@article{rivera_bilton_burclaff_czerwinski_liu_trueblood_hinesley_breau_deal_joshi_et al._2023, title={Hypoxia Primes Human ISCs for Interleukin-Dependent Rescue of Stem Cell Activity}, volume={16}, ISSN={["2352-345X"]}, DOI={10.1016/j.jcmgh.2023.07.012}, abstractNote={Background and AimsHypoxia in the intestinal epithelium can be caused by acute ischemic events or chronic inflammation in which immune cell infiltration produces inflammatory hypoxia starving the mucosa of oxygen. The epithelium has the capacity to regenerate after some ischemic and inflammatory conditions suggesting that intestinal stem cells (ISCs) are highly tolerant to acute and chronic hypoxia; however, the impact of hypoxia on human ISC (hISC) function has not been reported. Here we present a new microphysiological system (MPS) to investigate how hypoxia affects hISCs from healthy donors and test the hypothesis that prolonged hypoxia modulates how hISCs respond to inflammation-associated interleukins (ILs).MethodshISCs were exposed to <1.0% oxygen in the MPS for 6, 24, 48, and 72 hours. Viability, hypoxia-inducible factor 1a (HIF1a) response, transcriptomics, cell cycle dynamics, and response to cytokines were evaluated in hISCs under hypoxia. HIF stabilizers and inhibitors were screened to evaluate HIF-dependent responses.ResultsThe MPS enables precise, real-time control and monitoring of oxygen levels at the cell surface. Under hypoxia, hISCs maintain viability until 72 hours and exhibit peak HIF1a at 24 hours. hISC activity was reduced at 24 hours but recovered at 48 hours. Hypoxia induced increases in the proportion of hISCs in G1 and expression changes in 16 IL receptors. Prolyl hydroxylase inhibition failed to reproduce hypoxia-dependent IL-receptor expression patterns. hISC activity increased when treated IL1β, IL2, IL4, IL6, IL10, IL13, and IL25 and rescued hISC activity caused by 24 hours of hypoxia.ConclusionsHypoxia pushes hISCs into a dormant but reversible proliferative state and primes hISCs to respond to a subset of ILs that preserves hISC activity. These findings have important implications for understanding intestinal epithelial regeneration mechanisms caused by inflammatory hypoxia. Hypoxia in the intestinal epithelium can be caused by acute ischemic events or chronic inflammation in which immune cell infiltration produces inflammatory hypoxia starving the mucosa of oxygen. The epithelium has the capacity to regenerate after some ischemic and inflammatory conditions suggesting that intestinal stem cells (ISCs) are highly tolerant to acute and chronic hypoxia; however, the impact of hypoxia on human ISC (hISC) function has not been reported. Here we present a new microphysiological system (MPS) to investigate how hypoxia affects hISCs from healthy donors and test the hypothesis that prolonged hypoxia modulates how hISCs respond to inflammation-associated interleukins (ILs). hISCs were exposed to <1.0% oxygen in the MPS for 6, 24, 48, and 72 hours. Viability, hypoxia-inducible factor 1a (HIF1a) response, transcriptomics, cell cycle dynamics, and response to cytokines were evaluated in hISCs under hypoxia. HIF stabilizers and inhibitors were screened to evaluate HIF-dependent responses. The MPS enables precise, real-time control and monitoring of oxygen levels at the cell surface. Under hypoxia, hISCs maintain viability until 72 hours and exhibit peak HIF1a at 24 hours. hISC activity was reduced at 24 hours but recovered at 48 hours. Hypoxia induced increases in the proportion of hISCs in G1 and expression changes in 16 IL receptors. Prolyl hydroxylase inhibition failed to reproduce hypoxia-dependent IL-receptor expression patterns. hISC activity increased when treated IL1β, IL2, IL4, IL6, IL10, IL13, and IL25 and rescued hISC activity caused by 24 hours of hypoxia. Hypoxia pushes hISCs into a dormant but reversible proliferative state and primes hISCs to respond to a subset of ILs that preserves hISC activity. These findings have important implications for understanding intestinal epithelial regeneration mechanisms caused by inflammatory hypoxia.}, number={5}, journal={CELLULAR AND MOLECULAR GASTROENTEROLOGY AND HEPATOLOGY}, author={Rivera, Kristina R. and Bilton, R. Jarrett and Burclaff, Joseph and Czerwinski, Michael J. and Liu, Jintong and Trueblood, Jessica M. and Hinesley, Caroline M. and Breau, Keith A. and Deal, Halston E. and Joshi, Shlok and et al.}, year={2023}, pages={823–846} }
 @article{prodromou_moore_chu_deal_san miguel_brown_daniele_pozdin_menegatti_2023, title={Molecular Engineering of Cyclic Azobenzene‐Peptide Hybrid Ligands for the Purification of Human Blood Factor VIII via Photo‐Affinity Chromatography}, volume={33}, ISSN={1616-301X 1616-3028}, url={http://dx.doi.org/10.1002/adfm.202213881}, DOI={10.1002/adfm.202213881}, abstractNote={Abstract}, number={14}, journal={Advanced Functional Materials}, publisher={Wiley}, author={Prodromou, Raphael and Moore, Brandyn David and Chu, Wenning and Deal, Halston and San Miguel, Adriana and Brown, Ashley Carson and Daniele, Michael Angelo‐Anthony and Pozdin, Vladimir Aleksandrovich and Menegatti, Stefano}, year={2023}, month={Jan} }
 @article{mihalko_sandry_mininni_nellenbach_deal_daniele_ghadimi_levy_brown_2021, title={Fibrin-modulating nanogels for treatment of disseminated intravascular coagulation}, volume={5}, ISSN={2473-9529 2473-9537}, url={http://dx.doi.org/10.1182/bloodadvances.2020003046}, DOI={10.1182/bloodadvances.2020003046}, abstractNote={Abstract}, number={3}, journal={Blood Advances}, publisher={American Society of Hematology}, author={Mihalko, Emily P. and Sandry, Megan and Mininni, Nicholas and Nellenbach, Kimberly and Deal, Halston and Daniele, Michael and Ghadimi, Kamrouz and Levy, Jerrold H. and Brown, Ashley C.}, year={2021}, month={Jan}, pages={613–627} }
 @article{petet_deal_zhao_he_tang_lemmon_2021, title={Rheological characterization of poly-dimethyl siloxane formulations with tunable viscoelastic properties}, volume={11}, ISSN={["2046-2069"]}, DOI={10.1039/d1ra03548g}, abstractNote={We have generated novel formulations of polydimethyl siloxane with varying viscoelastic properties that can be used to study cellular response. We present equations that can be used to predict the storage and loss moduli of these polymers.}, number={57}, journal={RSC ADVANCES}, author={Petet, Thomas J., Jr. and Deal, Halston E. and Zhao, Hanhsen S. and He, Amanda Y. and Tang, Christina and Lemmon, Christopher A.}, year={2021}, month={Nov}, pages={35910–35917} }
 @article{nandi_mihalko_nellenbach_castaneda_schneible_harp_deal_daniele_menegatti_barker_et al._2021, title={Synthetic Platelet Microgels Containing Fibrin Knob B Mimetic Motifs Enhance Clotting Responses}, volume={4}, ISSN={2366-3987 2366-3987}, url={http://dx.doi.org/10.1002/adtp.202100010}, DOI={10.1002/adtp.202100010}, abstractNote={Abstract}, number={5}, journal={Advanced Therapeutics}, publisher={Wiley}, author={Nandi, Seema and Mihalko, Emily and Nellenbach, Kimberly and Castaneda, Mario and Schneible, John and Harp, Mary and Deal, Halston and Daniele, Michael and Menegatti, Stefano and Barker, Thomas H. and et al.}, year={2021}, month={Mar} }
 @article{deal_brown_daniele_2020, title={Microphysiological systems for the modeling of wound healing and evaluation of pro-healing therapies}, volume={8}, ISSN={2050-750X 2050-7518}, url={http://dx.doi.org/10.1039/D0TB00544D}, DOI={10.1039/d0tb00544d}, abstractNote={Wound healing microphysiological systems have been engineered with synthetic and natural materials and techniques such as bioprinting or viscous finger patterning. Model designs focus on particular phases of wound healing or the recapitulation of micro-anatomies.}, number={32}, journal={Journal of Materials Chemistry B}, publisher={Royal Society of Chemistry (RSC)}, author={Deal, Halston E. and Brown, Ashley C. and Daniele, Michael A.}, year={2020}, pages={7062–7075} }