@article{tong_pang_hu_huang_sun_wang_burclaff_mills_wang_miao_2024, title={Gastric intestinal metaplasia: progress and remaining challenges}, volume={1}, ISSN={["1435-5922"]}, DOI={10.1007/s00535-023-02073-9}, journal={JOURNAL OF GASTROENTEROLOGY}, author={Tong, Qi-Yue and Pang, Min-Jiao and Hu, Xiao-Hai and Huang, Xuan-Zhang and Sun, Jing-Xu and Wang, Xin-Yu and Burclaff, Joseph and Mills, Jason C. and Wang, Zhen-Ning and Miao, Zhi-Feng}, year={2024}, month={Jan} }
 @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={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{a proximal-to-distal survey of healthy adult human small intestine and colon epithelium by single-cell transcriptomics._2022, url={https://europepmc.org/articles/PMC9043569}, DOI={10.1016/j.jcmgh.2022.02.007}, abstractNote={Single-cell transcriptomics offer unprecedented resolution of tissue function at the cellular level, yet studies analyzing healthy adult human small intestine and colon are sparse. Here, we present single-cell transcriptomics covering the duodenum, jejunum, ileum, and ascending, transverse, and descending colon from 3 human beings.A total of 12,590 single epithelial cells from 3 independently processed organ donors were evaluated for organ-specific lineage biomarkers, differentially regulated genes, receptors, and drug targets. Analyses focused on intrinsic cell properties and their capacity for response to extrinsic signals along the gut axis across different human beings.Cells were assigned to 25 epithelial lineage clusters. Multiple accepted intestinal stem cell markers do not specifically mark all human intestinal stem cells. Lysozyme expression is not unique to human Paneth cells, and Paneth cells lack expression of expected niche factors. Bestrophin 4 (BEST4)+ cells express Neuropeptide Y (NPY) and show maturational differences between the small intestine and colon. Tuft cells possess a broad ability to interact with the innate and adaptive immune systems through previously unreported receptors. Some classes of mucins, hormones, cell junctions, and nutrient absorption genes show unappreciated regional expression differences across lineages. The differential expression of receptors and drug targets across lineages show biological variation and the potential for variegated responses.Our study identifies novel lineage marker genes, covers regional differences, shows important differences between mouse and human gut epithelium, and reveals insight into how the epithelium responds to the environment and drugs. This comprehensive cell atlas of the healthy adult human intestinal epithelium resolves likely functional differences across anatomic regions along the gastrointestinal tract and advances our understanding of human intestinal physiology.}, journal={Cellular and molecular gastroenterology and hepatology}, year={2022}, month={Feb} }
 @article{a metformin-responsive metabolic pathway controls distinct steps in gastric progenitor fate decisions and maturation._2020, url={https://doi.org/10.1016/j.stem.2020.03.006}, DOI={10.1016/j.stem.2020.03.006}, abstractNote={<h2>Summary</h2> Cellular metabolism plays important functions in dictating stem cell behaviors, although its role in stomach epithelial homeostasis has not been evaluated in depth. Here, we show that the energy sensor AMP kinase (AMPK) governs gastric epithelial progenitor differentiation. Administering the AMPK activator metformin decreases epithelial progenitor proliferation and increases acid-secreting parietal cells (PCs) in mice and organoids. AMPK activation targets Krüppel-like factor 4 (KLF4), known to govern progenitor proliferation and PC fate choice, and PGC1α, which we show controls PC maturation after their specification. PC-specific deletion of AMPKα or PGC1α causes defective PC maturation, which could not be rescued by metformin. However, metformin treatment still increases KLF4 levels and suppresses progenitor proliferation. Thus, AMPK activates KLF4 in progenitors to reduce self-renewal and promote PC fate, whereas AMPK-PGC1α activation within the PC lineage promotes maturation, providing a potential suggestion for why metformin increases acid secretion and reduces gastric cancer risk in humans.}, journal={Cell stem cell}, year={2020}, month={Apr} }
 @article{proliferation and differentiation of gastric mucous neck and chief cells during homeostasis and injury-induced metaplasia._2019, url={https://doi.org/10.1053/j.gastro.2019.09.037}, DOI={10.1053/j.gastro.2019.09.037}, abstractNote={BACKGROUND & AIMS
Adult zymogen-producing (zymogenic) chief cells (ZCs) in the mammalian gastric gland base are believed to arise from descending mucous neck cells, which arise from stem cells. Gastric injury, such as from Helicobacter pylori infection in patients with chronic atrophic gastritis, can cause metaplasia, characterized by gastric cell expression of markers of wound-healing; these cells are called spasmolytic polypeptide-expressing metaplasia (SPEM) cells. We investigated differentiation and proliferation patterns of neck cells, ZCs, and SPEM cells in mice.


METHODS
C57BL/6 mice were given intraperitoneal injections of high-dose tamoxifen to induce SPEM or gavaged with H pylori (PMSS1) to induce chronic gastric injury. Mice were then given pulses of 5-bromo-2'-deoxyuridine (BrdU) in their drinking water, followed by chase periods without BrdU, or combined with intraperitoneal injections of 5-ethynyl-2'-deoxyuridine. We collected gastric tissues and performed immunofluorescence and immunohistochemical analyses to study gastric cell proliferation, differentiation, and turnover.


RESULTS
After 8 weeks of continuous BrdU administration, less than 10% of homeostatic ZCs incorporated BrdU whereas 88% of neck cells were labeled. In pulse-chase experiments, various chase periods decreased neck cell label but did not increase labeling of ZCs. When mice were given BrdU at the same time as tamoxifen, more than 90% of cells were labeled in all gastric lineages. After 3 months' recovery (no tamoxifen), ZCs became the predominant BrdU-labeled population whereas other cells-including neck cells-were mostly negative. When we tracked the labeled cells in such mice over time, we observed that the proportion of BrdU-positive ZCs remained greater than 60% up to 11 months. In mice whose ZCs were the principal BrdU-positive population, acute injury by tamoxifen or chronic injury by H pylori infection resulted in SPEM cells becoming the principal BrdU-positive population. After withdrawal of tamoxifen, BrdU-positive ZCs reappeared.


CONCLUSIONS
We studied mice in homeostasis or with tamoxifen- or H pylori-induced SPEM. Our findings indicated that mucous neck cells do not contribute substantially to generation of ZCs during homeostasis and that ZCs maintain their own census, likely through infrequent self-replication. After metaplasia-inducing injury, ZCs can become SPEM cells, and then re-differentiate into ZCs upon injury resolution.}, journal={Gastroenterology}, year={2019}, month={Oct} }
 @article{plasticity of differentiated cells in wound repair and tumorigenesis, part i: stomach and pancreas._2018, url={http://europepmc.org/articles/PMC6078397}, DOI={10.1242/dmm.033373}, abstractNote={ABSTRACT}, journal={Disease models & mechanisms}, year={2018}, month={Jul} }
 @article{plasticity of differentiated cells in wound repair and tumorigenesis, part ii: skin and intestine._2018, url={http://europepmc.org/articles/PMC6177008}, DOI={10.1242/dmm.035071}, abstractNote={ABSTRACT}, journal={Disease models & mechanisms}, year={2018}, month={Aug} }
 @article{regenerative proliferation of differentiated cells by mtorc1-dependent paligenosis._2018, url={http://europepmc.org/articles/PMC5881627}, DOI={10.15252/embj.201798311}, abstractNote={In 1900, Adami speculated that a sequence of context‐independent energetic and structural changes governed the reversion of differentiated cells to a proliferative, regenerative state. Accordingly, we show here that differentiated cells in diverse organs become proliferative via a shared program. Metaplasia‐inducing injury caused both gastric chief and pancreatic acinar cells to decrease mTORC1 activity and massively upregulate lysosomes/autophagosomes; then increase damage associated metaplastic genes such as Sox9; and finally reactivate mTORC1 and re‐enter the cell cycle. Blocking mTORC1 permitted autophagy and metaplastic gene induction but blocked cell cycle re‐entry at S‐phase. In kidney and liver regeneration and in human gastric metaplasia, mTORC1 also correlated with proliferation. In lysosome‐defective Gnptab−/− mice, both metaplasia‐associated gene expression changes and mTORC1‐mediated proliferation were deficient in pancreas and stomach. Our findings indicate differentiated cells become proliferative using a sequential program with intervening checkpoints: (i) differentiated cell structure degradation; (ii) metaplasia‐ or progenitor‐associated gene induction; (iii) cell cycle re‐entry. We propose this program, which we term “paligenosis”, is a fundamental process, like apoptosis, available to differentiated cells to fuel regeneration following injury.}, journal={The EMBO journal}, year={2018}, month={Feb} }
 @article{burclaff_mills_2017, title={Cell biology: Healthy skin rejects cancer}, volume={548}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85027870170&partnerID=MN8TOARS}, DOI={10.1038/nature23534}, number={7667}, journal={Nature}, author={Burclaff, J. and Mills, J.C.}, year={2017}, pages={289–290} }
 @article{metaplastic cells in the stomach arise, independently of stem cells, via dedifferentiation or transdifferentiation of chief cells._2017, url={http://europepmc.org/articles/PMC5847468}, DOI={10.1053/j.gastro.2017.11.278}, abstractNote={Spasmolytic polypeptide-expressing metaplasia (SPEM) develops in patients with chronic atrophic gastritis due to infection with Helicobacter pylori; it might be a precursor to intestinal metaplasia and gastric adenocarcinoma. Lineage tracing experiments of the gastric corpus in mice have not established whether SPEM derives from proliferating stem cells or differentiated, post-mitotic zymogenic chief cells in the gland base. We investigated whether differentiated cells can give rise to SPEM using a nongenetic approach in mice. Mice were given intraperitoneal injections of 5-fluorouracil, which blocked gastric cell proliferation, plus tamoxifen to induce SPEM. Based on analyses of molecular and histologic markers, we found SPEM developed even in the absence of cell proliferation. SPEM therefore did not arise from stem cells. In histologic analyses of gastric resection specimens from 10 patients with adenocarcinoma, we found normal zymogenic chief cells that were transitioning into SPEM cells only in gland bases, rather than the proliferative stem cell zone. Our findings indicate that SPEM can arise by direct reprogramming of existing cells-mainly of chief cells.}, journal={Gastroenterology}, year={2017}, month={Dec} }
 @article{burclaff_osaki_liu_goldenring_mills_2017, title={Targeted Apoptosis of Parietal Cells Is Insufficient to Induce Metaplasia in Stomach}, volume={152}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85014316912&partnerID=MN8TOARS}, DOI={10.1053/j.gastro.2016.12.001}, abstractNote={Parietal cell atrophy is considered to cause metaplasia in the stomach. We developed mice that express the diphtheria toxin receptor specifically in parietal cells to induce their death, and found this to increase proliferation in the normal stem cell zone and neck but not to cause metaplastic reprogramming of chief cells. Furthermore, the metaplasia-inducing agents tamoxifen or DMP-777 still induced metaplasia even after previous destruction of parietal cells by diphtheria toxin. Atrophy of parietal cells alone therefore is not sufficient to induce metaplasia: completion of metaplastic reprogramming of chief cells requires mechanisms beyond parietal cell injury or death.}, number={4}, journal={Gastroenterology}, author={Burclaff, J. and Osaki, L.H. and Liu, D. and Goldenring, J.R. and Mills, J.C.}, year={2017}, pages={762–766} }
 @article{lim_burclaff_he_mills_long_2017, title={Unintended targeting of Dmp1-Cre reveals a critical role for Bmpr1a signaling in the gastrointestinal mesenchyme of adult mice}, volume={5}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-85011306014&partnerID=MN8TOARS}, DOI={10.1038/boneres.2016.49}, abstractNote={Abstract}, journal={Bone Research}, author={Lim, J. and Burclaff, J. and He, G. and Mills, J.C. and Long, F.}, year={2017} }
 @inbook{saenz_burclaff_mills_2016, place={New York, NY}, title={Modeling Murine Gastric Metaplasia Through Tamoxifen-Induced Acute Parietal Cell Loss}, url={http://dx.doi.org/10.1007/978-1-4939-3603-8_28}, DOI={10.1007/978-1-4939-3603-8_28}, abstractNote={Parietal cell loss represents the initial step in the sequential progression toward gastric adenocarcinoma. In the setting of chronic inflammation, the expansion of the mucosal response to parietal cell loss characterizes a crucial transition en route to gastric dysplasia. Here, we detail methods for using the selective estrogen receptor modulator tamoxifen as a novel tool to rapidly and reversibly induce parietal cell loss in mice in order to study the mechanisms that underlie these pre-neoplastic events.}, booktitle={Gastrointestinal Physiology and Diseases: Methods and Protocols}, publisher={Springer New York}, author={Saenz, Jose B. and Burclaff, Joseph and Mills, Jason C.}, editor={Ivanov, I. AndreiEditor}, year={2016}, pages={329–339} }
 @article{li_burclaff_anderson_2016, title={Mutations in Mtr4 structural domains reveal their important role in regulating tRNA<inf>i</inf><sup>Met</sup> turnover in saccharomyces cerevisiae and Mtr4p enzymatic activities in vitro}, volume={11}, url={http://www.scopus.com/inward/record.url?eid=2-s2.0-84958211904&partnerID=MN8TOARS}, DOI={10.1371/journal.pone.0148090}, abstractNote={RNA processing and turnover play important roles in the maturation, metabolism and quality control of a large variety of RNAs thereby contributing to gene expression and cellular health. The TRAMP complex, composed of Air2p, Trf4p and Mtr4p, stimulates nuclear exosome-dependent RNA processing and degradation in Saccharomyces cerevisiae. The Mtr4 protein structure is composed of a helicase core and a novel so-called arch domain, which protrudes from the core. The helicase core contains highly conserved helicase domains RecA-1 and 2, and two structural domains of unclear functions, winged helix domain (WH) and ratchet domain. How the structural domains (arch, WH and ratchet domain) coordinate with the helicase domains and what roles they are playing in regulating Mtr4p helicase activity are unknown. We created a library of Mtr4p structural domain mutants for the first time and screened for those defective in the turnover of TRAMP and exosome substrate, hypomodified tRNAiMet. We found these domains regulate Mtr4p enzymatic activities differently through characterizing the arch domain mutants K700N and P731S, WH mutant K904N, and ratchet domain mutant R1030G. Arch domain mutants greatly reduced Mtr4p RNA binding, which surprisingly did not lead to significant defects on either in vivo tRNAiMet turnover, or in vitro unwinding activities. WH mutant K904N and Ratchet domain mutant R1030G showed decreased tRNAiMet turnover in vivo, as well as reduced RNA binding, ATPase and unwinding activities of Mtr4p in vitro. Particularly, K904 was found to be very important for steady protein levels in vivo. Overall, we conclude that arch domain plays a role in RNA binding but is largely dispensable for Mtr4p enzymatic activities, however the structural domains in the helicase core significantly contribute to Mtr4p ATPase and unwinding activities.}, number={1}, journal={PLoS ONE}, author={Li, Y and Burclaff, J and Anderson, JT}, year={2016}, pages={0148090,} }