compression therapy has shown significant benefits for people suffering from lymphedema. The objective of this study was to determine the effect of a novel, equine-specific pneumatic compression device on the lymphatic flow of healthy horse forelimbs as determined by Tc-99m sulfur colloid lymphoscintigraphy. ANIMALS 6 healthy Thoroughbreds. PROCEDURES In a randomized crossover design, horses underwent bilateral forelimb lymphoscintigraphy following subcutaneous injection of Tc-99m sulfur colloid at the coronary band as untreated control or with pneumatic compression therapy using the EQ Press. Lateral, static images were obtained of the distal limb (time 0 to 60 minutes) and proximal limb (time 30 to 60 minutes) using a standard gamma camera. Lymphatic flow was determined by assigning a score to the time point at which Tc-99m sulfur colloid was first visualized at the level of the accessory carpal bone (1 to 7) in the distal limb and the cubital lymph node (1 to 4) in the proximal limb. RESULTS EQ Press treatment led to a significantly faster lymphatic flow of Tc-99m sulfur colloid to the predetermined anatomic locations of the accessory carpal bone ( P = .002) in the distal limb and the cubital lymph node ( P = .001) in the proximal limb. CLINICAL RELEVANCE Pneumatic compression therapy as provided by an equine-specific device encouraged lymphatic flow in healthy, nonedematous equine forelimbs. These data support further study of the EQ Press for pneumatic compression therapy in horses clinically affected by lymphedema and lymphatic drainage disorders.}, number={4}, journal={AMERICAN JOURNAL OF VETERINARY RESEARCH}, author={Koch, Drew W. and Schnabel, Lauren V and Reynolds, Justin and Berry, Clifford R.}, year={2023}, month={Apr} }
 @article{gilbertie_schaer_engiles_seiler_deddens_schubert_jacob_stefanovski_ruthel_hickok_et al._2022, title={A Platelet-Rich Plasma-Derived Biologic Clears Staphylococcus aureus Biofilms While Mitigating Cartilage Degeneration and Joint Inflammation in a Clinically Relevant Large Animal Infectious Arthritis Model}, volume={12}, ISSN={2235-2988}, url={http://dx.doi.org/10.3389/fcimb.2022.895022}, DOI={10.3389/fcimb.2022.895022}, abstractNote={The leading cause of treatment failure in Staphylococcus aureus infections is the development of biofilms. Biofilms are highly tolerant to conventional antibiotics which were developed against planktonic cells. Consequently, there is a lack of antibiofilm agents in the antibiotic development pipeline. To address this problem, we developed a platelet-rich plasma (PRP)-derived biologic, termed BIO-PLY (for the BIOactive fraction of Platelet-rich plasma LYsate) which has potent in vitro bactericidal activity against S. aureus synovial fluid free-floating biofilm aggregates. Additional in vitro studies using equine synoviocytes and chondrocytes showed that BIO-PLY protected these cells of the joint from inflammation. The goal of this study was to test BIO-PLY for in vivo efficacy using an equine model of infectious arthritis. We found that horses experimentally infected with S. aureus and subsequently treated with BIO-PLY combined with the antibiotic amikacin (AMK) had decreased bacterial concentrations within both synovial fluid and synovial tissue and exhibited lower systemic and local inflammatory scores compared to horses treated with AMK alone. Most importantly, AMK+BIO-PLY treatment reduced the loss of infection-associated cartilage proteoglycan content in articular cartilage and decreased synovial tissue fibrosis and inflammation. Our results demonstrate the in vivo efficacy of AMK+BIO-PLY and represents a new approach to restore and potentiate antimicrobial activity against synovial fluid biofilms.}, journal={Frontiers in Cellular and Infection Microbiology}, publisher={Frontiers Media SA}, author={Gilbertie, Jessica M. and Schaer, Thomas P. and Engiles, Julie B. and Seiler, Gabriela S. and Deddens, Bennett L. and Schubert, Alicia G. and Jacob, Megan E. and Stefanovski, Darko and Ruthel, Gordon and Hickok, Noreen J. and et al.}, year={2022}, month={May} }
 @article{mcparland_horne_robertson_schnabel_nelson_2022, title={Alterations to the synovial invaginations of the navicular bone are associated with pathology of both the navicular apparatus and distal interphalangeal joint when evaluated using high field MRI}, volume={8}, ISSN={["1740-8261"]}, DOI={10.1111/vru.13140}, abstractNote={Limited information exists regarding associations between distal interphalangeal joint (DIPJ) abnormalities and synovial invagination changes in the distal sesamoid (navicular) bone. This retrospective, analytical study aimed to measure specific characteristics of the synovial invaginations of the navicular bone to determine whether any single characteristic was associated with abnormalities in the DIPJ or navicular apparatus (NA) using high field MRI and a sample of 200 horses' feet. The DIPJ and NA were graded independently by three scorers. The grades were averaged, creating a global pathology score for the DIPJ, NA, and synovial invaginations. Higher global scores represented more severe pathology. The number of invaginations, depth of penetration, invagination shape, and cross-sectional area (CSA) of the largest invagination were recorded. Interobserver agreement was measured using Cohen's Kappa. Associations of global scores of the DIPJ and NA with individual invagination characteristics were assessed using linear mixed modeling. A significant relationship was found between the number of invaginations and global DIPJ score, with higher invagination numbers associated with higher DIPJ scores. For invagination depth and CSA, a significant relationship was noted with global scores of both the DIPJ and NA. Reliable relationships between the shape of synovial invaginations and global scores of DIPJ and NA were not found, likely due to poor interobserver scoring (0.305). These findings suggest that primary DIPJ disease and NA pathology should be considered when noticing alterations to navicular synovial invaginations on MRI. This contrasts traditional views that synovial invagination abnormalities are indicative solely of NA pathology.}, journal={VETERINARY RADIOLOGY & ULTRASOUND}, author={McParland, Thomas J. and Horne, Caitlyn R. and Robertson, James B. and Schnabel, Lauren V. and Nelson, Nathan C.}, year={2022}, month={Aug} }
 @article{koch_berglund_messenger_gilbertie_ellis_schnabel_2022, title={Interleukin-1 beta in tendon injury enhances reparative gene and protein expression in mesenchymal stem cells}, volume={9}, ISSN={["2297-1769"]}, DOI={10.3389/fvets.2022.963759}, abstractNote={Tendon injury in the horse carries a high morbidity and monetary burden. Despite appropriate therapy, reinjury is estimated to occur in 50-65% of cases. Although intralesional mesenchymal stem cell (MSC) therapy has improved tissue architecture and reinjury rates, the mechanisms by which they promote repair are still being investigated. Additionally, reevaluating our application of MSCs in tendon injury is necessary given recent evidence that suggests MSCs exposed to inflammation (deemed MSC licensing) have an enhanced reparative effect. However, applying MSC therapy in this context is limited by the inadequate quantification of the temporal cytokine profile in tendon injury, which hinders our ability to administer MSCs into an environment that could potentiate their effect. Therefore, the objectives of this study were to define the temporal cytokine microenvironment in a surgically induced model of equine tendon injury using ultrafiltration probes and subsequently evaluate changes in MSC gene and protein expression following in vitro inflammatory licensing with cytokines of similar concentration as identified in vivo. In our in vivo surgically induced tendon injury model, IL-1β and IL-6 were the predominant pro-inflammatory cytokines present in tendon ultrafiltrate where a discrete peak in cytokine concentration occurred within 48 h following injury. Thereafter, MSCs were licensed in vitro with IL-1β and IL-6 at a concentration identified from the in vivo study; however, only IL-1β induced upregulation of multiple genes beneficial to tendon healing as identified by RNA-sequencing. Specifically, vascular development, ECM synthesis and remodeling, chemokine and growth factor function alteration, and immunomodulation and tissue reparative genes were significantly upregulated. A significant increase in the protein expression of IL-6, VEGF, and PGE2 was confirmed in IL-1β-licensed MSCs compared to naïve MSCs. This study improves our knowledge of the temporal tendon cytokine microenvironment following injury, which could be beneficial for the development and determining optimal timing of administration of regenerative therapies. Furthermore, these data support the need to further study the benefit of MSCs administered within the inflamed tendon microenvironment or exogenously licensed with IL-1β in vitro prior to treatment as licensed MSCs could enhance their therapeutic benefit in the healing tendon.}, journal={FRONTIERS IN VETERINARY SCIENCE}, author={Koch, Drew W. W. and Berglund, Alix K. K. and Messenger, Kristen M. M. and Gilbertie, Jessica M. M. and Ellis, Ilene M. M. and Schnabel, Lauren V. V.}, year={2022}, month={Aug} }
 @article{elkhamary_keenihan_schnabel_redding_schumacher_2022, title={Leveraging MRI characterization of longitudinal tears of the deep digital flexor tendon in horses using machine learning}, ISSN={["1740-8261"]}, DOI={10.1111/vru.13090}, abstractNote={Abstract While MRI is the modality of choice for the diagnosis of longitudinal tears (LTs) of the deep digital flexor tendon (DDFT) of horses, differentiating between various grades of tears based on imaging characteristics is challenging due to overlapping imaging features. In this retrospective, exploratory, diagnostic accuracy study, a machine learning (ML) scheme was applied to link quantitative features and qualitative descriptors to leverage MRI characteristics of different grades of tearing of the DDFT of horses. A qualitative MRI characteristic scheme, combining tendon morphologic features, altered signal intensity, and synovial sheath distention, was used for LT classification with an excellent diagnostic accuracy of the high‐grade tears but more limited accuracy for the detection of low‐grade tears. A quantitative ML approach was followed to measure the contribution of 30 quantitative phenotypic features for characterizing and classifying tendinous tears. Among the 30 imaging features, boundary curvature represented by the standard deviation and maximum had the most significant discriminatory power ( P < 0.05) between normal and abnormal tendons and could be used as an aid for classifying the different grades of LTs of DDFTs. Imaging analysis‐based 3D interactive surface plot supports qualitative characterization of different grades of LTs of the DDFT through clearer visualization of the tendon in three dimensions and simple integration of two perspectives features (i.e., margin/distribution and intensity/distribution). A systematic approach combining quantitative features with qualitative analyses using ML was diagnostically beneficial in MRI characterization and in discriminating between different grades of LTs of the DDFT of horses.}, journal={VETERINARY RADIOLOGY & ULTRASOUND}, author={ELKhamary, Ahmed N. and Keenihan, Erin K. and Schnabel, Lauren V and Redding, William R. and Schumacher, Jim}, year={2022}, month={Apr} }
 @article{jacobs_schnabel_mcilwraith_blikslager_2022, title={Non-steroidal anti-inflammatory drugs in equine orthopaedics}, volume={2}, ISSN={["2042-3306"]}, DOI={10.1111/evj.13561}, abstractNote={Summary Orthopaedic disorders are commonly encountered in equine veterinary medicine, and non‐steroidal anti‐inflammatory drugs (NSAIDs) play an important role in the management of many equine orthopaedic disorders. There are multiple NSAIDs available for use in horses, including both non‐selective and selective NSAIDS, and the body of literature evaluating the efficacy of these medications, their effects on normal and inflamed musculoskeletal tissues, and their side effects is broad. This review aims to summarise the current literature on the use of NSAIDs for equine orthopaedic disorders and examines new and future avenues for the management of inflammation in equine orthopaedics.}, journal={EQUINE VETERINARY JOURNAL}, author={Jacobs, Carrie C. and Schnabel, Lauren V. and McIlwraith, C. Wayne and Blikslager, Anthony T.}, year={2022}, month={Feb} }
 @article{gilbertie_ulloa_daiker_nguyen_smelter_rose_geriak_schnabel_nizet_sakoulas_2022, title={Potent Activity of Ertapenem Plus Cefazolin Within Staphylococcal Biofilms: A Contributing Factor in the Treatment of Methicillin-Susceptible Staphylococcus aureus Endocarditis}, volume={9}, ISSN={["2328-8957"]}, DOI={10.1093/ofid/ofac159}, abstractNote={Besides antistaphylococcal beta-lactams and source control, there are limited validated antimicrobial salvage options in patients with prolonged methicillin-susceptible Staphylococcus aureus (MSSA) bacteremia, including infective endocarditis (IE).MSSA IE cases treated with ertapenem (ETP) plus cefazolin (CZ) were compared with matched IE cases treated with standard beta-lactam monotherapy. The bactericidal activity of ETP plus CZ was also compared with nafcillin (NAF), CZ, and ETP alone using an in vitro MSSA biofilm model.The median duration of bacteremia experienced by patients (n = 12) while on CZ or NAF was 4 days (range 1-16 days) compared with 1 day (range 1-3 days) for patients (n = 5) treated with ETP + CZ (P = .01, Mann-Whitney U test). Cefazolin and NAF alone or in combination did not achieve biofilm eradication at clinically relevant concentrations. However, the addition of ETP to CZ led to bactericidal eradication within biofilms at standard dosing.Ertapenem reduces CZ concentrations required to eradicate MSSA biofilms to those achievable in vivo by standard dosing, translating into shorter bacteremia duration in patients with MSSA endocarditis. Larger studies are needed to investigate ETP plus CZ therapy in the treatment of biofilm-related MSSA infections such as endocarditis.}, number={5}, journal={OPEN FORUM INFECTIOUS DISEASES}, author={Gilbertie, Jessica and Ulloa, Erlinda R. and Daiker, Jennifer C. and Nguyen, Khanh and Smelter, Dan and Rose, Warren and Geriak, Matthew and Schnabel, Lauren V and Nizet, Victor and Sakoulas, George}, year={2022}, month={May} }
 @article{koch_schnabel_ellis_bates_berglund_2022, title={TGF-beta 2 enhances expression of equine bone marrow-derived mesenchymal stem cell paracrine factors with known associations to tendon healing}, volume={13}, ISSN={["1757-6512"]}, DOI={10.1186/s13287-022-03172-9}, abstractNote={Mesenchymal stem cells (MSCs) secrete paracrine factors and extracellular matrix proteins that contribute to their ability to support tissue healing and regeneration. Both the transcriptome and the secretome of MSCs can be altered by treating the cells with cytokines, but neither have been thoroughly investigated following treatment with the specific cytokine transforming growth factor (TGF)-β2.RNA-sequencing and western blotting were used to compare gene and protein expression between untreated and TGF-β2-treated equine bone marrow-derived MSCs (BM-MSCs). A co-culture system was utilized to compare equine tenocyte migration during co-culture with untreated and TGF-β2-treated BM-MSCs.TGF-β2 treatment significantly upregulated gene expression of collagens, extracellular matrix molecules, and growth factors. Protein expression of collagen type I and tenascin-C was also confirmed to be upregulated in TGF-β2-treated BM-MSCs compared to untreated BM-MSCs. Both untreated and TGF-β2-treated BM-MSCs increased tenocyte migration in vitro.Treating equine BM-MSCs with TGF-β2 significantly increases production of paracrine factors and extracellular matrix molecules important for tendon healing and promotes the migration of tenocytes in vitro.}, number={1}, journal={STEM CELL RESEARCH & THERAPY}, author={Koch, Drew W. and Schnabel, Lauren V and Ellis, Ilene M. and Bates, Rowan E. and Berglund, Alix K.}, year={2022}, month={Sep} }
 @article{pezzanite_chow_phillips_griffenhagen_moore_schaer_engiles_werpy_gilbertie_schnabel_et al._2022, title={TLR-activated mesenchymal stromal cell therapy and antibiotics to treat multi-drug resistant Staphylococcal septic arthritis in an equine model}, ISSN={["2305-5847"]}, DOI={10.21037/atm-22-1746}, abstractNote={Background: Rapid development of antibiotic resistance necessitates advancement of novel therapeutic strategies to treat infection. Mesenchymal stromal cells (MSC) possess antimicrobial and immunomodulatory properties, mediated through antimicrobial peptide secretion and recruitment of innate immune cells including neutrophils and monocytes. TLR-3 activation of human, canine and equine MSC has been shown to enhance bacterial killing and clearance in vitro, in rodent Staphylococcal biofilm infection models and dogs with spontaneous multi-drug-resistant infections. The objective of this study was to determine if intra-articular (IA) TLR-3-activated MSC with antibiotics improved clinical parameters and reduced bacterial counts and inflammatory cytokine concentrations in synovial fluid (SF) of horses with induced septic arthritis.}, journal={ANNALS OF TRANSLATIONAL MEDICINE}, author={Pezzanite, Lynn M. and Chow, Lyndah and Phillips, Jennifer and Griffenhagen, Gregg M. and Moore, A. Russell and Schaer, Thomas P. and Engiles, Julie B. and Werpy, Natasha and Gilbertie, Jessica and Schnabel, Lauren V. and et al.}, year={2022}, month={Sep} }
 @article{schnabel_horne_jacobs_2022, title={Tendon sheath masses - What are the differential diagnoses and what diagnostics are needed?}, ISSN={["2042-3292"]}, DOI={10.1111/eve.13665}, journal={EQUINE VETERINARY EDUCATION}, author={Schnabel, Lauren V and Horne, Caitlyn R. and Jacobs, Carrie C.}, year={2022}, month={Jun} }
 @article{cameron_even_linardi_berglund_schnabel_engiles_ortved_2021, title={Adeno-Associated Virus-Mediated Overexpression of Interleukin-10 Affects the Immunomodulatory Properties of Equine Bone Marrow-Derived Mesenchymal Stem Cells}, volume={32}, ISSN={["1557-7422"]}, DOI={10.1089/hum.2020.319}, abstractNote={Joint injury can cause posttraumatic inflammation, which if severe enough can lead to posttraumatic osteoarthritis (PTOA), a progressive and debilitating condition. Posttraumatic inflammation is characterized by an influx of T lymphocytes and upregulation of inflammatory cytokines and degradative enzymes by activated chondrocytes and synoviocytes. Intra-articular bone marrow-derived mesenchymal stem cell (BM-MSC) injection for the treatment of osteoarthritis (OA) has been of interest due to the immunomodulatory properties of these cells. Interleukin (IL)-10, a potent immunomodulatory cytokine, has also been investigated as an OA therapeutic. Therefore, the objective of this study was to evaluate the combinatorial effects of BM-MSCs and IL-10 in OA using a gene therapy approach. We hypothesized that BM-MSCs overexpressing IL-10 would have superior immunomodulatory effects leading to increased suppression of T cell proliferation and decreased production of proinflammatory cytokines, providing protection of the extracellular matrix (ECM) in a stimulated, co-culture OA model. Treatment groups included the following: untransduced BM-MSC, adeno-associated virus (AAV)-IL10-transduced BM-MSC, and AAV-null transduced BM-MSC, which were unstimulated or stimulated with IL-1β/tumor necrosis factor-α (TNF-α). T cell proliferation was significantly decreased by the presence of BM-MSCs, especially when these BM-MSCs were AAV transduced. There was no significant difference in T cell suppression when cells were cultured with AAV-IL10-transduced or AAV-null transduced BM-MSCs. AAV transduction itself was associated with decreased synthesis of IL-1β, IL-6, and TNF-α. Expression of IL-1β and MMP13 was downregulated in AAV-transduced BM-MSCs and MMP13 expression was downregulated in cartilage explants co-cultured with AAV-transduced BM-MSCs. Despite mitigation of some proinflammatory cascades, rescue of ECM loss, as determined by glycosaminoglycan quantification and histological evaluation, did not occur in either AAV-IL10-transduced or AAV-null transduced co-cultures. Although IL-10 overexpression may enhance BM-MSC-mediated T cell suppression, we did not observe significant modulation of inflammation-driven cartilage degradation in cultures containing AAV-IL10-transduced BM-MSCs. AAV transduction itself does appear to affect paracrine signaling by BM-MSCs, which warrants further investigation.}, number={17-18}, journal={HUMAN GENE THERAPY}, author={Cameron, Ashley D. and Even, Kayla M. and Linardi, Renata L. and Berglund, Alix K. and Schnabel, Lauren V. and Engiles, Julie B. and Ortved, Kyla F.}, year={2021}, month={Sep}, pages={907–918} }
 @article{rowland_miller_berglund_schnabel_levine_antczak_watts_2021, title={Cross-matching of allogeneic mesenchymal stromal cells eliminates recipient immune targeting}, volume={10}, ISSN={["2157-6580"]}, DOI={10.1002/sctm.20-0435}, abstractNote={Allogeneic mesenchymal stromal cells (MSCs) have been used clinically for decades, without cross-matching, on the assumption that they are immune-privileged. In the equine model, we demonstrate innate and adaptive immune responses after repeated intra-articular injection with major histocompatibility complex (MHC) mismatched allogeneic MSCs, but not MHC matched allogeneic or autologous MSCs. We document increased peri-articular edema and synovial effusion, increased synovial cytokine and chemokine concentrations, and development of donor-specific antibodies in mismatched recipients compared with recipients receiving matched allogeneic or autologous MSCs. Importantly, in matched allogeneic and autologous recipients, but not mismatched allogeneic recipients, there was increased stromal derived factor-1 along with increased MSC concentrations in synovial fluid. Until immune recognition of MSCs can be avoided, repeated clinical use of MSCs should be limited to autologous or cross-matched allogeneic MSCs. When non-cross-matched allogeneic MSCs are used in single MSC dose applications, presensitization against donor MHC should be assessed.}, number={5}, journal={STEM CELLS TRANSLATIONAL MEDICINE}, author={Rowland, Aileen L. and Miller, Donald and Berglund, Alix and Schnabel, Lauren V and Levine, Gwendolyn J. and Antczak, Douglas F. and Watts, Ashlee E.}, year={2021}, month={May}, pages={694–710} }
 @article{connard_linardi_even_berglund_schnabel_ortved_2021, title={Effects of continuous passage on the immunomodulator properties of equine bone marrow-derived mesenchymal stem cells in vitro (vol 234, 110203, 2021)}, volume={242}, ISSN={["1873-2534"]}, DOI={10.1016/j.vetimm.2021.110340}, journal={VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY}, author={Connard, Shannon S. and Linardi, Renata L. and Even, Kayla M. and Berglund, Alix K. and Schnabel, Lauren V. and Ortved, Kyla F.}, year={2021}, month={Dec} }
 @article{connard_linardi_even_berglund_schnabel_ortved_2021, title={Effects of continuous passage on the immunomodulatory properties of equine bone marrow-derived mesenchymal stem cells in vitro}, volume={234}, ISSN={["1873-2534"]}, DOI={10.1016/j.vetimm.2021.110203}, abstractNote={The immunomodulatory properties of mesenchymal stem cells (MSCs) have been studied extensively due to their increasing clinical application for tissue regeneration and repair following culture expansion. We have studied the effect of continuous passage on the immunomodulatory capacity of equine bone marrow-derived MSCs (BM-MSCs). Equine BM-MSCs were isolated and culture expanded to passage three, six, and nine (P3, P6, P9). Immunomodulatory properties of each passage were assessed using a T cell proliferation assay and cytokine synthesis following stimulation with interferon gamma (IFN-γ). Equine BM-MSCs maintained their primary cell morphology and immunophenotype throughout all passages. T cell proliferation was suppressed by all passages of BM-MSCs, compared to peripheral blood mononuclear cells (PBMCs) alone. There was no significant difference in suppression of T cell proliferation between P3, P6, and P9 BM-MSCs. All passages of BM-MSCs significantly increased cytokine synthesis in response to stimulation with IFN-γ. There were no significant differences in production of interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1) or regulate on activation, normal T cell expressed and secreted (RANTES) following stimulation with IFN-γ between P3, P6, and P9 BM-MSCs. P9 BM-MSCs had significantly increased production of tumor necrosis factor alpha (TNF-α), (IL-1β), and (IL-10) compared to P3 BM-MSCs. Additionally, there was a significant increase in production of (IL-8) in P6 and P9 BM-MSCs in comparison to P3 BM-MSCs. Our findings demonstrate that culture expansion affects some of the immunomodulatory properties of BM-MSCs in vitro, which may suggest that MSCs isolated from a single collection of bone marrow may be culture expanded, but only those from lower passage numbers would be ideal for clinical application.}, journal={VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY}, author={Connard, Shannon S. and Linardi, Renata L. and Even, Kayla M. and Berglund, Alix K. and Schnabel, Lauren V and Ortved, Kyla F.}, year={2021}, month={Apr} }
 @article{didomenico_fowler_horne_bizikova_schnabel_stowe_2021, title={Pathology in Practice}, volume={258}, ISSN={0003-1488}, url={http://dx.doi.org/10.2460/javma.258.9.961}, DOI={10.2460/javma.258.9.961}, number={9}, journal={Journal of the American Veterinary Medical Association}, publisher={American Veterinary Medical Association (AVMA)}, author={DiDomenico, Amy E. and Fowler, Alexander W. and Horne, Caitlyn R. and Bizikova, Petra and Schnabel, Lauren V. and Stowe, Devorah M.}, year={2021}, month={May}, pages={961–964} }
 @article{berglund_long_robertson_schnabel_2021, title={TGF-beta 2 Reduces the Cell-Mediated Immunogenicity of Equine MHC-Mismatched Bone Marrow-Derived Mesenchymal Stem Cells Without Altering Immunomodulatory Properties}, volume={9}, ISSN={["2296-634X"]}, DOI={10.3389/fcell.2021.628382}, abstractNote={Allogeneic mesenchymal stem cells (MSCs) are a promising cell therapy for treating numerous diseases, but major histocompatibility complex (MHC)-mismatched MSCs can be rejected by the recipient’s immune system. Pre-treating MSCs with transforming growth factor-β2 (TGF-β2) to downregulate surface expression of MHC molecules may enhance the ability of allogeneic MSCs to evade immune responses. We used lymphocyte proliferation assays and ELISAs to analyze the immunomodulatory potential of TGF-β2-treated equine bone marrow-derived MSCs. T cell activation and cytotoxicity assays were then used to measure the in vitro cell-mediated immunogenicity. Similar to untreated MSCs, TGF-β2-treated MSCs inhibited T cell proliferation and did not stimulate MHC-mismatched T cells to proliferate. Additionally, similar quantities of prostaglandin E2 and TGF-β1 were detected in assays with untreated and TGF-β2-treated MSCs supporting that TGF-β2-treated MSCs retain their strong immunomodulatory properties in vitro . Compared to untreated MSCs, TGF-β2-treated MSCs induced less T cell activation and had reduced cell-mediated cytotoxicity in vitro . These results indicate that treating MSCs with TGF-β2 is a promising strategy to reduce the cell-mediated immunogenicity of MHC-mismatched MSCs and facilitate allogeneic MSC therapy.}, journal={FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY}, author={Berglund, Alix K. and Long, Julie M. and Robertson, James B. and Schnabel, Lauren V}, year={2021}, month={Feb} }
 @article{copp_flanders_gagliardi_gilbertie_sessions_chubinskaya_loeser_schnabel_diekman_2021, title={The combination of mitogenic stimulation and DNA damage induces chondrocyte senescence}, volume={29}, ISSN={["1522-9653"]}, DOI={10.1016/j.joca.2020.11.004}, abstractNote={Cellular senescence is a phenotypic state characterized by stable cell-cycle arrest, enhanced lysosomal activity, and the secretion of inflammatory molecules and matrix degrading enzymes. Senescence has been implicated in osteoarthritis (OA) pathophysiology; however, the mechanisms that drive senescence induction in cartilage and other joint tissues are unknown. While numerous physiological signals are capable of initiating senescence, one emerging theme is that damaged cells convert to senescence in response to sustained mitogenic stimulation. The goal of this study was to develop an in vitro articular cartilage explant model to investigate the mechanisms of senescence induction.This study utilized healthy cartilage derived from cadaveric equine stifles and human ankles. Explants were irradiated to initiate DNA damage, and mitogenic stimulation was provided through serum-containing medium and treatment with transforming growth factor β1 and basic fibroblastic growth factor. Readouts of senescence were a quantitative flow cytometry assay to detect senescence-associated β galactosidase activity (SA-β-gal), immunofluorescence for p16 and γH2AX, and qPCR for the expression of inflammatory genes.Human cartilage explants required both irradiation and mitogenic stimulation to induce senescence as compared to baseline control conditions (7.16% vs 2.34% SA-β-gal high, p = 0.0007). These conditions also resulted in chondrocyte clusters within explants, a persistent DNA damage response, increased p16, and gene expression changes.Treatment of cartilage explants with mitogenic stimuli in the context of cellular damage reliably induces high levels of SA-β-gal activity and other senescence markers, which provides a physiologically relevant model system to investigate the mechanisms of senescence induction.}, number={3}, journal={OSTEOARTHRITIS AND CARTILAGE}, author={Copp, M. E. and Flanders, M. C. and Gagliardi, R. and Gilbertie, J. M. and Sessions, G. A. and Chubinskaya, S. and Loeser, R. F. and Schnabel, L. and Diekman, B. O.}, year={2021}, month={Mar}, pages={402–412} }
 @article{dinh_paudel_brochu_popowski_gracieux_cores_huang_hensley_harrell_vandergriff_et al._2020, title={Inhalation of lung spheroid cell secretome and exosomes promotes lung repair in pulmonary fibrosis}, volume={11}, ISSN={["2041-1723"]}, url={http://dx.doi.org/10.1038/s41467-020-14344-7}, DOI={10.1038/s41467-020-14344-7}, abstractNote={Abstract Idiopathic pulmonary fibrosis (IPF) is a fatal and incurable form of interstitial lung disease in which persistent injury results in scar tissue formation. As fibrosis thickens, the lung tissue loses the ability to facilitate gas exchange and provide cells with needed oxygen. Currently, IPF has few treatment options and no effective therapies, aside from lung transplant. Here we present a series of studies utilizing lung spheroid cell-secretome (LSC-Sec) and exosomes (LSC-Exo) by inhalation to treat different models of lung injury and fibrosis. Analysis reveals that LSC-Sec and LSC-Exo treatments could attenuate and resolve bleomycin- and silica-induced fibrosis by reestablishing normal alveolar structure and decreasing both collagen accumulation and myofibroblast proliferation. Additionally, LSC-Sec and LSC-Exo exhibit superior therapeutic benefits than their counterparts derived from mesenchymal stem cells in some measures. We showed that an inhalation treatment of secretome and exosome exhibited therapeutic potential for lung regeneration in two experimental models of pulmonary fibrosis.}, number={1}, journal={NATURE COMMUNICATIONS}, publisher={Springer Science and Business Media LLC}, author={Dinh, Phuong-Uyen C. and Paudel, Dipti and Brochu, Hayden and Popowski, Kristen D. and Gracieux, M. Cyndell and Cores, Jhon and Huang, Ke and Hensley, M. Taylor and Harrell, Erin and Vandergriff, Adam C. and et al.}, year={2020}, month={Feb} }
 @article{fortier_goodrich_ribitsch_schnabel_shepard_watts_smith_2020, title={One health in regenerative medicine: report on the second Havemeyer symposium on regenerative medicine in horses}, volume={15}, ISSN={["1746-076X"]}, DOI={10.2217/rme-2019-0143}, abstractNote={Regenerative medicine is commonly used in human and equine athletes. Potential therapies include culture expanded stem cells, stromal vascular fraction of adipose tissue, platelet-rich plasma, bone marrow concentrate, or autologous conditioned serum. The purpose of this manuscript is to disseminate findings from a workshop on the development of translational regenerative medicine in the equine field. Five themes emerged: stem cell characterization and tenogenic differentiation; interactions between mesenchymal stem cells, other cells and the environment; scaffolds and cell packaging; blood- and bone marrow-based regenerative medicines; clinical use of regenerative therapies. Evidence gained through the use of regenerative medicine applications in the horse should continue to translate to the human patient, bringing novel regenerative therapies to both humans and horses.}, number={6}, journal={REGENERATIVE MEDICINE}, author={Fortier, Lisa Ann and Goodrich, Laurie Ruth and Ribitsch, Iris and Schnabel, Lauren Virginia and Shepard, David Owen and Watts, Ashlee Elizabeth and Smith, Roger Kenneth Whealands}, year={2020}, month={Jun}, pages={1775–1787} }
 @article{gilbertie_schaer_schubert_jacob_menegatti_lavoie_schnabel_2020, title={Platelet-rich plasma lysate displays antibiofilm properties and restores antimicrobial activity against synovial fluid biofilms in vitro}, volume={38}, ISSN={["1554-527X"]}, DOI={10.1002/jor.24584}, abstractNote={Abstract Infectious arthritis is difficult to treat in both human and veterinary clinical practice. Recent literature reports Staphylococcus aureus as well as other gram‐positive and gram‐negative isolates forming free‐floating biofilms in both human and equine synovial fluid that are tolerant to traditional antimicrobial therapy. Using an in vitro equine model, we investigated the ability of platelet‐rich plasma (PRP) formulations to combat synovial fluid biofilm aggregates. Synovial fluid was infected, and biofilm aggregates allowed to form over a 2‐hour period. PRP was collected and processed into different formulations by platelet concentration, leukocyte presence, and activation or lysis. Infected synovial fluid was treated with different PRP formulations with or without aminoglycoside cotreatment. Bacterial load (colony‐forming unit/mL) was determined by serial dilutions and plate counting at 8 hours posttreatment. All PRP formulations displayed antimicrobial properties; however, formulations containing higher concentrations of platelets without leukocytes had increased antimicrobial activity. Lysis of PRP and pooling of the PRP lysate (PRP‐L) from multiple horses as compared to individual horses further increased antimicrobial activity. This activity was lost with the removal of the plasma component or inhibition of the proteolytic activity within the plasma. Fractionation of pooled PRP‐L identified the bioactive components to be cationic and low‐molecular weight (<10 kDa). Overall, PRP‐L exhibited synergism with amikacin against aminoglycoside tolerant biofilm aggregates with greater activity against gram‐positive bacteria. In conclusion, the use of PRP‐L has the potential to augment current antimicrobial treatment regimens which could lead to a decrease in morbidity and mortality associated with infectious arthritis.}, number={6}, journal={JOURNAL OF ORTHOPAEDIC RESEARCH}, author={Gilbertie, Jessica M. and Schaer, Thomas P. and Schubert, Alicia G. and Jacob, Megan E. and Menegatti, Stefano and Lavoie, R. Ashton and Schnabel, Lauren V}, year={2020}, month={Jun}, pages={1365–1374} }
 @article{frohock_gilbertie_daiker_schnabel_pierce_2019, title={5-Benzylidene-4-Oxazolidinones Are Synergistic with Antibiotics for the Treatment of Staphylococcus aureus Biofilms}, volume={12}, ISBN={1439-7633}, url={https://doi.org/10.1002/cbic.201900633}, DOI={10.1002/cbic.201900633}, abstractNote={Abstract The failure of frontline antibiotics in the clinic is one of the most serious threats to human health and requires a multitude of novel therapeutics and innovative approaches to treatment so as to curtail the growing crisis. In addition to traditional resistance mechanisms resulting in the lack of efficacy of many antibiotics, most chronic and recurring infections are further made tolerant to antibiotic action by the presence of biofilms. Herein, we report an expanded set of 5‐benzylidene‐4‐oxazolidinones that are able to inhibit the formation of Staphylococcus aureus biofilms, disperse preformed biofilms, and, in combination with common antibiotics, are able to significantly reduce the bacterial load in a robust collagen‐matrix model of biofilm infection.}, journal={CHEMBIOCHEM}, publisher={Wiley}, author={Frohock, Bram H. and Gilbertie, Jessica M. and Daiker, Jennifer C. and Schnabel, Lauren V and Pierce, Joshua G.}, year={2019} }
 @article{fowler_gilbertie_watson_prange_osborne_schnabel_2019, title={Effects of acellular equine amniotic allografts on the healing of experimentally induced full-thickness distal limb wounds in horses}, volume={48}, ISSN={["1532-950X"]}, DOI={10.1111/vsu.13304}, abstractNote={To characterize the growth factors contained in equine amniotic membrane allograft (eAM; StemWrap scaffold and StemWrap+ injection) and to evaluate the effect of eAM on equine distal limb wound healing.Prospective experimental controlled study.Eight adult horses.Transforming growth factor (TGF)-β1, vascular endothelial growth factor (VEGF), epidermal growth factor, platelet-derived growth factor-BB, and prostaglandin E2 (PGE2 ) concentrations in StemWrap+ were assessed with enzyme-linked immunosorbent assay. Two full-thickness 6.25-cm2 skin wounds were created on each metacarpus. On one forelimb, one wound was treated with eAM, and the other was left untreated (eAM control). On the contralateral limb, one wound was treated with a silicone dressing, and the other served as negative control. Three-dimensional images were obtained to determine wound circumference and surface area analyses at each bandage change until healed. Excessive granulation tissue was debrided once weekly for 4 weeks. Biopsy samples were taken to evaluate quality of wound healing via histologic and immunohistochemistry assays.StemWrap+ contained moderate concentrations of TGF-β1 (494.10 pg/mL), VEGF (212.52 pg/mL), and PGE2 (1811.61 pg/mL). Treatment of wounds with eAM did not affect time to healing or histologic quality of the healing compared with other groups but was associated with increased granulation tissue production early in the study, particularly on day 7.Application of eAM resulted in increased granulation tissue production while maintaining appropriate healing of experimental wounds.Use of eAM is likely most beneficial for substantial wounds in which expedient production of large amounts of granulation tissue is desirable.}, number={8}, journal={VETERINARY SURGERY}, author={Fowler, Alexander W. and Gilbertie, Jessica M. and Watson, Victoria E. and Prange, Timo and Osborne, Jason A. and Schnabel, Lauren V}, year={2019}, month={Nov}, pages={1416–1428} }
 @article{gilbertie_schnabel_hickok_jacob_conlon_shapiro_parvizi_schaer_2019, title={Equine or porcine synovial fluid as a novel ex vivo model for the study of bacterial free-floating biofilms that form in human joint infections}, volume={14}, ISSN={["1932-6203"]}, DOI={10.1371/journal.pone.0221012}, abstractNote={Bacterial invasion of synovial joints, as in infectious or septic arthritis, can be difficult to treat in both veterinary and human clinical practice. Biofilms, in the form of free-floating clumps or aggregates, are involved with the pathogenesis of infectious arthritis and periprosthetic joint infection (PJI). Infection of a joint containing an orthopedic implant can additionally complicate these infections due to the presence of adherent biofilms. Because of these biofilm phenotypes, bacteria within these infected joints show increased antimicrobial tolerance even at high antibiotic concentrations. To date, animal models of PJI or infectious arthritis have been limited to small animals such as rodents or rabbits. Small animal models, however, yield limited quantities of synovial fluid making them impractical for in vitro research. Herein, we describe the use of ex vivo equine and porcine models for the study of synovial fluid induced biofilm aggregate formation and antimicrobial tolerance. We observed Staphylococcus aureus and other bacterial pathogens adapt the same biofilm aggregate phenotype with significant antimicrobial tolerance in both equine and porcine synovial fluid, analogous to human synovial fluid. We also demonstrate that enzymatic dispersal of synovial fluid aggregates restores the activity of antimicrobials. Future studies investigating the interaction of bacterial cell surface proteins with host synovial fluid proteins can be readily carried out in equine or porcine ex vivo models to identify novel drug targets for treatment of prevention of these difficult to treat infectious diseases.}, number={8}, journal={PLOS ONE}, author={Gilbertie, Jessica M. and Schnabel, Lauren V. and Hickok, Noreen J. and Jacob, Megan E. and Conlon, Brian P. and Shapiro, Irving M. and Parvizi, Javad and Schaer, Thomas P.}, year={2019}, month={Aug} }
 @article{gilbertie_davis_davidson_mcdonald_schirmer_schnabel_2019, title={Oral reserpine administration in horses results in low plasma concentrations that alter platelet biology}, volume={51}, ISSN={["2042-3306"]}, DOI={10.1111/evj.13048}, abstractNote={Summary Background Reserpine is a popular drug in the equine industry for long‐term tranquilisation. Clinical observations revealed that blood from horses receiving oral reserpine was hypercoagulable. No studies have documented the pharmacokinetics of orally administered reserpine nor the effects of reserpine on platelets in horses. Objectives To evaluate the pharmacokinetics of oral reserpine in horses and the effects of clinically relevant concentrations of reserpine on platelet functionality in vitro. Study design Experimental controlled study. Methods The pharmacokinetics of oral reserpine (2.5 mg/horse, once) were determined in six healthy adult horses. Plasma samples were collected and concentrations of reserpine were determined by UPLC ‐ MS / MS . Using this data, the in vitro effects of reserpine on platelets were examined. Aggregation, adhesion and releasate assays for serotonin and thromboxane B 2 were performed on platelets exposed to varying concentrations of reserpine (0.01–10 ng/mL), aspirin (negative control) and saline (unexposed control). Results Oral reserpine administration demonstrated low plasma concentrations with a C max of 0.2 ± 0.06 ng/mL and a prolonged half‐life of 23.6 ± 6.24 h. Simulations over a dose range of 2–8 μg/kg predicted C max at steady state between 0.06–0.9 ng/mL. Platelets exposed to these reserpine concentrations in vitro displayed increased aggregation and adhesion compared to unexposed or aspirin‐exposed platelets as well as compared to higher concentrations of reserpine. These functional changes correlated with lower concentrations of serotonin and higher concentrations of thromboxane B 2 in the platelet suspension supernatant. Main limitations This study used a small number of horses and only in vitro platelet experiments. Conclusions Oral reserpine demonstrates low plasma concentrations and a prolonged half‐life in horses. At these concentrations, reserpine causes significant changes in platelet function, most likely due to serotonin release and re‐uptake which primes platelets for activation and thromboxane B 2 release. These findings suggest that clinicians should harvest blood for biological processing prior to the onset of reserpine administration.}, number={4}, journal={EQUINE VETERINARY JOURNAL}, author={Gilbertie, J. M. and Davis, J. L. and Davidson, G. S. and McDonald, A. M. and Schirmer, J. M. and Schnabel, L. V.}, year={2019}, month={Jul}, pages={537–543} }
 @misc{schnabel_redding_2018, title={Diagnosis and management of proximal sesamoid bone fractures in the horse}, volume={30}, ISSN={["2042-3292"]}, DOI={10.1111/eve.12615}, abstractNote={Summary Fractures of the proximal sesamoid bones ( PSB s) range in severity from simple to complex and comminuted and can be articular or nonarticular. The majority of PSB fractures are diagnosed in racehorses, but PSB fractures, especially simple ones, do occur in sport horses undertaking various disciplines. For simple apical, basilar and abaxial articular PSB fractures, surgical removal via arthroscopy carries the best prognosis for return to athletic performance. Removal of apical and abaxial PSB fractures generally result in a favourable prognosis for return to racing but are dependent on the amount of suspensory ligament injury. Removal of basilar PSB fracture fragments results in a less favourable or fair prognosis for return to racing. Mid‐body PSB fractures typically require (lag screw) surgical fixation preferably with arthroscopic guidance and carry a fair to guarded prognosis for return to racing.}, number={8}, journal={EQUINE VETERINARY EDUCATION}, author={Schnabel, L. V. and Redding, W. R.}, year={2018}, month={Aug}, pages={450–455} }
 @article{gilbertie_schnabel_stefanovski_kelly_jacob_schaer_2018, title={Gram-negative multi-drug resistant bacteria influence survival to discharge for horses with septic synovial structures: 206 Cases (2010-2015)}, volume={226}, ISSN={["1873-2542"]}, DOI={10.1016/j.vetmic.2018.10.009}, abstractNote={Bacterial colonization of synovial structures can cause infections that are difficult to treat. Systemic and local antimicrobials and repeated joint lavages are the mainstays of therapy. However, despite aggressive treatments, infection may persist, leading to significant tissue damage or death of the patient. In order to investigate the impact of bacterial culture and antimicrobial resistance on survival to discharge, we reviewed medical records of horses admitted to the University of Pennsylvania's large animal teaching hospital from 2010-2015. Two-hundred and six cases with a definitive diagnosis of septic synovitis and a synovial fluid sample submitted for microbiological culture were included in the study. Of these horses, 48% were culture negative and 52% were positive for any bacterial growth, of which 66% were gram-positive and 28% were gram-negative aerobic organisms with 4% anaerobic and 2% fungal organisms. Overall survival to discharge from hospital was 86%. Horses that had negative growth on culture were more likely to survive until discharge (p < 0.02). Multivariable analyses revealed that the likelihood of euthanasia was significantly associated with identification of coagulase positive Staphylococcus spp. (OR 7.66, 5.46-10.74, p < 0.0001), β-hemolytic Streptococcus spp. (OR 5.18, 3.56-7.55, p < 0.0001), Enterococcus spp. (OR 18.38, 11.45-29.52, p = 0.002), Enterobacteriaceae (OR 31.37, 22.28-44.17, p < 0.0001), Pseudomonas aeruginosa (OR 9.31, 5.30-16.34, p = 0.0004) or other gram-negative species (OR 3.51, 2.07-5.94, p = 0.001). Multi-drug resistance and gram-negative bacteria species were associated with significantly decreased survival rates (OR 119.24, 70.57-201.46, p < 0.0001). In conclusion, prognosis for survival to discharge was poor for horses that were infected with gram-negative organisms, particularly those with MDR phenotypes.}, journal={VETERINARY MICROBIOLOGY}, author={Gilbertie, Jessica M. and Schnabel, Lauren V and Stefanovski, Darko and Kelly, Donna J. and Jacob, Megan E. and Schaer, Thomas P.}, year={2018}, month={Nov}, pages={64–73} }
 @article{cassano_schnabel_goodale_fortier_2018, title={Inflammatory licensed equine MSCs are chondroprotective and exhibit enhanced immunomodulation in an inflammatory environment}, volume={9}, ISSN={["1757-6512"]}, DOI={10.1186/s13287-018-0840-2}, abstractNote={Inflammatory licensed mesenchymal stem cells (MSCs) have the ability to promote functional tissue repair. This study specifically sought to understand how the recipient tissue environment reciprocally affects MSC function. Inflammatory polarized macrophages, modeling an injured tissue environment, were exposed to licensed MSCs, and the resultant effects of MSC immunomodulation and functionality of the MSC secretome on chondrocyte homeostasis were studied.Inflammatory licensed MSCs were generated through priming with either IFN-γ or polyinosinic:polycytidylic acid (poly I:C). Macrophages were polarized to an inflammatory phenotype using IFN-γ. Licensed MSCs were co-cultured with inflammatory macrophages and immunomodulation of MSCs was assessed in a T-cell proliferation assay. MSC gene expression was analyzed for changes in immunogenicity (MHC-I, MHC-II), immunomodulation (IDO, PTGS2, NOS2, TGF-β1), cytokine (IL-6, IL-8), and chemokine (CCL2, CXCL10) expression. Macrophages were assessed for changes in cytokine (IL-6, IL-10, TNF-α, IFN-γ) and chemokine (CCL2, CXCL10) expression. Conditioned medium representing the secretome from IFN-γ or poly I:C-primed MSCs was applied to IL-1β-stimulated chondrocytes, which were analyzed for catabolic (IL-6, TNF-α, CCL2, CXCL10, MMP-13, PTGS2) and matrix synthesis (ACAN, COL2A1) genes.IFN-γ-primed MSCs had a superior ability to suppress T-cell proliferation compared to naïve MSCs, and this ability was maintained following exposure to proinflammatory macrophages. In naïve and licensed MSCs exposed to inflammatory macrophages, MHC-I and MHC-II gene expression was upregulated. The secretome from licensed MSCs was chondroprotective and downregulated inflammatory gene expression in IL-1β-stimulated chondrocytes.In-vitro inflammatory licensing agents enhanced the immunomodulatory ability of MSCs exposed to inflammatory macrophages, and the resultant secretome was biologically active, protecting chondrocytes from catabolic stimulation. Use of licensing agents produced a more consistent immunomodulatory MSC population compared to exposure to inflammatory macrophages. The clinical implications of this study are that in-vitro licensing prior to therapeutic application could result in a more predictable immunomodulatory and reparative response to MSC therapy compared to in-vivo inflammatory licensing by the recipient environment.}, journal={STEM CELL RESEARCH & THERAPY}, author={Cassano, Jennifer M. and Schnabel, Lauren V and Goodale, Margaret B. and Fortier, Lisa A.}, year={2018}, month={Apr} }
 @article{gilbertie_long_schubert_berglund_schaer_schnabel_2018, title={Pooled Platelet-Rich Plasma Lysate Therapy Increases Synoviocyte Proliferation and Hyaluronic Acid Production While Protecting Chondrocytes From Synoviocyte-Derived Inflammatory Mediators}, volume={5}, ISSN={["2297-1769"]}, DOI={10.3389/fvets.2018.00150}, abstractNote={Platelet-rich plasma (PRP) preparations are being used with moderate success to treat osteoarthritis (OA) in humans and in veterinary species. Such preparations are hindered, however, by being autologous in nature and subject to tremendous patient and processing variability. For this reason, there has been increasing interest in the use of plasma lysate preparations instead of traditional PRP. Platelet lysate preparations are acellular, thereby reducing concerns over immunogenicity, and contain high concentrations of growth factors and cytokines. In addition, platelet lysate preparations can be stored frozen for readily available use. The purpose of this study was to evaluate the effects of a pooled allogeneic platelet-rich plasma lysate (PRP-L) preparation on equine synoviocytes and chondrocytes challenged with inflammatory mediators in-vitro to mimic the OA joint environment. Our hypothesis was that PRP-L treatment of inflamed synoviocytes would protect chondrocytes challenged with synoviocyte conditioned media by reducing synoviocyte pro-inflammatory cytokine production while increasing synoviocyte anti-inflammatory cytokine production. Synoviocytes were stimulated with either interleukin-1 (IL-1) or lipopolysaccharide (LPS) for 24 hours followed by no treatment or treatment with platelet poor plasma lysate (PPP-L) or PRP-L for 48 hours. Synoviocyte growth was evaluated at the end of the treatment period and synoviocyte conditioned media was assessed for concentrations of hyaluronic acid (HA), IL-1, tumor necrosis factor alpha (TNF-), and interleukin-6 (IL-6). Chondrocytes were then challenged for 48 hours with synoviocyte conditioned media from each stimulation and treatment group and examined for gene expression of collagen types I (COL1A1), II (COL2A1), and III (COL3A1), aggrecan (ACAN), lubricin (PRG4), and matrix metallopeptidase 3 (MMP-3) and 13 (MMP-13). Treatment of inflamed synoviocytes with PRP-L resulted in increased synoviocyte growth and increased synoviocyte HA and IL-6 production. Challenge of chondrocytes with conditioned media from PRP-L treated synoviocytes resulted in increased collagen type II and aggrecan gene expression as well as decreased MMP-13 gene expression. The results of this study support continued investigation into the use of pooled PRP-L for the treatment of osteoarthritis and warrant further in-vitro studies to discern the mechanisms of action of PRP-L.}, journal={FRONTIERS IN VETERINARY SCIENCE}, author={Gilbertie, Jessica M. and Long, Julie M. and Schubert, Alicia G. and Berglund, Alix K. and Schaer, Thomas P. and Schnabel, Lauren V.}, year={2018}, month={Jul} }
 @article{cassano_schnabel_goodale_fortier_2018, title={The immunomodulatory function of equine MSCs is enhanced by priming through an inflammatory microenvironment or TLR3 ligand}, volume={195}, ISSN={["1873-2534"]}, DOI={10.1016/j.vetimm.2017.10.003}, abstractNote={Mesenchymal stem cells (MSCs) have the therapeutic potential to treat a variety of inflammatory and degenerative disease processes, however the effects of the tissue environment on MSCs have been overlooked. Our hypothesis was that the immunomodulatory function of MSCs would be impaired by TLR4 stimulation or exposure to inflammatory macrophages, whereas their immunosuppressive properties would be enhanced by TLR3 stimulation. MSCs were exposed to polyinosinic:polycytidylic acid (poly I:C) to stimulate TLR3 receptors or lipopolysaccharide (LPS) to stimulate TLR4 receptors. MSC1 proinflammatory phenotype in human MSCs was associated with increased IL-6 and IL-8 and MSC2 regenerative phenotype was associated with increased CCL2 and CXCL10. MSC immunomodulatory function was assessed by measuring the ability of primed MSCs to suppress mitogen-stimulated T cell proliferation. Peripheral blood monocytes were isolated using CD14 MACs positive selection, differentiated into macrophages, and polarized using interferon-gamma (IFN-γ). Polarization was confirmed by increased gene expression of TNFα, CCL2, and CXCL10. Inflammatory macrophages were co-cultured with MSCs for 6 h, and the resultant MSC phenotype was analyzed as described above. Both TLR3 and TLR4 priming and co-culture of MSCs with inflammatory macrophages resulted in increased expression of IL-6, CCL2, and CXCL10 in MSCs. Both TLR3 and TLR4 priming or exposure of MSCs to inflammatory macrophages significantly (p < 0.05) enhanced their immunomodulatory function, demonstrated by a decrease in T cell proliferation in the presence of poly I:C primed MSCs (11%), LPS primed MSCs (7%), or MSCs exposed to inflammatory macrophages (12%), compared to unstimulated MSCs. Additionally, MHC class II positive MSCs tended to have a greater magnitude of response to priming compared to MHC class II negative MSCs. These results suggest that MSCs can be activated by a variety of inflammatory stimuli, but the recipient injured tissue bed in chronic injuries may not contain sufficient inflammatory signals to activate MSC immunomodulatory function. Enhancement of MSCs immunomodulatory function through inflammatory priming prior to clinical application might improve the therapeutic effect of MSC treatments.}, journal={VETERINARY IMMUNOLOGY AND IMMUNOPATHOLOGY}, author={Cassano, Jennifer M. and Schnabel, Lauren V. and Goodale, Margaret B. and Fortier, Lisa A.}, year={2018}, month={Jan}, pages={33–39} }
 @article{berglund_schnabel_2017, title={Allogeneic major histocompatibility complex-mismatched equine bone marrow-derived mesenchymal stem cells are targeted for death by cytotoxic anti-major histocompatibility complex antibodies}, volume={49}, ISSN={["2042-3306"]}, DOI={10.1111/evj.12647}, abstractNote={Summary Background Allogeneic mesenchymal stem cells ( MSC s) are a promising cell source for treating musculoskeletal injuries in horses. Controversy exists, however, over whether major histocompatibility complex ( MHC )‐mismatched MSC s are recognised by the recipient immune system and targeted for death by a cytotoxic antibody response. Objectives To determine if cytotoxic anti‐ MHC antibodies generated in vivo following MHC ‐mismatched MSC injections are capable of initiating complement‐dependent cytotoxicity of MSC s. Study design Experimental controlled study. Methods Antisera previously collected at Days 0, 7, 14 and 21 post‐injection from 4 horses injected with donor MHC ‐mismatched equine leucocyte antigen ( ELA )‐A2 haplotype MSC s and one control horse injected with donor MHC ‐matched ELA ‐A2 MSC s were utilised in this study. Antisera were incubated with ELA ‐A2 MSC s before adding complement in microcytotoxicity assays and cell death was analysed via eosin dye exclusion. ELA ‐A2 peripheral blood leucocytes ( PBL s) were used in the assays as a positive control. Results Antisera from all 4 horses injected with MHC ‐mismatched MSC s contained antibodies that caused the death of ELA ‐A2 haplotype MSC s in the microcytotoxicity assays. In 2 of the 4 horses, antibodies were present as early as Day 7 post‐injection. MSC death was consistently equivalent to that of ELA ‐A2 haplotype PBL death at all time points and antisera dilutions. Antisera from the control horse that was injected with MHC ‐matched MSC s did not contain cytotoxic ELA ‐A2 antibodies at any of the time points examined. Main limitations This study examined MSC death in vitro only and utilized antisera from a small number of horses. Conclusions The cytotoxic antibody response induced in recipient horses following injection with donor MHC ‐mismatched MSC s is capable of killing donor MSC s in vitro. These results suggest that the use of allogeneic MHC ‐mismatched MSC s must be cautioned against, not only for potential adverse events, but also for reduced therapeutic efficacy due to targeted MSC death.}, number={4}, journal={EQUINE VETERINARY JOURNAL}, author={Berglund, A. K. and Schnabel, L. V.}, year={2017}, month={Jul}, pages={539–544} }
 @article{sherman_gilger_berglund_schnabel_2017, title={Effect of bone marrow-derived mesenchymal stem cells and stem cell supernatant on equine corneal wound healing in vitro}, volume={8}, ISSN={1757-6512}, url={http://dx.doi.org/10.1186/s13287-017-0577-3}, DOI={10.1186/s13287-017-0577-3}, abstractNote={We aimed to determine and compare the in vitro effects of autologous bone marrow-derived mesenchymal stem cells (BM-MSCs) and mesenchymal stem cell supernatant (MSC-Sp) on the wound healing capacity of equine corneal fibroblasts using a scratch assay.Bone marrow aspirates and eyes were collected from normal, euthanized horses with subsequent isolation and culture of BM-MSCs and corneal stromal cells. Corneal stromal cells were culture-expanded in the culture well of transwell plates and then treated with an autologous BM-MSC suspension (dose: 2.5 × 105/100 μL media with the BM-MSCs contained within the insert well), MSC-Sp solution, or naive culture media (control) for 72 h. A linear defect in confluent cell cultures was created (i.e., corneal scratch assay) to assess the cellular closure ("healing") over time. Three representative areas of the scratch in each culture were photographed at each time point and the scratch area was quantitated using image analysis software (ImageJ). Media from the scratches were analyzed for various growth factors using human enzyme-linked immunosorbent assay (ELISA) kits that crossreact with the horse.There was a significant percentage decrease in the scratch area remaining in the BM-MSC and MSC-Sp groups compared to the control group. There was also a significant percentage decrease in the scratch area remaining in the BM-MSC group compared to the MSC-Sp group at 36 h post-scratch and all time points thereafter. The concentration of transforming growth factor (TGF)-β1 in the media was significantly higher in the BM-MSC group compared to the control group.The significant decrease in scratch area in equine corneal fibroblast cultures treated with autologous BM-MSCs compared to MSC-Sp or control treatments suggests that BM-MSCs may substantially improve corneal wound healing in horses. MSC-Sp may also improve corneal wound healing given the significant decrease in scratch area compared to control treatments, and would be an immediately available and cost-effective treatment option.}, number={1}, journal={Stem Cell Research & Therapy}, publisher={Springer Science and Business Media LLC}, author={Sherman, Amanda B. and Gilger, Brian C. and Berglund, Alix K. and Schnabel, Lauren V.}, year={2017}, month={May} }
 @article{lustgarten_redding_schnabel_prange_seiler_2016, title={Navigational ultrasound imaging: A novel imaging tool for aiding interventional therapies of equine musculoskeletal injuries}, volume={48}, ISSN={["2042-3306"]}, DOI={10.1111/evj.12410}, abstractNote={Summary Reasons for performing study Navigational ultrasound imaging, also known as fusion imaging, is a novel technology that allows real‐time ultrasound imaging to be correlated with a previously acquired computed tomography ( CT ) or magnetic resonance imaging ( MRI ) study. It has been used in man to aid interventional therapies and has been shown to be valuable for sampling and assessing lesions diagnosed with MRI or CT that are equivocal on ultrasonography. To date, there are no reports of the use of this modality in veterinary medicine. Objectives To assess whether navigational ultrasound imaging can be used to assist commonly performed interventional therapies for the treatment of equine musculoskeletal injuries diagnosed with MRI and determine the appropriateness of regional anatomical landmarks as registration sites. Study design Retrospective, descriptive clinical study. Methods Horses with musculoskeletal injuries of the distal limb diagnosed with MRI scheduled for ultrasound‐guided interventional therapies were evaluated (n = 17 horses with a total of 29 lesions). Anatomical landmarks used for image registration for the navigational procedure were documented. Accuracy of lesion location and success of the procedure were assessed subjectively and described using a grading scale. Results All procedures were accurately registered using regional anatomical landmarks and considered successful based on our criteria. Anatomical landmarks were described for each lesion type. The addition of navigational imaging was considered to greatly aid the procedures in 59% of cases and added information to the remainder of the procedures. The technique was considered to improve the precision of these interventional procedures. Conclusions Navigational ultrasound imaging is a complementary imaging modality that can be used for the treatment of equine soft tissue musculoskeletal injuries diagnosed with MRI .}, number={2}, journal={EQUINE VETERINARY JOURNAL}, author={Lustgarten, M. and Redding, W. R. and Schnabel, L. V. and Prange, T. and Seiler, G. S.}, year={2016}, month={Mar}, pages={195–200} }
 @article{pezzanite_fortier_antczak_cassano_brosnahan_miller_schnabel_2015, title={Equine allogeneic bone marrow-derived mesenchymal stromal cells elicit antibody responses in vivo}, volume={6}, ISSN={["1757-6512"]}, DOI={10.1186/s13287-015-0053-x}, abstractNote={This study tested the hypothesis that Major Histocompatibility Complex (MHC) incompatible equine mesenchymal stromal cells (MSCs) would induce cytotoxic antibodies to donor MHC antigens in recipient horses after intradermal injection. No studies to date have explored recipient antibody responses to allogeneic donor MSC transplantation in the horse. This information is critical because the horse is a valuable species for assessing the safety and efficacy of MSC treatment prior to human clinical application. Six MHC heterozygote horses were identified as non-ELA-A2 haplotype by microsatellite typing and used as allogeneic MHC-mismatched MSC recipients. MHC homozygote horses of known ELA-A2 haplotype were used as MSC and peripheral blood leukocyte (PBL) donors. One MHC homozygote horse of the ELA-A2 haplotype was the recipient of ELA-A2 donor MSCs as an MHC-matched control. Donor MSCs, which were previously isolated and immunophenotyped, were thawed and culture expanded to achieve between 30x106 and 50x106 cells for intradermal injection into the recipient’s neck. Recipient serum was collected and tested for the presence of anti-donor antibodies prior to MSC injection and every 7 days after MSC injection for the duration of the 8-week study using the standard two-stage lymphocyte microcytotoxicity dye-exclusion test. In addition to anti-ELA-A2 antibodies, recipient serum was examined for the presence of cross-reactive antibodies including anti-ELA-A3 and anti-RBC antibodies. All MHC-mismatched recipient horses produced anti-ELA-A2 antibodies following injection of ELA-A2 MSCs and developed a wheal at the injection site that persisted for the duration of the experiment. Anti-ELA-A2 antibody responses were varied both in terms of strength and timing. Four recipient horses had high-titered anti-ELA-A2 antibody responses resulting in greater than 80% donor PBL death in the microcytotoxicity assays and one of these horses also developed antibodies that cross-reacted when tested on lymphocyte targets from a horse with an unrelated MHC type. Allogeneic MSCs are capable of eliciting antibody responses in vivo that can be strong and also cross-reactive with MHC types other than that of the donor. Such responses could limit the effectiveness of repeated allogeneic MSC use in a single horse, and could also result in untoward inflammatory responses in recipients.}, journal={STEM CELL RESEARCH & THERAPY}, author={Pezzanite, Lynn M. and Fortier, Lisa A. and Antczak, Douglas F. and Cassano, Jennifer M. and Brosnahan, Margaret M. and Miller, Donald and Schnabel, Lauren V.}, year={2015}, month={Apr} }
 @article{cassano_schnabel_betancourt_antczak_fortier_2015, title={Mesenchymal Stem Cell Therapy: Clinical Progress and Opportunities for Advancement}, volume={3}, ISSN={2167-485X}, url={http://dx.doi.org/10.1007/S40139-015-0064-4}, DOI={10.1007/S40139-015-0064-4}, number={1}, journal={Current Pathobiology Reports}, publisher={Springer Science and Business Media LLC}, author={Cassano, Jennifer M. and Schnabel, Lauren V. and Betancourt, Aline M. and Antczak, Douglas F. and Fortier, Lisa A.}, year={2015}, month={Jan}, pages={1–7} }
 @article{schnabel_pezzanite_antczak_felippe_fortier_2014, title={Equine bone marrow-derived mesenchymal stromal cells are heterogeneous in MHC class II expression and capable of inciting an immune response in vitro}, volume={5}, ISSN={["1757-6512"]}, DOI={10.1186/scrt402}, abstractNote={The horse is a valuable species to assess the effect of allogeneic mesenchymal stromal cells (MSCs) in regenerative treatments. No studies to date have examined recipient response to major histocompatibility complex (MHC)-mismatched equine MSCs. The purposes of this study were to immunophenotype MSCs from horses of known MHC haplotype and to compare the immunogenicity of MSCs with differing MHC class II expression.MSCs and peripheral blood leukocytes (PBLs) were obtained from Thoroughbred horses (n=10) of known MHC haplotype (ELA-A2, -A3, and -A9 homozygotes). MSCs were cultured through P8; cells from each passage (P2 to P8) were cryopreserved until used. Immunophenotyping of MHC class I and II, CD44, CD29, CD90, LFA-1, and CD45RB was performed by using flow cytometry. Tri-lineage differentiation assays were performed to confirm MSC multipotency. Recombinant equine IFN-γ was used to stimulate MHC class II negative MSCs in culture, after which expression of MHC class II was re-examined. To assess the ability of MHC class II negative or positive MSCs to stimulate an immune response, modified one-way mixed leukocyte reactions (MLRs) were performed by using MHC-matched and mismatched responder PBLs and stimulator PBLs or MSCs. Proliferation of gated CFSE-labeled CD3+ responder T cells was evaluated via CFSE attenuation by using flow cytometry and reported as the number of cells in the proliferating T-cell gate.MSCs varied widely in MHC class II expression despite being homogenous in terms of "stemness" marker expression and ability to undergo trilineage differentiation. Stimulation of MHC class II negative MSCs with IFN-γ resulted in markedly increased expression of MHC class II. MLR results revealed that MHC-mismatched MHC class II-positive MSCs caused significantly increased responder T-cell proliferation compared with MHC-mismatched MHC class II-negative and MHC-matched MSCs, and equivalent to that of the positive control of MHC-mismatched leukocytes.The results of this study suggest that MSCs should be confirmed as MHC class II negative before allogeneic application. Additionally, it must be considered that even MHC class II-negative MSCs could upregulate MHC class II expression if implanted into an area of active inflammation, as demonstrated with in vitro stimulation with IFN-γ.}, journal={STEM CELL RESEARCH & THERAPY}, author={Schnabel, Lauren V. and Pezzanite, Lynn M. and Antczak, Douglas F. and Felippe, M. Julia Bevilaqua and Fortier, Lisa A.}, year={2014}, month={Jan} }
 @article{schnabel_abratte_schimenti_felippe_cassano_southard_cross_fortier_2014, title={Induced pluripotent stem cells have similar immunogenic and more potent immunomodulatory properties compared with bone marrow-derived stromal cells in vitro}, volume={9}, ISSN={["1746-076X"]}, DOI={10.2217/rme.14.29}, abstractNote={To evaluate the in vitro immunogenic and immunomodulatory properties of induced pluripotent stem cells (iPSCs) compared with bone marrow-derived mesenchymal stromal cells (MSCs).Mouse embryonic fibroblasts (MEFs) were isolated from C3HeB/FeJ and C57BL/6J mice, and reprogrammed to generate iPSCs. Mixed leukocyte reactions were performed using MHC-matched and -mismatched responder leukocytes and stimulator leukocytes, iPSCs or MSCs. To assess immunogenic potential, iPSCs and MSCs were used as stimulator cells for responder leukocytes. To assess immunomodulatory properties, iPSCs and MSCs were cultured in the presence of stimulator and responder leukocytes. MEFs were used as a control.iPSCs had similar immunogenic properties but more potent immunomodulatory effects than MSCs. Co-culture of MHC-mismatched leukocytes with MHC-matched iPSCs resulted in significantly less responder T-cell proliferation than observed for MHC-mismatched leukocytes alone and at more responder leukocyte concentrations than with MSCs. In addition, MHC-mismatched iPSCs significantly reduced responder T-cell proliferation when co-cultured with MHC-mismatched leukocytes, while MHC-mismatched MSCs did not.These results provide important information when considering the use of iPSCs in place of MSCs in both regenerative and transplantation medicine.}, number={5}, journal={REGENERATIVE MEDICINE}, author={Schnabel, Lauren V. and Abratte, Christian M. and Schimenti, John C. and Felippe, M. Julia Bevilaqua and Cassano, Jennifer M. and Southard, Teresa L. and Cross, Jessica A. and Fortier, Lisa A.}, year={2014}, pages={621–635} }
 @article{schnabel_fortier_wayne mcilwraith_nobert_2013, title={Therapeutic use of stem cells in horses: Which type, how, and when?}, volume={197}, ISSN={1090-0233}, url={http://dx.doi.org/10.1016/J.TVJL.2013.04.018}, DOI={10.1016/J.TVJL.2013.04.018}, abstractNote={Stem cells are commonly used in equine practice to treat musculoskeletal disorders including tendonitis, osteoarthritis, and more recently laminitis. As the field of regenerative medicine continues to advance, equine practitioners need contemporary information regarding the choice of stem cell type and recommendations regarding clinical implementation of stem cell therapies. Clinicians must also be aware of the limitation in current knowledge regarding stem cells, and the impending regulatory laws that may limit the use of equine stem cells in clinical patients.}, number={3}, journal={The Veterinary Journal}, publisher={Elsevier BV}, author={Schnabel, Lauren V. and Fortier, Lisa A. and Wayne McIlwraith, C. and Nobert, Karl M.}, year={2013}, month={Sep}, pages={570–577} }
 @article{nixon_watts_schnabel_2012, title={Cell- and gene-based approaches to tendon regeneration}, volume={21}, ISSN={1058-2746}, url={http://dx.doi.org/10.1016/j.jse.2011.11.015}, DOI={10.1016/j.jse.2011.11.015}, abstractNote={Repair of rotator cuff tears in experimental models has been significantly improved by the use of enhanced biologic approaches, including platelet-rich plasma, bone marrow aspirate, growth factor supplements, and cell- and gene-modified cell therapy. Despite added complexity, cell-based therapies form an important part of enhanced repair, and combinations of carrier vehicles, growth factors, and implanted cells provide the best opportunity for robust repair. Bone marrow-derived mesenchymal stem cells provide a stimulus for repair in flexor tendons, but application in rotator cuff repair has not shown universally positive results. The use of scaffolds such as platelet-rich plasma, fibrin, and synthetic vehicles and the use of gene priming for stem cell differentiation and local anabolic and anti-inflammatory impact have both provided essential components for enhanced tendon and tendon-to-bone repair in rotator cuff disruption. Application of these research techniques in human rotator cuff injury has generally been limited to autologous platelet-rich plasma, bone marrow concentrate, or bone marrow aspirates combined with scaffold materials. Cultured mesenchymal progenitor therapy and gene-enhanced function have not yet reached clinical trials in humans. Research in several animal species indicates that the concept of gene-primed stem cells, particularly embryonic stem cells, combined with effective culture conditions, transduction with long-term integrating vectors carrying anabolic growth factors, and development of cells conditioned by use of RNA interference gene therapy to resist matrix metalloproteinase degradation, may constitute potential advances in rotator cuff repair. This review summarizes cell- and gene-enhanced cell research for tendon repair and provides future directions for rotator cuff repair using biologic composites.}, number={2}, journal={Journal of Shoulder and Elbow Surgery}, publisher={Elsevier BV}, author={Nixon, Alan J. and Watts, Ashlee E. and Schnabel, Lauren V.}, year={2012}, month={Feb}, pages={278–294} }
 @article{schnabel_lynch_van der meulen_yeager_kornatowski_nixon_2009, title={Mesenchymal stem cells and insulin-like growth factor-I gene-enhanced mesenchymal stem cells improve structural aspects of healing in equine flexor digitorum superficialis tendons}, volume={27}, ISSN={0736-0266 1554-527X}, url={http://dx.doi.org/10.1002/jor.20887}, DOI={10.1002/jor.20887}, abstractNote={Abstract Tendinitis remains a catastrophic injury among athletes. Mesenchymal stem cells (MSCs) have recently been investigated for use in the treatment of tendinitis. Previous work has demonstrated the value of insulin‐like growth factor‐I (IGF‐I) to stimulate cellular proliferation and tendon fiber deposition in the core lesion of tendinitis. This study examined the effects of MSCs, as well as IGF‐I gene‐enhanced MSCs (AdIGF‐MSCs) on tendon healing in vivo. Collagenase‐induced bilateral tendinitis lesions were created in equine flexor digitorum superficialis tendons (SDFT). Tendons were treated with 10 × 10 6 MSCs or 10 × 10 6 AdIGF‐MSCs. Control limbs were injected with 1 mL of phosphate‐buffered saline (PBS). Ultrasound examinations were performed at t = 0, 2, 4, 6, and 8 weeks. Horses were euthanized at 8 weeks and SDFTs were mechanically tested to failure and evaluated for biochemical composition and histologic characteristics. Expression of collagen types I and III, IGF‐I, cartilage oligomeric matrix protein (COMP), matrix metalloproteinase‐3 (MMP‐3), matrix metalloproteinase‐13 (MMP‐13), and aggrecanase‐1 (ADAMTS‐4) were similar in MSC and control tendons. Both MSC and AdIGF‐MSC injection resulted in significantly improved tendon histological scores. These findings indicate a benefit to the use of MSCs and AdIGF‐MSCs for the treatment of tendinitis. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:1392–1398, 2009}, number={10}, journal={Journal of Orthopaedic Research}, publisher={Wiley}, author={Schnabel, Lauren V. and Lynch, Maureen E. and van der Meulen, Marjolein C.H. and Yeager, Amy E. and Kornatowski, Matthew A. and Nixon, Alan J.}, year={2009}, month={Oct}, pages={1392–1398} }
 @article{schnabel_mohammed_miller_mcdermott_jacobson_santangelo_fortier_2007, title={Platelet rich plasma (PRP) enhances anabolic gene expression patterns in flexor digitorum superficialis tendons}, volume={25}, ISSN={0736-0266 1554-527X}, url={http://dx.doi.org/10.1002/jor.20278}, DOI={10.1002/jor.20278}, abstractNote={Platelet rich plasma (PRP) has recently been investigated for use in tissue regeneration studies that seek to utilize the numerous growth factors released from platelet α-granules. This study examined gene expression patterns, DNA, and collagen content of equine flexor digitorum superficialis tendon (SDFT) explants cultured in media consisting of PRP and other blood products. Blood and bone marrow aspirate (BMA) were collected from horses and processed to obtain plasma, PRP, and platelet poor plasma (PPP). IGF-I, TGF-β1, and PDGF-BB were quantified in all blood products using ELISA. Tendons were cultured in explant fashion with blood, plasma, PRP, PPP, or BMA at concentrations of 100%, 50%, or 10% in serum-free DMEM with amino acids. Quantitative RT-PCR for expression of collagen type I (COL1A1), collagen type III (COL3A1), cartilage oligomeric matrix protein (COMP), decorin, matrix metalloproteinase-3 (MMP-3), and matrix metalloproteinase-13 (MMP-13) was performed as were DNA and total soluble collagen assays. TGF-β1 and PDGF-BB concentrations were higher in PRP compared to all other blood products tested. Tendons cultured in 100% PRP showed enhanced gene expression of the matrix molecules COL1A1, COL3A1, and COMP with no concomitant increase in the catabolic molecules MMP-3 and MMP-13. These findings support in vivo investigation of PRP as an autogenous, patient-side treatment for tendonitis. © 2006 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 25:230–240, 2007}, number={2}, journal={Journal of Orthopaedic Research}, publisher={Wiley}, author={Schnabel, Lauren V. and Mohammed, Hussni O. and Miller, Brian J. and McDermott, William G. and Jacobson, May S. and Santangelo, Kelly S. and Fortier, Lisa A.}, year={2007}, month={Feb}, pages={230–240} }