ArticleGastroenterology2023
Stiffness Restricts the Stemness of the Intestinal Stem Cells and Skews Their Differentiation Toward Goblet Cells.
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Article in Gastroenterology, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 54 papers.
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54 citing papers in PubMed, 68 citations in OpenAlex.
- An Integrated Workflow for Culturing and AI-Based Profiling of Mouse Intestinal Epithelium.Methods in molecular biology (Clifton, N.J.) · 2027Article
- Using In Silico Pseudobulk Differential Expression and Trajectory Analysis of Single Cell RNA Sequencing to Reveal Stem Cell State Transitions in Colonic Inflammation.Methods in molecular biology (Clifton, N.J.) · 2027Article
- Tutorial: interrogating biology using organoid technologies.Nature protocols · 2026Review
- A Fully Defined GelMA-Based Matrix Allows Fine Tuning of Tissue-Relevant Biomechanical and Biochemical Cues for Organoid Culture.Advanced healthcare materials · 2026Article
- Nanofiber-Supported Decellularized Matrix Membrane Creates a Biomimetic Biochemical and Biophysical Niche for Intestinal Organoid Epithelium.Advanced healthcare materials · 2026Article
- Glycocholic acid inhibits TRIB3-ID1 axis to acelerate colitis progression via suppressing intestinal stem cell renewal.Nature communications · 2026Article
- Stiffness-dependent CMOT hydrogels promote mucosal repair in ulcerative colitis through YAP‑mediated mechanosensing in intestinal epithelial cells.Journal of nanobiotechnology · 2026Article
- Preservation of Human Colonic Stem Cells Requires an ERK Dynamics Checkpoint Mediated by AKT.bioRxiv : the preprint server for biology · 2026Article
- Generation of biologically responsive colon-like intestinal tissue patches from human induced pluripotent stem cells using a rapid co-differentiation platform.Stem cell research & therapy · 2026Article
- The Synthetic Extracellular Matrix as a Maestro of the In Vitro Stem Cell Niche: Orchestrating Fate and Function.Biomedicines · 2026Review
- Filtration-Based Rapid ECM-Hydrogel Elimination Enables Robust MALDI MSI of Intestinal Organoids.Analytical chemistry · 2026Article
- Intestinal stem cells as innate immune sentinels: coupling environmental sensing to epithelial adaptation.Frontiers in immunology · 2026Review
- Therapeutic potential of maggot-derived bioactive peptides in modulating inflammatory responses in mice model of inflammatory bowel disease.Frontiers in cell and developmental biology · 2026Article
- Mechanomedicine in digestive surgery: a theranostic framework integrating mechanical diagnostics and therapeutic modulation across the perioperative continuum.Theranostics · 2026Review
- Construction of Vascularized Intestinal Organoids Based on Scaffolds, Hydrogels, and 3D Printing Technologies and Their Applications in Drug Delivery.International journal of nanomedicine · 2026Review
- Dynamic hydrogel mechanics in organoid engineering: From matrix design to translational paradigms.Bioactive materials · 2026Review
- From mucus secretion to immune surveillance: the evolving roles of goblet cells in intestinal homeostasis and inflammation.Frontiers in immunology · 2026Review
- Biomechanical Phenotyping Reveals Unique Mechanobiological Signatures of Early-Onset Colorectal Cancer.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- AnBiofabrication · 2025Article
- Diallyl disulfide attenuates DSS-induced colonic fibrosis in mice by modulating gut microbiota and Nrf2 signaling.Inflammopharmacology · 2025Article
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Authors and funding
25 authors at 9 institutions in 2 countries.
Shijie HeDivision of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Shriners Hospital for Children, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
Peng LeiDivision of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Shriners Hospital for Children, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
Wenying KangDepartment of Otolaryngology-Head and Neck Surgery, Stanford Medical School, Stanford, California.
Priscilla CheungHarvard Medical School, Boston, Massachusetts; Stem Cell Program and Department of Hematology/Oncology, Children's Hospital, Boston, Massachusetts.
Tao XuHarvard Medical School, Boston, Massachusetts; Section on Pathophysiology and Molecular Pharmacology, Joslin Diabetes Center, Boston, Massachusetts.
Miyeko ManaKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Chan Young ParkDepartment of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
Hongyan WangDivision of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
Shinya ImadaKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Jacquelyn O RussellHarvard Medical School, Boston, Massachusetts; Stem Cell Program and Department of Hematology/Oncology, Children's Hospital, Boston, Massachusetts.
Jianxun WangDivision of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Shriners Hospital for Children, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
Ruizhi WangDepartment of Mechanical Engineering, Boston University, Boston, Massachusetts.
Ziheng ZhouDivision of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Shriners Hospital for Children, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
Kashish ChetalHarvard Medical School, Boston, Massachusetts; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts.
Eric StasHarvard Medical School, Boston, Massachusetts; Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts.
Vidisha MohadDivision of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
Peter Bruun-RasmussenDepartment of Clinical Immunology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark.
Ruslan I SadreyevHarvard Medical School, Boston, Massachusetts; Department of Molecular Biology, Massachusetts General Hospital, Boston, Massachusetts; Department of Pathology, Massachusetts General Hospital, Boston, Massachusetts.
Richard A HodinDivision of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts.
Yanhang ZhangDepartment of Mechanical Engineering, Boston University, Boston, Massachusetts.
David T BreaultHarvard Medical School, Boston, Massachusetts; Division of Endocrinology, Boston Children's Hospital, Boston, Massachusetts; Harvard Stem Cell Institute, Cambridge, Massachusetts.
Fernando D CamargoHarvard Medical School, Boston, Massachusetts; Stem Cell Program and Department of Hematology/Oncology, Children's Hospital, Boston, Massachusetts; Harvard Stem Cell Institute, Cambridge, Massachusetts.
Ömer H YilmazKoch Institute for Integrative Cancer Research, Massachusetts Institute of Technology, Cambridge, Massachusetts.
Jeffrey J FredbergDepartment of Environmental Health, Harvard T.H. Chan School of Public Health, Boston, Massachusetts.
Nima SaeidiDivision of Gastrointestinal and Oncologic Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Center for Engineering in Medicine and Surgery, Department of Surgery, Massachusetts General Hospital, Boston, Massachusetts; Shriners Hospital for Children, Boston, Massachusetts; Harvard Medical School, Boston, Massachusetts; Harvard Stem Cell Institute, Cambridge, Massachusetts. Electronic address: nsaeidi@mgh.harvard.edu.
Harvard University · USMassachusetts General Hospital · USMassachusetts Institute of Technology · USBoston University · USBoston Children's Hospital · USCopenhagen University Hospital · DKHarvard Stem Cell Institute · USJoslin Diabetes Center · USStanford Medicine · US
Funding
Pilot & Feasibility ProgramP30DK043351 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI RAYMOND T CHUNG · 1991 to 2026
$35.3MSTRUCTURE-FUNCTION RELATIONSHIPS IN THE ALIMENTARY TRACTP30DK034854 · NIDDK · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI JONATHAN C KAGAN · 1986 to 2026
$32.4MROLE OF DIETARY CONSTITUENTS ON GENE EXPRESSION IN INTESTINAL EPITHELIUMP30DK040561 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI Elizabeth Austen Lawson, Takara Leah Stanley · 1994 to 2026
$31.6MEpithelial layer jamming in breast cancer cell migrationU01CA202123 · NCI · HARVARD SCHOOL OF PUBLIC HEALTH · PI FREDBERG, JEFFREY J · 2015 to 2019
$3.4MPhysics of bronchial epithelial unjammingR01HL148152 · NHLBI · HARVARD SCHOOL OF PUBLIC HEALTH · PI FREDBERG, JEFFREY J, PARK, JIN-AH · 2019 to 2022
$2.2MCentral and direct role of the small intestine in the improvement of type 2 diabetes following RYGBR01DK123219 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI SAEIDI, NIMA · 2020 to 2023
$1.8MGastrointestinal Weight Loss Surgery Regulates Glucose Metabolism via Intestinal Metabolic RemodelingK01DK103947 · NIDDK · MASSACHUSETTS GENERAL HOSPITAL · PI SAEIDI, NIMA · 2015 to 2017
$480kNCI NIH HHS U01 CA202123NHLBI NIH HHS R01 HL148152NIDDK NIH HHS K01 DK103947NIDDK NIH HHS P30 DK034854NIDDK NIH HHS P30 DK040561NIDDK NIH HHS P30 DK043351NIDDK NIH HHS R01 DK123219
Abstract
BACKGROUND &
aimsFibrosis and tissue stiffening are hallmarks of inflammatory bowel disease (IBD). We have hypothesized that the increased stiffness directly contributes to the dysregulation of the epithelial cell homeostasis in IBD. Here, we aim to determine the impact of tissue stiffening on the fate and function of the intestinal stem cells (ISCs).
methodsWe developed a long-term culture system consisting of 2.5-dimensional intestinal organoids grown on a hydrogel matrix with tunable stiffness. Single-cell RNA sequencing provided stiffness-regulated transcriptional signatures of the ISCs and their differentiated progeny. YAP-knockout and YAP-overexpression mice were used to manipulate YAP expression. In addition, we analyzed colon samples from murine colitis models and human IBD samples to assess the impact of stiffness on ISCs in vivo.
resultsWe demonstrated that increasing the stiffness potently reduced the population of LGR5
conclusionsCollectively, our findings highlight that matrix stiffness potently regulates the stemness of ISCs and their differentiation trajectory, supporting the hypothesis that fibrosis-induced gut stiffening plays a direct role in epithelial remodeling in IBD.
Indexed as
ColitisInflammatory Bowel DiseasesAnimalsCell DifferentiationGoblet CellsHumansIntestinal MucosaMiceStem CellsFibrosisIBDIntestinal OrganoidsIntestinal Stem CellsStiffening
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