Intestinal mucosal healing is the primary therapeutic goal of medical treatments for inflammatory bowel disease (IBD). Epithelial stem cells are key players in the healing process. Lgr5+ stem cells maintain cellular turnover during homeostasis in the colonic crypt. However, they are lost and dispensable for repair in a wide variety of injury models, including dextran sulfate sodium (DSS) colitis, radiation, helminth infection, and T-cell activation. The direct loss of Lgr5+ cells activates a plasticity response in the epithelium in which other cell types can serve as stem cells. Whether this paradigm applies to mouse models of IBD remains unknown. In contrast to previously tested models, IBD models involve an inflammatory response rooted in the loss of immunologic tolerance to intestinal luminal contents including the microbiome. Here, we show the persistence of Lgr5+ cells in oxazolone, 2,4,6-trinitrobenzene sulfonic acid (TNBS), and , and IBD models. This contrasts with results obtained from DSS-induced injury. Through high-throughput expression profiling, we find that these colitis models were associated with distinct patterns of cytokine expression. Direct exposure of colonic epithelial organoids to DSS, oxazolone, or TNBS resulted in increased apoptosis and loss of Lgr5+ cells. Targeted ablation of Lgr5+ cells resulted in severe exacerbation of chronic, antibody-induced IL-10-deficient colitis, but had only modest effects in TNBS-induced colitis. These results show that distinct mouse models of IBD-like colitis induce different patterns of Lgr5+ stem cell retention and function. Acute intestinal injury and epithelial repair are associated with the loss of fast-cycling Lgr5+ stem cells and plasticity in the activation of formerly quiescent cell populations. In contrast, here we show in murine inflammatory bowel disease the persistence of the Lgr5+ stem cell population and its essential role in restricting the severity of chronic colitis. This demonstrates a diversity of stem cell responses to colitis.
Download full-text PDF |
Source |
---|---|
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8461791 | PMC |
http://dx.doi.org/10.1152/ajpgi.00248.2020 | DOI Listing |
Cytotherapy
January 2025
Osteoarthritis Research Program, Division of Orthopedic Surgery, Schroeder Arthritis Institute, University Health Network, Toronto, Ontario, Canada; Krembil Research Institute, University Health Network, Toronto, Ontario, Canada; Institute of Biomedical Engineering, University of Toronto, Toronto, Ontario, Canada; Department of Medicine, Division of Hematology, University of Toronto, Toronto, Ontario, Canada. Electronic address:
The December 2024 US Food and Drug Administration (FDA) approval of Mesoblast's Ryoncil (remestemcel-L-rknd)-allogeneic bone marrow mesenchymal stromal cell (MSC(M)) therapy-in pediatric acute steroid-refractory graft-versus-host-disease finally ended a long-lasting drought on approved MSC clinical products in the United States. While other jurisdictions-including Europe, Japan, India, and South Korea-have marketed autologous or allogeneic MSC products, the United States has lagged in its approval. The sponsor's significant efforts and investments, working closely with the FDA addressing concerns regarding clinical efficacy and consistent MSC potency through an iterative process that spanned several years, was rewarded with this landmark approval.
View Article and Find Full Text PDFMol Ther
January 2025
Department of Molecular Medicine, University of Southern Denmark; Odense, 5230, Denmark. Electronic address:
Neovascular age-related macular degeneration and diabetic macular edema are leading causes of vision-loss evoked by retinal neovascularization and vascular leakage. The glycoprotein microfibrillar-associated protein 4 (MFAP4) is an integrin αβ ligand present in the extracellular matrix. Single-cell transcriptomics reveal MFAP4 expression in cell-types in close proximity to vascular endothelial cells including choroidal vascular mural cells and retinal astrocytes and Müller cells.
View Article and Find Full Text PDFCell Commun Signal
January 2025
Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, One Gustave L. Levy Place, New York, NY, 10029, USA.
One hallmark of cancer is the upregulation and dependency on glucose metabolism to fuel macromolecule biosynthesis and rapid proliferation. Despite significant pre-clinical effort to exploit this pathway, additional mechanistic insights are necessary to prioritize the diversity of metabolic adaptations upon acute loss of glucose metabolism. Here, we investigated a potent small molecule inhibitor to Class I glucose transporters, KL-11743, using glycolytic leukemia cell lines and patient-based model systems.
View Article and Find Full Text PDFCell Biosci
January 2025
School of Biomedical Sciences, Faculty of Medicine, The Chinese University of Hong Kong, Hong Kong S.A.R., China.
Background: Pathogenic or null mutations in WRN helicase is a cause of premature aging disease Werner syndrome (WS). WRN is known to protect somatic cells including adult stem cells from premature senescence. Loss of WRN in mesenchymal stem cells (MSCs) not only drives the cells to premature senescence but also significantly impairs the function of the stem cells in tissue repair or regeneration.
View Article and Find Full Text PDFBMC Genomics
January 2025
College of Animal Science and Technology, Northwest A&F University, Yangling, Shaanxi, 712100, China.
Background: Rex rabbit is famous for its silky and soft fur coat, a characteristic predominantly attributed to its hair follicles. Numerous studies have confirmed the crucial roles of mRNAs and non-coding RNAs (ncRNAs) in regulating key cellular processes such as cell proliferation, differentiation, apoptosis and immunity. However, their involvement in the regulation of the hair cycle in Rex rabbits remains unknown.
View Article and Find Full Text PDFEnter search terms and have AI summaries delivered each week - change queries or unsubscribe any time!