1
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Li C, Zhou Y, Yin Z, Jiang Y, Liu J, Weiss HL, Wang Q, Evers BM. miR-181a-5p mediates the effects of BMP4 on intestinal cell proliferation and differentiation. Cell Death Dis 2025; 16:420. [PMID: 40436833 PMCID: PMC12120108 DOI: 10.1038/s41419-025-07730-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 04/25/2025] [Accepted: 05/09/2025] [Indexed: 06/01/2025]
Abstract
The intestinal mucosa undergoes a dynamic process of continual proliferation, differentiation, and apoptosis. Delineating the mechanisms involved in intestinal epithelial cell (IEC) differentiation is crucial to our understanding of not only normal gut adaptation but also aberrant intestinal growth. Bone morphogenetic protein (BMP) signaling is a pivotal regulator of intestinal proliferation and differentiation. However, the molecular underpinnings of the BMP pathway in this context are not entirely known. Here, we show a key role for the BMP4/microRNA (miR)-181/glycolysis signaling pathway in the maintenance of intestinal epithelial cell proliferation and differentiation. Treatment with BMP4 increased the expression of enterocyte markers and decreased proliferation of IECs, and importantly, decreased the expression of miR-181a-5p in mouse and human intestinal organoids. miR-181a-5p is a member of the miR-181 family with the highest expression in IECs. Treatment with locked nucleic acid (LNA) miR-181a-5p inhibitor significantly increased enterocyte differentiation as noted by increased expression of enterocyte markers in human and mouse intestinal organoids. In addition, LNA miR-181a-5p inhibitor repressed intestinal stem cell self-renewal as noted by the decreased organoid forming efficiency and expression of Ki67, cyclin D1, OLFM4 in human and mouse intestinal organoids. Moreover, in vivo administration of LNA miR-181a-5p inhibitor enhanced increased intestinal enterocyte differentiation and repressed intestinal cell proliferation. In contrast, overexpression of miR-181a-5p mimic decreased basal and BMP4-induced expression of enterocyte markers. Moreover, BMP4 treatment or inhibition of miR-181a-5p repressed hexokinase (HK) 1 expression and inhibited glycolysis. Consistently, knockdown of HK1 or inhibition of glycolysis using 2-deoxyglucose (2-DG) promoted enterocyte maturation and inhibited proliferation of IECs. Together, we provide evidence showing that miR-181a-5p inhibits intestinal enterocyte differentiation and promotes IEC proliferation through HK1-dependent glycolysis. Importantly, our findings identify miR-181a-5p as downstream in mediating BMP4 induction of enterocyte differentiation and inhibition of proliferation in IECs.
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Affiliation(s)
- Chang Li
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Yuning Zhou
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Zhijie Yin
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Yinping Jiang
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Jinpeng Liu
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Heidi L Weiss
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Qingding Wang
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
- Department of Surgery, University of Kentucky, Lexington, KY, USA.
| | - B Mark Evers
- Markey Cancer Center, University of Kentucky, Lexington, KY, USA.
- Department of Surgery, University of Kentucky, Lexington, KY, USA.
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2
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Surakhy M, Matheson J, Barnes DJ, Carter EJ, Hughes J, Bühnemann C, Sanegre S, Morreau H, Metz P, Imianowski CJ, Hassan AB. Smad4 and TGFβ1 dependent gene expression signatures in conditional intestinal adenoma, organoids and colorectal cancer. Sci Rep 2025; 15:16330. [PMID: 40348815 PMCID: PMC12065906 DOI: 10.1038/s41598-025-00908-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 05/02/2025] [Indexed: 05/14/2025] Open
Abstract
TGF-β ligands suppress growth yet can paradoxically and potently promote cancer invasion and metastasis depending on downstream pathway mutational context, such as loss of Mothers against decapentaplegic homolog 4 (Smad4). Here, we characterised phenotypes and associated gene expression signatures in conditional murine intestinal adenoma with and without Smad4. Conditional Lgr5-CreERT2 activation in Apcfl/flSmad4fl/fl mice resulted in homozygote floxed alleles (ApcΔ/ΔSmad4Δ/Δ) and adenoma formation. The adenoma phenotype was discordant, with reduced small intestinal adenoma burden yet development of large non-metastatic caecal adenoma with nuclear localisation of phospho-Smad2/3. Derived ApcΔ/ΔSmad4Δ/Δ adenoma organoids resisted TGF-β1 dose dependent growth arrest and cell death (IC50 534 pM) compared to ApcΔ/ΔSmad4+/+ (IC50 24 pM). TGF-β1 (390 pM) altered adenoma bulk mRNA expression most significantly for Id1low and Spp1high in ApcΔ/ΔSmad4Δ/Δ. Single cell RNAseq of caecal adenoma identified expansion of Lgr5low, Pak3high and Id1low progenitor populations in ApcΔ/ΔSmad4Δ/Δ. Of the 76 Smad4 and TGF-β1 dependent genes identified in Apcfl/flSmad4fl/fl adenoma organoids, only 7 human equivalent genes were differentially expressed in SMAD4 mutated colorectal cancer (TCGA cohorts), including ID1low. SMAD4low, ID1low SPP1high and PAK3high all correlated with poorer survival. Murine adenoma identified Smad4 dependent gene expression signatures that require further evaluation as functional biomarker classifiers of SMAD4 mutated cancer subtypes.
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Affiliation(s)
- Mirvat Surakhy
- Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK
| | - Julia Matheson
- Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK
| | - David J Barnes
- Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, B15 2TT, UK
| | - Emma J Carter
- Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK
| | - Jennifer Hughes
- Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK
| | - Claudia Bühnemann
- Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK
| | - Sabina Sanegre
- Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK
| | - Hans Morreau
- Department of Pathology, Leiden University Medical Centre, Leiden, The Netherlands
| | - Paul Metz
- Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK
| | - Charlotte J Imianowski
- Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK
| | - Andrew Bassim Hassan
- Oxford Molecular Pathology Institute, Sir William Dunn School of Pathology, University of Oxford, South Parks Road, Oxford, OX1 3RE, UK.
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3
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Heuberger J, Liu L, Berger H, van den Heuvel J, Lin M, Müllerke S, Bayram S, Beccaceci G, de Jonge H, Gherardi E, Sigal M. Extrusion of BMP2+ surface colonocytes promotes stromal remodeling and tissue regeneration. Nat Commun 2025; 16:4131. [PMID: 40319019 PMCID: PMC12049494 DOI: 10.1038/s41467-025-59474-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Accepted: 04/23/2025] [Indexed: 05/07/2025] Open
Abstract
The colon epithelium frequently incurs damage through toxic influences. Repair is rapid, mediated by cellular plasticity and acquisition of the highly proliferative regenerative state. However, the mechanisms that promote the regenerative state are not well understood. Here, we reveal that upon injury and subsequent inflammatory response, IFN-γ drives widespread epithelial remodeling. IFN-γ promotes rapid apoptotic extrusion of fully differentiated surface colonocytes, while simultaneously causing differentiation of crypt-base stem and progenitor cells towards a colonocyte-like lineage. However, unlike homeostatic colonocytes, these IFN-γ-induced colonocytes neither respond to nor produce BMP-2 but retain regenerative capacity. The reduction of BMP-2-producing epithelial surface cells causes a remodeling of the surrounding mesenchymal niche, inducing high expression of HGF, which promotes proliferation of the IFN-γ-induced colonocytes. This mechanism of lineage replacement and subsequent remodeling of the mesenchymal niche enables tissue-wide adaptation to injury and efficient repair.
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Affiliation(s)
- Julian Heuberger
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany
- Department Experimental Toxicology and ZEBET, German Federal Institute for Risk Assessment, Berlin, Germany
| | - Lichao Liu
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Hilmar Berger
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | | | - Manqiang Lin
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Stefanie Müllerke
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Safak Bayram
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Giulia Beccaceci
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Berlin, Germany
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany
| | - Hugo de Jonge
- Immunology and General Pathology Unit, Department of Molecular Medicine, Università di Pavia, Pavia, Italy
| | - Ermanno Gherardi
- Immunology and General Pathology Unit, Department of Molecular Medicine, Università di Pavia, Pavia, Italy
| | - Michael Sigal
- Department of Hepatology and Gastroenterology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
- Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine, Berlin, Germany.
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4
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Lynch EB, Kapur N, Goretsky T, Bradford EM, Vekaria H, Bhogoju S, Hassan SA, Pauw E, Avdiushko MG, Lee G, Gao T, Sullivan PG, Barrett TA. Phosphatidylinositol 3-Kinase Signaling Enhances Intestinal Crypt Epithelial Cell Recovery after Radiation. THE AMERICAN JOURNAL OF PATHOLOGY 2025:S0002-9440(25)00151-8. [PMID: 40316215 DOI: 10.1016/j.ajpath.2025.04.010] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/20/2024] [Revised: 03/24/2025] [Accepted: 04/10/2025] [Indexed: 05/04/2025]
Abstract
Intestinal stem cell (ISC) signaling maintains the balance of self-renewal and differentiation. The role of phosphatidylinositol 3-kinase (PI3K) signaling in ISC responses to radiation was interrogated using Villin-Cre pik3r1lox/lox (p85ΔIEC) mice and p85α-deficient human enteroids (shp85α). Lethal whole-body irradiation in mice was performed to monitor PI3K-mediated survival responses. Rectal biopsies from patients with radiation proctitis were examined by immunohistochemistry for the PI3K/Akt- and Wnt-target survivin. The intestinal epithelial cells (IECs) from p85ΔIEC mice showed increased protein levels of phosphorylated phosphatase and tensin homolog, phosphorylated AktSer473, survivin, cyclin D1, and ρ-β-cateninSer552, as well as increased mRNA for ISC/progenitor cell. In situ hybridization showed that enhanced PI3K signaling reduced Lgr5+ cells but expansion of Axin2+ cells. The shp85α enteroids showed increased mRNA expression of Wnt targets and transcription factor ASCL2, needed for dedifferentiation-mediated restoration of ablated ISCs. The p85α-deficient enteroids showed reduced HES1 mRNA and increases in secretory (ATOH1/MATH1) signaling determinants GFI1 and SPDEF, indicative of reduced NOTCH signaling. Seahorse analyses and phosphorylated p38 staining in IECΔp85 mice indicated that enhanced PI3K signaling led to increased IEC mitochondrial respiration and reactive oxygen species generation. Expression of survivin correlated with the radiation injury in patients. The current data indicate that PI3K signaling increases mitochondrial reactive oxygen species generation and ISC activation that improves IEC recovery from radiation-induced injury. The results suggest that increasing PI3K signaling and induced mitochondrial respiration may improve mucosal healing from radiation injury in patients.
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Affiliation(s)
- Evan B Lynch
- Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky, Lexington, Kentucky; Division of Plastic Surgery, Department of Surgery, University of Kentucky, Lexington, Kentucky; Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky
| | - Neeraj Kapur
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky
| | - Tatiana Goretsky
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky
| | - Emily M Bradford
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky
| | - Hemendra Vekaria
- Lexington VA Healthcare System, Lexington, Kentucky; Department of Neuroscience, University of Kentucky, Lexington, Kentucky
| | - Sarayu Bhogoju
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky
| | - Syed A Hassan
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky
| | - Emily Pauw
- College of Medicine, University of Kentucky, Lexington, Kentucky
| | - Margarita G Avdiushko
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky
| | - Goo Lee
- The University of Alabama at Birmingham, Heersink School of Medicine, Birmingham, Alabama
| | - Tianyan Gao
- Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky
| | - Patrick G Sullivan
- Lexington VA Healthcare System, Lexington, Kentucky; Department of Neuroscience, University of Kentucky, Lexington, Kentucky
| | - Terrence A Barrett
- Division of Digestive Diseases and Nutrition, Department of Medicine, University of Kentucky, Lexington, Kentucky; Lexington VA Healthcare System, Lexington, Kentucky.
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5
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Lin Q, Zhang S, Zhang J, Jin Y, Chen T, Lin R, Lv J, Xu W, Wu T, Tian S, Ying L, Li X, Huang Z, Niu J. Colonic epithelial-derived FGF1 drives intestinal stem cell commitment toward goblet cells to suppress inflammatory bowel disease. Nat Commun 2025; 16:3264. [PMID: 40188210 PMCID: PMC11972292 DOI: 10.1038/s41467-025-58644-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Accepted: 03/31/2025] [Indexed: 04/07/2025] Open
Abstract
Understanding the molecular mechanisms that regulate intestinal epithelial cell (IEC) renewal provides potential targets for inflammatory bowel disease (IBD). Growing evidence has highlighted the importance of epithelial signals in regulating intestinal stem cell (ISC) differentiation. However, it remains unclear which IEC-derived cytokines can precisely regulate ISC commitment toward specific mature cells. Here we systematically analyze all fibroblast growth factors (FGFs) expression and find that colonic FGF1 levels are inversely correlated with the severity of IBD in mouse models and patients. IEC-specific Fgf1 deletion leads to impaired goblet cell differentiation and exacerbated colitis, while pharmacological administration of recombinant FGF1 (rFGF1) alleviates colitis by enhancing goblet cell differentiation and improving colonic epithelial integrity. Mechanistic studies reveal that rFGF1 directs ISC differentiation toward goblet cells via FGFR2-TCF4-ATOH1 signaling axis. In conclusion, our study identifies an epithelial niche-derived FGF1 that regulates ISC commitment toward goblet cells, shedding light on strategies for treating IBD.
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Affiliation(s)
- Qian Lin
- State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Sudan Zhang
- State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Jiaren Zhang
- State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Yi Jin
- Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, Zhejiang, China
| | - Taoli Chen
- Department of Pharmacy, The Second Affiliated Hospital of Jiaxing University, Jiaxing, 314000, Zhejiang, China
| | - Ruoyu Lin
- State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Jiaxuan Lv
- State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Wenjing Xu
- State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Tianzhen Wu
- State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Shenyu Tian
- State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Lei Ying
- School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Xiaokun Li
- State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China
| | - Zhifeng Huang
- State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
- Translational Medicine Laboratory, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
| | - Jianlou Niu
- State Key Laboratory of Macromolecular Drugs and Large-scale Preparation, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, Zhejiang, 325035, China.
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6
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Yang S, Liu H, Liu Y. Advances in intestinal epithelium and gut microbiota interaction. Front Microbiol 2025; 16:1499202. [PMID: 40104591 PMCID: PMC11914147 DOI: 10.3389/fmicb.2025.1499202] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2024] [Accepted: 02/17/2025] [Indexed: 03/20/2025] Open
Abstract
The intestinal epithelium represents a critical interface between the host and external environment, serving as the second largest surface area in the human body after the lungs. This dynamic barrier is sustained by specialized epithelial cell types and their complex interactions with the gut microbiota. This review comprehensively examines the recent advances in understanding the bidirectional communication between intestinal epithelial cells and the microbiome. We briefly highlight the role of various intestinal epithelial cell types, such as Paneth cells, goblet cells, and enteroendocrine cells, in maintaining intestinal homeostasis and barrier function. Gut microbiota-derived metabolites, particularly short-chain fatty acids and bile acids, influence epithelial cell function and intestinal barrier integrity. Additionally, we highlight emerging evidence of the sophisticated cooperation between different epithelial cell types, with special emphasis on the interaction between tuft cells and Paneth cells in maintaining microbial balance. Understanding these complex interactions has important implications for developing targeted therapeutic strategies for various gastrointestinal disorders, including inflammatory bowel disease, metabolic disorders, and colorectal cancer.
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Affiliation(s)
- Sen Yang
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
- Department of Pediatrics, The Fifth Peoples Hospital of Chengdu, Chengdu, China
| | - Hanmin Liu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
- NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China
- The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China
| | - Yang Liu
- Department of Pediatric Pulmonology and Immunology, West China Second University Hospital, Sichuan University, Chengdu, China
- Key Laboratory of Birth Defects and Related Diseases of Women and Children (Sichuan University), Ministry of Education, Chengdu, China
- NHC Key Laboratory of Chronobiology (Sichuan University), Chengdu, China
- The Joint Laboratory for Lung Development and Related Diseases of West China Second University Hospital, Sichuan University and School of Life Sciences of Fudan University, West China Institute of Women and Children's Health, West China Second University Hospital, Sichuan University, Chengdu, China
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7
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Lee I, Takahashi Y, Sasaki T, Yamauchi Y, Sato R. Human colon organoid differentiation from induced pluripotent stem cells using an improved method. FEBS Lett 2025; 599:912-924. [PMID: 39716027 PMCID: PMC11931984 DOI: 10.1002/1873-3468.15082] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2024] [Revised: 12/04/2024] [Accepted: 12/05/2024] [Indexed: 12/25/2024]
Abstract
The colonic epithelium plays a crucial role in gastrointestinal homeostasis, and colon organoids enable investigation into the molecular mechanisms underlying colonic physiology. However, the method for differentiating induced pluripotent stem cells (iPSCs) into human colon organoids (HCOs) is not necessarily standardized, and studies using HCOs are limited. This study refines the differentiation of HCOs by comparing two protocols reported in Cell Stem Cell and Nature Medicine journals. The former protocol, which uses transient bone morphogenetic protein 2 (BMP2) signaling activation, demonstrated superior efficacy in upregulating colon-specific markers. Additionally, adenovirus-mediated transduction of the transcription factors HOXD13 or SATB2 during hindgut endoderm development, together with BMP2 treatment, enhanced colonic identity, suggesting improved colonic maturation. This optimized protocol advances the generation of mature HCOs, offering a better model for investigating colonic epithelial biology and pathology.
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Affiliation(s)
- I‐Ting Lee
- Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life SciencesThe University of TokyoJapan
| | - Yu Takahashi
- Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life SciencesThe University of TokyoJapan
| | - Takashi Sasaki
- Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life SciencesThe University of TokyoJapan
| | - Yoshio Yamauchi
- Food Biochemistry Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life SciencesThe University of TokyoJapan
| | - Ryuichiro Sato
- Nutri‐Life Science Laboratory, Department of Applied Biological Chemistry, Graduate School of Agricultural and Life SciencesThe University of TokyoJapan
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8
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Hinnant TD, Joo C, Lechler T. Mesenchymal cell contractility regulates villus morphogenesis and intestinal architecture. Dev Biol 2025; 519:96-105. [PMID: 39708944 PMCID: PMC11758735 DOI: 10.1016/j.ydbio.2024.12.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2024] [Revised: 12/12/2024] [Accepted: 12/17/2024] [Indexed: 12/23/2024]
Abstract
The large absorptive surface area of the small intestine is imparted by finger-like projections called villi. Villi formation is instructed by stromal-derived clusters of cells which have been proposed to induce epithelial bending through actomyosin contraction. Their functions in the elongation of villi have not been studied. Here, we explored the function of mesenchymal contractility at later stages of villus morphogenesis. We induced contractility specifically in the mesenchyme of the developing intestine through inducible overexpression of the RhoA GTPase activator Arhgef11. This resulted in overgrowth of the clusters through a YAP-mediated increase in cell proliferation. While epithelial bending occurred in the presence of contractile clusters, the resulting villi had architectural defects, being shorter and wider than controls. These villi also had defects in epithelial organization and the establishment of nutrient-absorbing enterocytes. While ectopic activation of YAP resulted in similar cluster overgrowth and wider villi, it did not affect villus elongation or enterocyte differentiation, demonstrating roles for contractility in addition to proliferation. We find that the specific contractility-induced effects were dependent upon cluster interaction with the extracellular matrix. Together, these data demonstrate effects of contractility on villus morphogenesis and distinguish separable roles for proliferation and contractility in controlling intestinal architecture.
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Affiliation(s)
- Taylor D Hinnant
- Department of Dermatology, Duke University Medical Center, Durham, NC, 27710, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710, USA
| | - Caroline Joo
- Department of Dermatology, Duke University Medical Center, Durham, NC, 27710, USA
| | - Terry Lechler
- Department of Dermatology, Duke University Medical Center, Durham, NC, 27710, USA; Department of Cell Biology, Duke University Medical Center, Durham, NC, 27710, USA.
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9
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Dang K, Singh A, Chen X, Cotton JL, Guo S, Hu X, Tao Z, Liu H, Zhu LJ, Ip YT, Wu X, Mao J. Mesenchymal Hippo signaling regulates intestinal homeostasis in adult mice. iScience 2025; 28:111847. [PMID: 39981512 PMCID: PMC11841074 DOI: 10.1016/j.isci.2025.111847] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2024] [Revised: 10/16/2024] [Accepted: 01/16/2025] [Indexed: 02/22/2025] Open
Abstract
Intestinal homeostasis is tightly regulated by the reciprocal interaction between the gut epithelium and adjacent mesenchyme. The Hippo pathway is intimately associated with intestinal epithelial homeostasis and regeneration; however, its role in postnatal gut mesenchyme remains poorly defined. Here, we find that removal of the core Hippo kinases Lats1/2 or activation of YAP in adult intestinal smooth muscle layers has largely no effect; however, Hippo-YAP signaling in the niche-forming Gli1+ mesenchymal cells plays intrinsic roles in regulating intestinal homeostasis. We find that Lats1/2 deletion drives robust mesenchymal over-proliferation, and YAP activation in Gli1+ pericryptal cells disrupts the intestinal epithelial-mesenchymal crosstalk via promoting Wnt ligand production. We show that YAP is upregulated in the stroma during dextran sodium sulfate (DSS)-induced injury, and mesenchymal YAP activation facilitates intestinal epithelial regeneration. Altogether, our data suggest an important role for mesenchymal Hippo-YAP signaling in the stem cell niche during intestinal homeostasis and pathogenesis.
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Affiliation(s)
- Kyvan Dang
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Alka Singh
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Xin Chen
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Jennifer L. Cotton
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Susu Guo
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Xiaodi Hu
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Zhipeng Tao
- Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
- Department of Nutrition and Food Sciences, Texas Woman’s University, Denton, TX 76204, USA
| | - Haibo Liu
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Lihua J. Zhu
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Y. Tony Ip
- Program in Molecular Medicine, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
| | - Xu Wu
- Cutaneous Biology Research Center, Massachusetts General Hospital, Harvard Medical School, Charlestown, MA, USA
| | - Junhao Mao
- Department of Molecular, Cell and Cancer Biology, University of Massachusetts Chan Medical School, Worcester, MA 01605, USA
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10
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Yang M, Tong Z, Yuan Z, Jiang B, Zhao Y, Xu D, Yuan Y. A Novel Missense Variant of BMPR1A in Juvenile Polyposis Syndrome: Assessment of Structural and Functional Alternations. Hum Mutat 2025; 2025:7317429. [PMID: 40226309 PMCID: PMC11919155 DOI: 10.1155/humu/7317429] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2024] [Accepted: 01/27/2025] [Indexed: 04/15/2025]
Abstract
Juvenile polyposis syndrome (JPS) is a rare precancerous condition associated with a high susceptibility to colorectal cancer. The genetic basis of JPS has been reported to lie in germline mutations in BMPR1A or SMAD4, resulting in diverse clinical manifestations and an elusive underlying mechanism. We firstly utilized a 139-gene next-generation sequencing (NGS) panel to detect the germline variants and further employed various prediction tools to assess the pathogenicity and functional alternations. Consequently, we identified a novel pathogenic BMPR1A missense variant (c.355C>T; p.R119C). More importantly, we proposed for the first time that the missense variant would lead to a decrease in molecular weight, potentially associated with reduced protein stability, diminished posttranslational modifications, and aberrant alternative splicing. These findings may provide novel perspectives for further exploration into the role of BMPR1A in JPS development. Also, we hope to encourage clinicians to underscore the importance of genetic testing and analysis in facilitating the diagnosis and treatment of diseases.
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Affiliation(s)
- Mengyuan Yang
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ziyan Tong
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Zhijun Yuan
- Department of Radiation Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Bingjing Jiang
- Department of Pathology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, Zhejiang, China
| | - Yingxin Zhao
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Dong Xu
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Department of Colorectal Surgery and Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
| | - Ying Yuan
- Department of Medical Oncology, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Cancer Institute, Key Laboratory of Cancer Prevention and Intervention, Ministry of Education, The Second Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, Zhejiang, China
- Zhejiang Provincial Clinical Research Center for Cancer, Hangzhou, Zhejiang, China
- Cancer Center of Zhejiang University, Hangzhou, Zhejiang, China
- Binjiang Institute of Zhejiang University, Hangzhou, Zhejiang, China
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11
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Mehra L, Bhowmik S, Makharia GK, Das P. Intestinal stem cell niche: An upcoming area of immense importance in gastrointestinal disorders. Indian J Gastroenterol 2025; 44:8-23. [PMID: 39514159 DOI: 10.1007/s12664-024-01699-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Accepted: 09/29/2024] [Indexed: 11/16/2024]
Abstract
The intestinal stem cell (ISC) niche is vital for maintaining the integrity and function of the intestinal epithelium. ISC populations, characterized by their high proliferation and multipotency, reside within a specialized microenvironment at the base of crypts. Crypt base columnar (CBC) cells at the deepest part of crypts serve as replicating ISCs, while position 4 label-retaining cells (LRCs) located higher up in the crypts are also important for ISC maintenance during experiments. The interplay between CBCs, position 4 LRCs, transient amplifying (TA) cells and other niche components, including the pericrypt stromal cells, ensures a continuous supply of differentiated epithelial cells. Recent advancements in ISC biomarker studies have provided valuable insights into their molecular signatures, regulatory pathways and roles in the pathogenesis of intestinal disorders. Understanding the ISC niche has significant therapeutic implications, as manipulating ISC behaviors and regenerating damaged or diseased intestinal tissue show promise for novel therapeutic approaches. ISC organoids have also provided a platform for studying intestinal diseases and testing personalized therapies. This comprehensive review covers the anatomical composition, physiological regulation, ISC biomarker studies, contribution to intestinal disorder pathogenesis and potential therapeutic implications of the ISC niche.
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Affiliation(s)
- Lalita Mehra
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Subham Bhowmik
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India
| | - Govind K Makharia
- Department of Gastroenterology and Human Nutritions, All India Institute of Medical Sciences, New Delhi, 110 029, India
| | - Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, Ansari Nagar, New Delhi, 110 029, India.
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12
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Kim H, Lee SH, Yang JY. Mechanobiological Approach for Intestinal Mucosal Immunology. BIOLOGY 2025; 14:110. [PMID: 40001878 PMCID: PMC11852114 DOI: 10.3390/biology14020110] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/24/2024] [Revised: 01/13/2025] [Accepted: 01/16/2025] [Indexed: 02/27/2025]
Abstract
The intestinal area is composed of diverse cell types that harmonize gut homeostasis, which is influenced by both endogenous and exogenous factors. Notably, the environment of the intestine is exposed to several types of mechanical forces, including shear stress generated by fluid flow, compression and stretch generated by luminal contents and peristaltic waves of the intestine, and stiffness attributed to the extracellular matrix. These forces play critical roles in the regulation of cell proliferation, differentiation, and migration. Many efforts have been made to simulate the actual intestinal environment in vitro. The three-dimensional organoid culture system has emerged as a powerful tool for studying the mechanism of the intestinal epithelial barrier, mimicking rapidly renewing epithelium from intestinal stem cells (ISCs) in vivo. However, many aspects of how mechanical forces, such as shear stress, stiffness, compression, and stretch forces, influence the intestinal area remain unresolved. Here, we review the recent studies elucidating the impact of mechanical forces on intestinal immunity, interaction with the gut microbiome, and intestinal diseases.
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Affiliation(s)
- Hyeyun Kim
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea; (H.K.); (S.-H.L.)
| | - Se-Hui Lee
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea; (H.K.); (S.-H.L.)
| | - Jin-Young Yang
- Department of Integrated Biological Science, Pusan National University, Busan 46241, Republic of Korea; (H.K.); (S.-H.L.)
- Institute for Future Earth, Pusan National University, Busan 46241, Republic of Korea
- Department of Biological Sciences, Pusan National University, Busan 46241, Republic of Korea
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13
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Zhang QY, Lai MQ, Chen YK, Zhong MT, Gi M, Wang Q, Xie XL. Inulin alleviates GenX-induced intestinal injury in mice by modulating the MAPK pathway, cell cycle, and cell adhesion proteins. ENVIRONMENTAL POLLUTION (BARKING, ESSEX : 1987) 2024; 362:124974. [PMID: 39332800 DOI: 10.1016/j.envpol.2024.124974] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/03/2024] [Revised: 08/17/2024] [Accepted: 09/14/2024] [Indexed: 09/29/2024]
Abstract
GenX, a substitute for perfluorooctanoic acid, has demonstrated potential enterotoxicity. The enterotoxic effects of GenX and effective interventions need further investigation. In the present study, the mice were administered GenX (2 mg/kg/day) with or without inulin supplementation (5 g/kg/day) for 12 weeks. Histopathological assessments revealed that GenX induced colonic gland atrophy, inflammatory cell infiltration, a reduction in goblet cell numbers, and decreased mucus secretion. Furthermore, a significant decrease in the protein levels of ZO-1, occludin, and claudin-5 indicated compromised barrier integrity. Transcriptomic analysis identified 2645 DEGs, which were mapped to 39 significant pathways. The TGF-β, BMP6, and β-catenin proteins were upregulated in the intestinal mucosa following GenX exposure, indicating activation of the TGF-β pathway. Conversely, the protein expression of PAK3, CyclinD2, contactin1, and Jam2 decreased, indicating disruptions in cell cycle progression and cell adhesion. Inulin cotreatment ameliorated these GenX-induced alterations, partially through modulating the MAPK pathway, as evidenced by the upregulation of the cell cycle and cell adhesion proteins. Collectively, these findings suggested that GenX exposure triggered intestinal injury in mice by activating the TGF-β pathway and disrupting proteins crucial for the cell cycle and cell adhesion, whereas inulin supplementation mitigated this injury by modulating the MAPK pathway.
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Affiliation(s)
- Qin-Yao Zhang
- Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515, Guangzhou, China
| | - Ming-Quan Lai
- Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515, Guangzhou, China
| | - Yu-Kui Chen
- Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515, Guangzhou, China
| | - Mei-Ting Zhong
- Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515, Guangzhou, China
| | - Min Gi
- Department of Environmental Risk Assessment, Graduate School of Medicine, Osaka Metropolitan University, Osaka, Japan
| | - Qi Wang
- Department of Forensic Pathology, School of Forensic Medicine, Southern Medical University, No. 1838 North Guangzhou Road, 510515, Guangzhou, China
| | - Xiao-Li Xie
- Department of Toxicology, School of Public Health, Southern Medical University (Guangdong Provincial Key Laboratory of Tropical Disease Research), No. 1838 North Guangzhou Road, 510515, Guangzhou, China.
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14
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Yang J, Wang J, Ding B, Jiang Z, Yu F, Li D, Sun W, Wang L, Xu H, Hu S. Feedback delivery of BMP 7 on the pathological oxidative stress via smart hyaluronic acid hydrogel potentiated the repairing of the gut epithelial integrity. Int J Biol Macromol 2024; 282:136794. [PMID: 39447783 DOI: 10.1016/j.ijbiomac.2024.136794] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2024] [Revised: 10/09/2024] [Accepted: 10/20/2024] [Indexed: 10/26/2024]
Abstract
The intestinal barrier integrity was substantially collapsed when colitis flaring up, accompanying by the hallmark of pathological oxidative stress. Bone morphogenetic protein 7 (BMP 7), an endogenous growth factor in gut had the potential to repair the damaged mucosa. Herein, a smart hydrogel (HDP) had been developed by the boronate-ester crosslinked hyaluronic acid to deliver BMP 7. Hydrogel loading BMP 7 (HDP-BMP 7) presented the comparable mechanical strength with that of the naïve gut mucus. HDP-BMP 7 as artificial mucus could specifically adhere to the inflamed colonic mucosa of colitis mice. Importantly, it could apperceive reactive oxygen species at diseased colon to adapt its intrinsic network, enabling the feedback release of BMP 7 on the pathological oxidative stress. Moreover, in vivo animal experiments showed that the disease symptoms of colitis mice were alleviated by HDP-BMP 7. Importantly, both the mucus barrier and the epithelial barriers were obviously recovered by HDP-BMP 7 treatment, which substantially attenuated the immune-inflammation response of colitis mice. Besides, HDP-BMP 7 enriched the diversity of gut flora, increasing the relative abundance of Lactobacillus and decreasing the ratio of Firmicutes/Bacteroidetes. Its therapeutic mechanism was associated with activating TGF-β/Smad signals. Conclusively, this smart hydrogel might potentiate the repairing effect of growth factors on the gut epithelial integrity.
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Affiliation(s)
- Jiaojiao Yang
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China; Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Jie Wang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Bingyu Ding
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Zhijiang Jiang
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Fengnan Yu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Dingwei Li
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Wenwen Sun
- Pathology Department, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China
| | - Lifen Wang
- Research Center for Drug Safety Evaluation, Hainan Medical University, Haikou City, Hainan Province, China.
| | - Helin Xu
- Department of Pharmaceutics, School of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou City, Zhejiang Province 325035, China.
| | - Sunkuan Hu
- Department of Gastroenterology, the First Affiliated Hospital of Wenzhou Medical University, Wenzhou City, Zhejiang Province 325000, China.
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15
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Li Y, Wang X, Huang M, Wang X, Li C, Li S, Tang Y, Yu S, Wang Y, Song W, Wu W, Liu Y, Chen YG. BMP suppresses Wnt signaling via the Bcl11b-regulated NuRD complex to maintain intestinal stem cells. EMBO J 2024; 43:6032-6051. [PMID: 39433900 PMCID: PMC11612440 DOI: 10.1038/s44318-024-00276-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 09/22/2024] [Accepted: 10/02/2024] [Indexed: 10/23/2024] Open
Abstract
Lgr5+ intestinal stem cells (ISCs) are crucial for the intestinal epithelium renewal and regeneration after injury. However, the mechanism underlying the interplay between Wnt and BMP signaling in this process is not fully understood. Here we report that Bcl11b, which is downregulated by BMP signaling, enhances Wnt signaling to maintain Lgr5+ ISCs and thus promotes the regeneration of the intestinal epithelium upon injury. Loss of Bcl11b function leads to a significant decrease of Lgr5+ ISCs in both intestinal crypts and cultured organoids. Mechanistically, BMP suppresses the expression of Bcl11b, which can positively regulate Wnt target genes by inhibiting the function of the Nucleosome Remodeling and Deacetylase (NuRD) complex and facilitating the β-catenin-TCF4 interaction. Bcl11b can also promote intestinal epithelium repair after injuries elicited by both irradiation and DSS-induced inflammation. Furthermore, Bcl11b deletion prevents proliferation and tumorigenesis of colorectal cancer cells. Together, our findings suggest that BMP suppresses Wnt signaling via Bcl11b regulation, thus balancing homeostasis and regeneration in the intestinal epithelium.
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Affiliation(s)
- Yehua Li
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Xiaodan Wang
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Meimei Huang
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Xu Wang
- Guangzhou National Laboratory, Guangzhou, 510700, China
| | - Chunlin Li
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Siqi Li
- Guangzhou National Laboratory, Guangzhou, 510700, China
| | - Yuhui Tang
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Shicheng Yu
- Guangzhou National Laboratory, Guangzhou, 510700, China
| | - Yalong Wang
- Guangzhou National Laboratory, Guangzhou, 510700, China
| | - Wanglu Song
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Wei Wu
- MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Yuan Liu
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
| | - Ye-Guang Chen
- The State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
- Guangzhou National Laboratory, Guangzhou, 510700, China.
- The MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, 330031, China.
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16
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Liu S, Ren J, Hu Y, Zhou F, Zhang L. TGFβ family signaling in human stem cell self-renewal and differentiation. CELL REGENERATION (LONDON, ENGLAND) 2024; 13:26. [PMID: 39604763 PMCID: PMC11602941 DOI: 10.1186/s13619-024-00207-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/28/2024] [Revised: 10/16/2024] [Accepted: 11/01/2024] [Indexed: 11/29/2024]
Abstract
Human stem cells are undifferentiated cells with the capacity for self-renewal and differentiation into distinct cell lineages, playing important role in the development and maintenance of diverse tissues and organs. The microenvironment of stem cell provides crucial factors and components that exert significant influence over the determination of cell fate. Among these factors, cytokines from the transforming growth factor β (TGFβ) superfamily, including TGFβ, bone morphogenic protein (BMP), Activin and Nodal, have been identified as important regulators governing stem cell maintenance and differentiation. In this review, we present a comprehensive overview of the pivotal roles played by TGFβ superfamily signaling in governing human embryonic stem cells, somatic stem cells, induced pluripotent stem cells, and cancer stem cells. Furthermore, we summarize the latest research and advancements of TGFβ family in various cancer stem cells and stem cell-based therapy, discussing their potential clinical applications in cancer therapy and regeneration medicine.
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Affiliation(s)
- Sijia Liu
- International Biomed-X Research Center, Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China
| | - Jiang Ren
- The First Affiliated Hospital, MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Institute of Biomedical Innovation, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China
| | - Yanmei Hu
- Department of Endocrinology and Metabolism, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, China
| | - Fangfang Zhou
- The First Affiliated Hospital, the Institutes of Biology and Medical Sciences, Suzhou Medical College, Soochow University, Suzhou, China.
| | - Long Zhang
- International Biomed-X Research Center, Key Laboratory of Precision Diagnosis and Treatment for Hepatobiliary and Pancreatic Tumor of Zhejiang Province, Second Affiliated Hospital of Zhejiang University School of Medicine, Zhejiang University, Hangzhou, China.
- The First Affiliated Hospital, MOE Basic Research and Innovation Center for the Targeted Therapeutics of Solid Tumors, Institute of Biomedical Innovation, School of Basic Medical Sciences, Jiangxi Medical College, Nanchang University, Nanchang, China.
- MOE Key Laboratory of Biosystems Homeostasis & Protection and Innovation Center for Cell Signaling Network, Life Sciences Institute, Zhejiang University, Hangzhou, 310058, China.
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17
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Trubin S, Patel DB, Tian A. Regulation of the Intestinal Stem Cell Pool and Proliferation in Drosophila. Cells 2024; 13:1856. [PMID: 39594605 PMCID: PMC11592481 DOI: 10.3390/cells13221856] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 11/07/2024] [Accepted: 11/07/2024] [Indexed: 11/28/2024] Open
Abstract
Understanding the regulation of somatic stem cells, both during homeostasis and in response to environmental challenges like injury, infection, chemical exposure, and nutritional changes, is critical because their dysregulation can result in tissue degeneration or tumorigenesis. The use of models such as the Drosophila and mammalian adult intestines offers valuable insights into tissue homeostasis and regeneration, advancing our knowledge of stem cell biology and cancer development. This review highlights significant findings from recent studies, unveiling the molecular mechanisms that govern self-renewal, proliferation, differentiation, and regeneration of intestinal stem cells (ISCs). These insights not only enhance our understanding of normal tissue maintenance but also provide critical perspectives on how ISC dysfunction can lead to pathological conditions such as colorectal cancer (CRC).
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Affiliation(s)
- Simona Trubin
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | - Dhruv B. Patel
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
| | - Aiguo Tian
- Department of Biochemistry and Molecular Biology, Tulane University School of Medicine, Louisiana Cancer Research Center, New Orleans, LA 70112, USA
- Tulane Aging Center, Tulane University School of Medicine, New Orleans, LA 70112, USA
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18
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Wei TT, Blanc E, Peidli S, Bischoff P, Trinks A, Horst D, Sers C, Blüthgen N, Beule D, Morkel M, Obermayer B. High-confidence calling of normal epithelial cells allows identification of a novel stem-like cell state in the colorectal cancer microenvironment. Int J Cancer 2024; 155:1655-1669. [PMID: 39031967 DOI: 10.1002/ijc.35079] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2024] [Revised: 05/29/2024] [Accepted: 06/10/2024] [Indexed: 07/22/2024]
Abstract
Single-cell analyses can be confounded by assigning unrelated groups of cells to common developmental trajectories. For instance, cancer cells and admixed normal epithelial cells could adopt similar cell states thus complicating analyses of their developmental potential. Here, we develop and benchmark CCISM (for Cancer Cell Identification using Somatic Mutations) to exploit genomic single nucleotide variants for the disambiguation of cancer cells from genomically normal non-cancer cells in single-cell data. We find that our method and others based on gene expression or allelic imbalances identify overlapping sets of colorectal cancer versus normal colon epithelial cells, depending on molecular characteristics of individual cancers. Further, we define consensus cell identities of normal and cancer epithelial cells with higher transcriptome cluster homogeneity than those derived using existing tools. Using the consensus identities, we identify significant shifts of cell state distributions in genomically normal epithelial cells developing in the cancer microenvironment, with immature states increased at the expense of terminal differentiation throughout the colon, and a novel stem-like cell state arising in the left colon. Trajectory analyses show that the new cell state extends the pseudo-time range of normal colon stem-like cells in a cancer context. We identify cancer-associated fibroblasts as sources of WNT and BMP ligands potentially contributing to increased plasticity of stem cells in the cancer microenvironment. Our analyses advocate careful interpretation of cell heterogeneity and plasticity in the cancer context and the consideration of genomic information in addition to gene expression data when possible.
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Affiliation(s)
- Tzu-Ting Wei
- Core Unit Bioinformatics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Eric Blanc
- Core Unit Bioinformatics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Stefan Peidli
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Institute of Biology, Humboldt University of Berlin, Berlin, Germany
| | - Philip Bischoff
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- BIH Biomedical Innovation Academy, BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
- German Cancer Consortium Partner Site Berlin, German Cancer Research Center, Heidelberg, Germany
| | - Alexandra Trinks
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Unit Bioportal Single Cells, Berlin, Germany
| | - David Horst
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium Partner Site Berlin, German Cancer Research Center, Heidelberg, Germany
| | - Christine Sers
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- German Cancer Consortium Partner Site Berlin, German Cancer Research Center, Heidelberg, Germany
| | - Nils Blüthgen
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Institute of Biology, Humboldt University of Berlin, Berlin, Germany
- German Cancer Consortium Partner Site Berlin, German Cancer Research Center, Heidelberg, Germany
| | - Dieter Beule
- Core Unit Bioinformatics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
| | - Markus Morkel
- Institute of Pathology, Charité - Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin, Germany
- Institute of Biology, Humboldt University of Berlin, Berlin, Germany
- Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Unit Bioportal Single Cells, Berlin, Germany
| | - Benedikt Obermayer
- Core Unit Bioinformatics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany
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19
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Chen SM, Guo BJ, Feng AQ, Wang XL, Zhang SL, Miao CY. Pathways regulating intestinal stem cells and potential therapeutic targets for radiation enteropathy. MOLECULAR BIOMEDICINE 2024; 5:46. [PMID: 39388072 PMCID: PMC11467144 DOI: 10.1186/s43556-024-00211-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2024] [Accepted: 09/19/2024] [Indexed: 10/12/2024] Open
Abstract
Radiotherapy is a pivotal intervention for cancer patients, significantly impacting their treatment outcomes and survival prospects. Nevertheless, in the course of treating those with abdominal, pelvic, or retroperitoneal malignant tumors, the procedure inadvertently exposes adjacent intestinal tissues to radiation, posing risks of radiation-induced enteropathy upon reaching threshold doses. Stem cells within the intestinal crypts, through their controlled proliferation and differentiation, support the critical functions of the intestinal epithelium, ensuring efficient nutrient absorption while upholding its protective barrier properties. Intestinal stem cells (ISCs) regulation is intricately orchestrated by diverse signaling pathways, among which are the WNT, BMP, NOTCH, EGF, Hippo, Hedgehog and NF-κB, each contributing to the complex control of these cells' behavior. Complementing these pathways are additional regulators such as nutrient metabolic states, and the intestinal microbiota, all of which contribute to the fine-tuning of ISCs behavior in the intestinal crypts. It is the harmonious interplay among these signaling cascades and modulating elements that preserves the homeostasis of intestinal epithelial cells (IECs), thereby ensuring the gut's overall health and function. This review delves into the molecular underpinnings of how stem cells respond in the context of radiation enteropathy, aiming to illuminate potential biological targets for therapeutic intervention. Furthermore, we have compiled a summary of several current treatment methodologies. By unraveling these mechanisms and treatment methods, we aspire to furnish a roadmap for the development of novel therapeutics, advancing our capabilities in mitigating radiation-induced intestinal damage.
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Affiliation(s)
- Si-Min Chen
- Department of Pharmacology, Second Military Medical University/Naval Medical University, 325 Guo He Road, Shanghai, 200433, China
| | - Bing-Jie Guo
- Yueyang Hospital of Integrated Traditional Chinese and Western Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - An-Qiang Feng
- Department of Digestive Disease, Xuzhou Central Hospital, Xuzhou, China
| | - Xue-Lian Wang
- School of Medicine, Shanghai University, Shanghai, China
| | - Sai-Long Zhang
- Department of Pharmacology, Second Military Medical University/Naval Medical University, 325 Guo He Road, Shanghai, 200433, China.
| | - Chao-Yu Miao
- Department of Pharmacology, Second Military Medical University/Naval Medical University, 325 Guo He Road, Shanghai, 200433, China.
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Kumari B, Tiwari A, Meena S, Ahirwar DK. Inflammation-Associated Stem Cells in Gastrointestinal Cancers: Their Utility as Prognostic Biomarkers and Therapeutic Targets. Cancers (Basel) 2024; 16:3134. [PMID: 39335106 PMCID: PMC11429849 DOI: 10.3390/cancers16183134] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2024] [Revised: 08/30/2024] [Accepted: 09/10/2024] [Indexed: 09/30/2024] Open
Abstract
Stem cells are critical for the development and homeostasis of the gastrointestinal (GI) tract. Inflammatory molecules are known to regulate the activity of stem cells. A comprehensive review specifically describing the role of inflammatory molecules in the regulation of stem cells within the GI tract and in GI cancers (GICs) is not available. This review focuses on understanding the role of inflammatory molecules and stem cells in maintaining homeostasis of the GI tract. We further discuss how inflammatory conditions contribute to the transformation of stem cells into tumor-initiating cells. We also describe the molecular mechanisms of inflammation and stem cell-driven progression and metastasis of GICs. Furthermore, we report on studies describing the prognostic value of cancer stem cells and the clinical trials evaluating their therapeutic utility. This review provides a detailed overview on the role of inflammatory molecules and stem cells in maintaining GI tract homeostasis and their implications for GI-related malignancies.
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Affiliation(s)
- Beauty Kumari
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342030, Rajasthan, India; (B.K.); (A.T.)
| | - Aniket Tiwari
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342030, Rajasthan, India; (B.K.); (A.T.)
| | - Sakshi Meena
- School of Life Sciences, Devi Ahilya Vishwavidyalaya Indore, Indore 452001, Madhya Pradesh, India;
| | - Dinesh Kumar Ahirwar
- Department of Bioscience & Bioengineering, Indian Institute of Technology Jodhpur, Jodhpur 342030, Rajasthan, India; (B.K.); (A.T.)
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21
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Yang J, Lewis JS, Zi J, Andl T, Lee E, Andl CD, Liu Q, Beauchamp RD, Means AL. Interaction of the tumor suppressor SMAD4 and WNT signaling in progression to oral squamous cell carcinoma. J Pathol 2024; 264:4-16. [PMID: 38922866 PMCID: PMC11300146 DOI: 10.1002/path.6318] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2023] [Revised: 04/30/2024] [Accepted: 05/15/2024] [Indexed: 06/28/2024]
Abstract
SMAD4 is a tumor suppressor mutated or silenced in multiple cancers, including oral cavity squamous cell carcinoma (OSCC). Human clinical samples and cell lines, mouse models and organoid culture were used to investigate the role that SMAD4 plays in progression from benign disease to invasive OSCC. Human OSCC lost detectable SMAD4 protein within tumor epithelium in 24% of cases, and this loss correlated with worse progression-free survival independent of other major clinical and pathological features. A mouse model engineered for KrasG12D expression in the adult oral epithelium induced benign papillomas, however the combination of KrasG12D with loss of epithelial Smad4 expression resulted in rapid development of invasive carcinoma with features of human OSCC. Examination of regulatory pathways in 3D organoid cultures of SMAD4+ and SMAD4- mouse tumors with Kras mutation found that either loss of SMAD4 or inhibition of TGFβ signaling upregulated the WNT pathway and altered the extracellular matrix. The gene signature of the mouse tumor organoids lacking SMAD4 was highly similar to the gene signature of human head and neck squamous cell carcinoma. In summary, this work has uncovered novel mechanisms by which SMAD4 acts as a tumor suppressor in OSCC. © 2024 The Author(s). The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.
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Affiliation(s)
- Jing Yang
- Dept. of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN
| | - James S. Lewis
- Dept. of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
| | - Jinghuan Zi
- Dept. of Surgery, Vanderbilt University Medical Center, Nashville, TN
| | - Thomas Andl
- Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL
| | - Ethan Lee
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
- Dept. of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN
| | - Claudia D. Andl
- Burnett School of Biomedical Sciences, University of Central Florida, Orlando, FL
| | - Qi Liu
- Dept. of Biostatistics, Vanderbilt University Medical Center, Nashville, TN
- Center for Quantitative Sciences, Vanderbilt University Medical Center, Nashville, TN
| | - Robert D. Beauchamp
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
- Dept. of Surgery, Vanderbilt University Medical Center, Nashville, TN
- Dept. of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN
- Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, TN
| | - Anna L. Means
- Vanderbilt Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN
- Dept. of Surgery, Vanderbilt University Medical Center, Nashville, TN
- Dept. of Cell and Developmental Biology, Vanderbilt University Medical Center, Nashville, TN
- Digestive Disease Research Center, Vanderbilt University Medical Center, Nashville, TN
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22
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Topczewska PM, Savvopoulou A, Cosovanu C, Klose CSN. Transcriptional profiling identifies IL-33-expressing intestinal stromal cells as a signaling hub poised to interact with enteric neurons. Front Cell Dev Biol 2024; 12:1420313. [PMID: 39149516 PMCID: PMC11325031 DOI: 10.3389/fcell.2024.1420313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2024] [Accepted: 07/18/2024] [Indexed: 08/17/2024] Open
Abstract
Recent advancements in mucosal immunology have unveiled a complex network of intercellular connections within diverse tissues, shedding light on the unique properties of different cell types. Central to this intricate network is the cytokine IL-33, which has gained significant attention for its critical role in various diseases, from allergy to cancer, triggering type 2 immune responses, among others. Recent research has challenged the prior assumptions attributing IL-33 expression to epithelial cells, highlighting stromal cells as the predominant source in adipose tissue and the lungs. However, in the complex landscape of the intestine, where IL-33 plays a crucial role in mediating immune surveillance and tolerance and is implicated in many gut-related disorders, its primary source, regulation, and main characteristics need more exploration. This study identifies stromal cells as the primary IL-33-expressing cell type in the small intestine. By investigating their transcriptome and intrinsic signaling pathways, we have uncovered a possible role of IL-33+ stromal cells in maintaining the stem cell niche and their potential crosstalk with neurons relevant to the regulation of axonogenesis. Importantly, our experiments have demonstrated that vasoactive intestinal peptide stimulation of a primary intestinal stromal cell culture significantly amplifies IL-33 expression on mRNA and protein level. Therefore, our study represents a significant leap forward in understanding the plethora of interactions IL-33+ intestinal stromal cells maintain in the intestine, paving the way for future investigations into stromal-neuro crosstalk in the gut. These findings hold great promise for developing targeted therapeutic strategies aimed at harnessing the potential of IL-33 across a spectrum of diseases.
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Affiliation(s)
- Patrycja M Topczewska
- Department of Microbiology, Infectious Diseases and Immunology, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Anna Savvopoulou
- Department of Microbiology, Infectious Diseases and Immunology, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Catalina Cosovanu
- Department of Microbiology, Infectious Diseases and Immunology, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany
| | - Christoph S N Klose
- Department of Microbiology, Infectious Diseases and Immunology, Corporate Member of Freie Universität Berlin and Humboldt-Universität Zu Berlin, Charité-Universitätsmedizin Berlin, Berlin, Germany
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23
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Shi R, Wang B. Nutrient metabolism in regulating intestinal stem cell homeostasis. Cell Prolif 2024; 57:e13602. [PMID: 38386338 PMCID: PMC11150145 DOI: 10.1111/cpr.13602] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2023] [Revised: 01/02/2024] [Accepted: 01/05/2024] [Indexed: 02/23/2024] Open
Abstract
Intestinal stem cells (ISCs) are known for their remarkable proliferative capacity, making them one of the most active cell populations in the body. However, a high turnover rate of intestinal epithelium raises the likelihood of dysregulated homeostasis, which is known to cause various diseases, including cancer. Maintaining precise control over the homeostasis of ISCs is crucial to preserve the intestinal epithelium's integrity during homeostasis or stressed conditions. Recent research has indicated that nutrients and metabolic pathways can extensively modulate the fate of ISCs. This review will explore recent findings concerning the influence of various nutrients, including lipids, carbohydrates, and vitamin D, on the delicate balance between ISC proliferation and differentiation.
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Affiliation(s)
- Ruicheng Shi
- Department of Comparative Biosciences, College of Veterinary MedicineUniversity of Illinois at Urbana‐ChampaignUrbanaIllinoisUSA
| | - Bo Wang
- Department of Comparative Biosciences, College of Veterinary MedicineUniversity of Illinois at Urbana‐ChampaignUrbanaIllinoisUSA
- Division of Nutritional Sciences, College of Agricultural, Consumer and Environmental SciencesUniversity of Illinois at Urbana‐ChampaignUrbanaIllinoisUSA
- Cancer Center at IllinoisUniversity of Illinois at Urbana‐ChampaignUrbanaIllinoisUSA
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24
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Zohud O, Midlej K, Lone IM, Nashef A, Abu-Elnaaj I, Iraqi FA. Studying the Effect of the Host Genetic Background of Juvenile Polyposis Development Using Collaborative Cross and Smad4 Knock-Out Mouse Models. Int J Mol Sci 2024; 25:5812. [PMID: 38891999 PMCID: PMC11172477 DOI: 10.3390/ijms25115812] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2024] [Revised: 05/17/2024] [Accepted: 05/22/2024] [Indexed: 06/21/2024] Open
Abstract
Juvenile polyposis syndrome (JPS) is a rare autosomal dominant disorder characterized by multiple juvenile polyps in the gastrointestinal tract, often associated with mutations in genes such as Smad4 and BMPR1A. This study explores the impact of Smad4 knock-out on the development of intestinal polyps using collaborative cross (CC) mice, a genetically diverse model. Our results reveal a significant increase in intestinal polyps in Smad4 knock-out mice across the entire population, emphasizing the broad influence of Smad4 on polyposis. Sex-specific analyses demonstrate higher polyp counts in knock-out males and females compared to their WT counterparts, with distinct correlation patterns. Line-specific effects highlight the nuanced response to Smad4 knock-out, underscoring the importance of genetic variability. Multimorbidity heat maps offer insights into complex relationships between polyp counts, locations, and sizes. Heritability analysis reveals a significant genetic basis for polyp counts and sizes, while machine learning models, including k-nearest neighbors and linear regression, identify key predictors, enhancing our understanding of juvenile polyposis genetics. Overall, this study provides new information on understanding the intricate genetic interplay in the context of Smad4 knock-out, offering valuable insights that could inform the identification of potential therapeutic targets for juvenile polyposis and related diseases.
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Affiliation(s)
- Osayd Zohud
- Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel; (O.Z.); (K.M.); (I.M.L.)
| | - Kareem Midlej
- Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel; (O.Z.); (K.M.); (I.M.L.)
| | - Iqbal M. Lone
- Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel; (O.Z.); (K.M.); (I.M.L.)
| | - Aysar Nashef
- Department of Oral and Maxillofacial Surgery, Baruch Padeh Medical Center, Poriya Tebaria 42310, Israel; (A.N.); (I.A.-E.)
- Department of Oral and Maxillofacial Surgery, Meir Medical Center, Faculty of Medicine and Health Sciences, Tel-Aviv University, Kfar-Saba 69978, Israel
| | - Imad Abu-Elnaaj
- Department of Oral and Maxillofacial Surgery, Baruch Padeh Medical Center, Poriya Tebaria 42310, Israel; (A.N.); (I.A.-E.)
- Azrieli Faculty of Medicine, Bar-Ilan University, Tsaft 33241, Israel
| | - Fuad A. Iraqi
- Department of Clinical Microbiology and Immunology, Faculty of Medicine and Health Sciences, Tel-Aviv University, Tel-Aviv 69978, Israel; (O.Z.); (K.M.); (I.M.L.)
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25
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Cox CM, Wu MH, Padilla-Rodriguez M, Blum I, Momtaz S, Mitchell SAT, Wilson JM. Regulation of YAP and Wnt signaling by the endosomal protein MAMDC4. PLoS One 2024; 19:e0296003. [PMID: 38787854 PMCID: PMC11125477 DOI: 10.1371/journal.pone.0296003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2023] [Accepted: 12/04/2023] [Indexed: 05/26/2024] Open
Abstract
Maintenance of the intestinal epithelium requires constant self-renewal and regeneration. Tight regulation of proliferation and differentiation of intestinal stem cells within the crypt region is critical to maintaining homeostasis. The transcriptional co-factors β-catenin and YAP are required for proliferation during normal homeostasis as well as intestinal regeneration after injury: aberrant signaling activity results in over proliferation and tumorigenesis. Although both YAP and β-catenin activity are controlled along canonical pathways, it is becoming increasingly clear that non-canonical regulation of these transcriptional regulators plays a role in fine tuning their activity. We have shown previously that MAMDC4 (Endotubin, AEGP), an integral membrane protein present in endosomes, regulates both YAP and β-catenin activity in kidney epithelial cells and in the developing intestinal epithelium. Here we show that MAMDC4 interacts with members of the signalosome and mediates cross-talk between YAP and β-catenin. Interestingly, this cross-talk occurs through a non-canonical pathway involving interactions between AMOT:YAP and AMOT:β-catenin.
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Affiliation(s)
- Christopher M. Cox
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, United States of America
| | - Meng-Han Wu
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, United States of America
| | - Marco Padilla-Rodriguez
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, United States of America
| | - Isabella Blum
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, United States of America
| | - Samina Momtaz
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, United States of America
| | - Stefanie A. T. Mitchell
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, United States of America
| | - Jean M. Wilson
- Department of Cellular and Molecular Medicine, University of Arizona, Tucson, AZ, United States of America
- The University of Arizona Cancer Center, University of Arizona, Tucson, AZ, United States of America
- Bio5 Institute, University of Arizona, Tucson, AZ, United States of America
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26
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Hu X, Yuan X, Zhang G, Song H, Ji P, Guo Y, Liu Z, Tian Y, Shen R, Wang D. The intestinal epithelial-macrophage-crypt stem cell axis plays a crucial role in regulating and maintaining intestinal homeostasis. Life Sci 2024; 344:122452. [PMID: 38462226 DOI: 10.1016/j.lfs.2024.122452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 01/18/2024] [Accepted: 01/18/2024] [Indexed: 03/12/2024]
Abstract
The intestinal tract plays a vital role in both digestion and immunity, making its equilibrium crucial for overall health. This equilibrium relies on the dynamic interplay among intestinal epithelial cells, macrophages, and crypt stem cells. Intestinal epithelial cells play a pivotal role in protecting and regulating the gut. They form vital barriers, modulate immune responses, and engage in pathogen defense and cytokine secretion. Moreover, they supervise the regulation of intestinal stem cells. Macrophages, serving as immune cells, actively influence the immune response through the phagocytosis of pathogens and the release of cytokines. They also contribute to regulating intestinal stem cells. Stem cells, known for their self-renewal and differentiation abilities, play a vital role in repairing damaged intestinal epithelium and maintaining homeostasis. Although research has primarily concentrated on the connections between epithelial and stem cells, interactions with macrophages have been less explored. This review aims to fill this gap by exploring the roles of the intestinal epithelial-macrophage-crypt stem cell axis in maintaining intestinal balance. It seeks to unravel the intricate dynamics and regulatory mechanisms among these essential players. A comprehensive understanding of these cell types' functions and interactions promises insights into intestinal homeostasis regulation. Moreover, it holds potential for innovative approaches to manage conditions like radiation-induced intestinal injury, inflammatory bowel disease, and related diseases.
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Affiliation(s)
- Xiaohui Hu
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Xinyi Yuan
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Guokun Zhang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Haoyun Song
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Pengfei Ji
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Yanan Guo
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Zihua Liu
- Lanzhou University Second Hospital, Lanzhou University, Lanzhou, Gansu Province 73000, China
| | - Yixiao Tian
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Rong Shen
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China.
| | - Degui Wang
- School of Basic Medical Sciences, Lanzhou University, Lanzhou, Gansu Province 73000, China; NHC Key Laboratory of Diagnosis and Therapy of Gastrointestinal Tumor, Lanzhou, Gansu Province 730000, China.
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27
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Ilhan M, Hastar N, Kampfrath B, Spierling DN, Jatzlau J, Knaus P. BMP Stimulation Differentially Affects Phosphorylation and Protein Stability of β-Catenin in Breast Cancer Cell Lines. Int J Mol Sci 2024; 25:4593. [PMID: 38731813 PMCID: PMC11083028 DOI: 10.3390/ijms25094593] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/19/2024] [Revised: 04/18/2024] [Accepted: 04/19/2024] [Indexed: 05/13/2024] Open
Abstract
Increased expression and nuclear translocation of β-CATENIN is frequently observed in breast cancer, and it correlates with poor prognosis. Current treatment strategies targeting β-CATENIN are not as efficient as desired. Therefore, detailed understanding of β-CATENIN regulation is crucial. Bone morphogenetic proteins (BMP) and Wingless/Integrated (WNT) pathway crosstalk is well-studied for many cancer types including colorectal cancer, whereas it is still poorly understood for breast cancer. Analysis of breast cancer patient data revealed that BMP2 and BMP6 were significantly downregulated in tumors. Since mutation frequency in genes enhancing β-CATENIN protein stability is relatively low in breast cancer, we aimed to investigate whether decreased BMP ligand expression could contribute to a high protein level of β-CATENIN in breast cancer cells. We demonstrated that downstream of BMP stimulation, SMAD4 is required to reduce β-CATENIN protein stability through the phosphorylation in MCF7 and T47D cells. Consequently, BMP stimulation reduces β-CATENIN levels and prevents its nuclear translocation and target gene expression in MCF7 cells. Conversely, BMP stimulation has no effect on β-CATENIN phosphorylation or stability in MDA-MB-231 and MDA-MB-468 cells. Likewise, SMAD4 modulation does not alter the response of those cells, indicating that SMAD4 alone is insufficient for BMP-induced β-CATENIN phosphorylation. While our data suggest that considering BMP activity may serve as a prognostic marker for understanding β-CATENIN accumulation risk, further investigation is needed to elucidate the differential responsiveness of breast cancer cell lines.
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Affiliation(s)
- Mustafa Ilhan
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
- Berlin School of Integrative Oncology, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Nurcan Hastar
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
- Brandenburg School for Regenerative Therapies, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Branka Kampfrath
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
| | - Deniz Neslihan Spierling
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
| | - Jerome Jatzlau
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
- Brandenburg School for Regenerative Therapies, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
| | - Petra Knaus
- Institute of Chemistry and Biochemistry, Freie Universität Berlin, 14195 Berlin, Germany; (M.I.); (N.H.); (B.K.); (D.N.S.)
- Berlin School of Integrative Oncology, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
- Brandenburg School for Regenerative Therapies, Charité—Universitätsmedizin Berlin, 13353 Berlin, Germany
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Das P, Battu S, Mehra L, Singh A, Ahmad M, Agarwal A, Chauhan A, Ahmad A, Vishnubhatla S, Gupta SD, Ahuja V, Makharia G. Correlation between intestinal stem cell niche changes and small bowel crypt failure in patients with treatment-naïve celiac disease. INDIAN J PATHOL MICR 2024; 67:259-266. [PMID: 38427764 DOI: 10.4103/ijpm.ijpm_760_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2023] [Accepted: 11/27/2023] [Indexed: 03/03/2024] Open
Abstract
OBJECTIVES We hypothesized that crypt failure in the small bowel results in villous flattening in patients with celiac disease (CeD). We investigated whether alterations in the stem cell niche (ISC) are responsible for this phenomenon. MATERIALS AND METHODS We included 92 duodenal (D2/3) biopsies from treatment-naive patients of CeD and 37 controls. All underwent screening for serum anti-tissue transglutaminase and endoscopic upper small bowel biopsy. Immunohistochemical markers were used to investigate ISC niche alterations, including LGR5 for crypt basal cells (CBC), Bmi1 for position 4+ cells, β-Defensin for Paneth cells, R-spondin1 as WNT activator, transcription factor-4 as WNT transcription factor, BMP receptor1A as WNT inhibitor, fibronectin-1 as periepithelial stromal cell marker, H2AX as apoptosis marker, and Ki67 as proliferation marker. We also analyzed IgA anti-tTG2 antibody deposits by using dual-color immunofluorescence staining. RESULTS We found that in biopsies from patients with treatment-naive CeD with modified Marsh grade 3a-3c changes, the epithelial H2AX apoptotic index was upregulated than in controls. LGR5+ crypt basal cells were upregulated in all modified Marsh grades compared to controls. However, the Ki67 proliferation index, expressions of WNT-activator RSPO1, and position-4 cell marker Bmi1 did not significantly alter in patients' biopsies as compared to controls ( P = 0.001). We also observed depletion of pericrypt stromal fibronectin-1 in patients with CeD compared to controls. In addition, we identified IgA anti-TG2 antibody deposits in pericrypt stroma. CONCLUSIONS Our data suggests that ISC niche failure is a plausible hypothesis for villous flattening in patients with CeD, resulting from pericrypt IgA anti-TG2 antibody complex-mediated stromal depletion.
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Affiliation(s)
- Prasenjit Das
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Sudha Battu
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Lalita Mehra
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Alka Singh
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Muzaffar Ahmad
- Department of Pathology, All India Institute of Medical Sciences, New Delhi, India
| | - Ashish Agarwal
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Ashish Chauhan
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Anam Ahmad
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | | | | | - Vineet Ahuja
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
| | - Govind Makharia
- Department of Gastroenterology and Human Nutrition, All India Institute of Medical Sciences, New Delhi, India
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Bravo Iniguez A, Du M, Zhu MJ. α-Ketoglutarate for Preventing and Managing Intestinal Epithelial Dysfunction. Adv Nutr 2024; 15:100200. [PMID: 38438107 PMCID: PMC11016550 DOI: 10.1016/j.advnut.2024.100200] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2023] [Revised: 02/16/2024] [Accepted: 02/29/2024] [Indexed: 03/06/2024] Open
Abstract
The epithelium lining the intestinal tract serves a multifaceted role. It plays a crucial role in nutrient absorption and immune regulation and also acts as a protective barrier, separating underlying tissues from the gut lumen content. Disruptions in the delicate balance of the gut epithelium trigger inflammatory responses, aggravate conditions such as inflammatory bowel disease, and potentially lead to more severe complications such as colorectal cancer. Maintaining intestinal epithelial homeostasis is vital for overall health, and there is growing interest in identifying nutraceuticals that can strengthen the intestinal epithelium. α-Ketoglutarate, a metabolite of the tricarboxylic acid cycle, displays a variety of bioactive effects, including functioning as an antioxidant, a necessary cofactor for epigenetic modification, and exerting anti-inflammatory effects. This article presents a comprehensive overview of studies investigating the potential of α-ketoglutarate supplementation in preventing dysfunction of the intestinal epithelium.
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Affiliation(s)
| | - Min Du
- Department of Animal Sciences, Washington State University, Pullman, WA, United States
| | - Mei-Jun Zhu
- School of Food Science, Washington State University, Pullman, WA, United States.
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30
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Lamichhane A, Tavana H. Three-Dimensional Tumor Models to Study Cancer Stemness-Mediated Drug Resistance. Cell Mol Bioeng 2024; 17:107-119. [PMID: 38737455 PMCID: PMC11082110 DOI: 10.1007/s12195-024-00798-y] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2023] [Accepted: 02/01/2024] [Indexed: 05/14/2024] Open
Abstract
Solid tumors often contain genetically different populations of cancer cells, stromal cells, various structural and soluble proteins, and other soluble signaling molecules. The American Cancer society estimated 1,958,310 new cancer cases and 609,820 cancer deaths in the United States in 2023. A major barrier against successful treatment of cancer patients is drug resistance. Gain of stem cell-like states by cancer cells under drug pressure or due to interactions with the tumor microenvironment is a major mechanism that renders therapies ineffective. Identifying approaches to target cancer stem cells is expected to improve treatment outcomes for patients. Most of our understanding of drug resistance and the role of cancer stemness is from monolayer cell cultures. Recent advances in cell culture technologies have enabled developing sophisticated three-dimensional tumor models that facilitate mechanistic studies of cancer drug resistance. This review summarizes the role of cancer stemness in drug resistance and highlights the various tumor models that are used to discover the underlying mechanisms and test potentially novel therapeutics.
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Affiliation(s)
- Astha Lamichhane
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325 USA
| | - Hossein Tavana
- Department of Biomedical Engineering, The University of Akron, Akron, OH 44325 USA
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31
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Xu X, Foley E. Vibrio cholerae arrests intestinal epithelial proliferation through T6SS-dependent activation of the bone morphogenetic protein pathway. Cell Rep 2024; 43:113750. [PMID: 38340318 DOI: 10.1016/j.celrep.2024.113750] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2023] [Revised: 12/19/2023] [Accepted: 01/22/2024] [Indexed: 02/12/2024] Open
Abstract
To maintain an effective barrier, intestinal progenitor cells must divide at a rate that matches the loss of dead and dying cells. Otherwise, epithelial breaches expose the host to systemic infection by gut-resident microbes. Unlike most pathogens, Vibrio cholerae blocks tissue repair by arresting progenitor proliferation in the Drosophila model. At present, we do not understand how V. cholerae circumvents such a critical antibacterial defense. We find that V. cholerae blocks epithelial repair by activating the growth inhibitor bone morphogenetic protein (BMP) pathway in progenitors. Specifically, we show that interactions between V. cholerae and gut commensals initiate BMP signaling via host innate immune defenses. Notably, we find that V. cholerae also activates BMP and arrests proliferation in zebrafish intestines, indicating an evolutionarily conserved link between infection and failure in tissue repair. Our study highlights how enteric pathogens engage host immune and growth regulatory pathways to disrupt intestinal epithelial repair.
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Affiliation(s)
- Xinyue Xu
- Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada
| | - Edan Foley
- Department of Medical Microbiology and Immunology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2E1, Canada; Department of Cell Biology, Faculty of Medicine and Dentistry, University of Alberta, Edmonton, AB T6G 2H7, Canada.
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32
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Kim G, Chen Z, Li J, Luo J, Castro-Martinez F, Wisniewski J, Cui K, Wang Y, Sun J, Ren X, Crawford SE, Becerra SP, Zhu J, Liu T, Wang S, Zhao K, Wu C. Gut-liver axis calibrates intestinal stem cell fitness. Cell 2024; 187:914-930.e20. [PMID: 38280375 PMCID: PMC10923069 DOI: 10.1016/j.cell.2024.01.001] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 10/25/2023] [Accepted: 01/02/2024] [Indexed: 01/29/2024]
Abstract
The gut and liver are recognized to mutually communicate through the biliary tract, portal vein, and systemic circulation. However, it remains unclear how this gut-liver axis regulates intestinal physiology. Through hepatectomy and transcriptomic and proteomic profiling, we identified pigment epithelium-derived factor (PEDF), a liver-derived soluble Wnt inhibitor, which restrains intestinal stem cell (ISC) hyperproliferation to maintain gut homeostasis by suppressing the Wnt/β-catenin signaling pathway. Furthermore, we found that microbial danger signals resulting from intestinal inflammation can be sensed by the liver, leading to the repression of PEDF production through peroxisome proliferator-activated receptor-α (PPARα). This repression liberates ISC proliferation to accelerate tissue repair in the gut. Additionally, treating mice with fenofibrate, a clinical PPARα agonist used for hypolipidemia, enhances colitis susceptibility due to PEDF activity. Therefore, we have identified a distinct role for PEDF in calibrating ISC expansion for intestinal homeostasis through reciprocal interactions between the gut and liver.
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Affiliation(s)
- Girak Kim
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Zuojia Chen
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jian Li
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jialie Luo
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Felipe Castro-Martinez
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jan Wisniewski
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Kairong Cui
- Laboratory of Epigenome Biology, Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yan Wang
- Mass Spectrometry Facility, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jialei Sun
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Xiaobai Ren
- Department of Ophthalmology, Mary M. and Sash A. Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94304, USA
| | - Susan E Crawford
- Department of Surgery, North Shore University Research Institute, University of Chicago Pritzker School of Medicine, Chicago, IL 60637, USA
| | - S Patricia Becerra
- Section of Protein Structure and Function, Laboratory of Retinal Cell and Molecular Biology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Jimin Zhu
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Taotao Liu
- Department of Gastroenterology and Hepatology, Shanghai Institute of Liver Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China
| | - Sui Wang
- Department of Ophthalmology, Mary M. and Sash A. Spencer Center for Vision Research, Byers Eye Institute, Stanford University, Stanford, CA 94304, USA
| | - Keji Zhao
- Laboratory of Epigenome Biology, Systems Biology Center, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Chuan Wu
- Experimental Immunology Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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Cameron O, Neves JF, Gentleman E. Listen to Your Gut: Key Concepts for Bioengineering Advanced Models of the Intestine. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2024; 11:e2302165. [PMID: 38009508 PMCID: PMC10837392 DOI: 10.1002/advs.202302165] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/04/2023] [Revised: 10/12/2023] [Indexed: 11/29/2023]
Abstract
The intestine performs functions central to human health by breaking down food and absorbing nutrients while maintaining a selective barrier against the intestinal microbiome. Key to this barrier function are the combined efforts of lumen-lining specialized intestinal epithelial cells, and the supportive underlying immune cell-rich stromal tissue. The discovery that the intestinal epithelium can be reproduced in vitro as intestinal organoids introduced a new way to understand intestinal development, homeostasis, and disease. However, organoids reflect the intestinal epithelium in isolation whereas the underlying tissue also contains myriad cell types and impressive chemical and structural complexity. This review dissects the cellular and matrix components of the intestine and discusses strategies to replicate them in vitro using principles drawing from bottom-up biological self-organization and top-down bioengineering. It also covers the cellular, biochemical and biophysical features of the intestinal microenvironment and how these can be replicated in vitro by combining strategies from organoid biology with materials science. Particularly accessible chemistries that mimic the native extracellular matrix are discussed, and bioengineering approaches that aim to overcome limitations in modelling the intestine are critically evaluated. Finally, the review considers how further advances may extend the applications of intestinal models and their suitability for clinical therapies.
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Affiliation(s)
- Oliver Cameron
- Centre for Craniofacial and Regenerative BiologyKing's College LondonLondonSE1 9RTUK
| | - Joana F. Neves
- Centre for Host‐Microbiome InteractionsKing's College LondonLondonSE1 9RTUK
| | - Eileen Gentleman
- Centre for Craniofacial and Regenerative BiologyKing's College LondonLondonSE1 9RTUK
- Department of Biomedical SciencesUniversity of LausanneLausanne1005Switzerland
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Sanketi BD, Mantri M, Huang L, Tavallaei MA, Hu S, Wang MFZ, De Vlaminck I, Kurpios NA. Origin and adult renewal of the gut lacteal musculature from villus myofibroblasts. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2023.01.19.523242. [PMID: 36712064 PMCID: PMC9882374 DOI: 10.1101/2023.01.19.523242] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
Abstract
Intestinal smooth muscles are the workhorse of the digestive system. Inside the millions of finger-like intestinal projections called villi, strands of smooth muscle cells contract to propel absorbed dietary fats through the adjacent lymphatic vessel, called the lacteal, sending fats into the blood circulation for energy production. Despite this vital function, how villus smooth muscles form, how they assemble alongside lacteals, and how they repair throughout life remain unknown. Here we combine single-cell RNA sequencing of the mouse intestine with quantitative lineage tracing to reveal the mechanisms of formation and differentiation of villus smooth muscle cells. Within the highly regenerative villus, we uncover a local hierarchy of subepithelial fibroblast progenitors that progress to become mature smooth muscle fibers, via an intermediate contractile myofibroblast-like phenotype. This continuum persists in the adult intestine as the major source of renewal of villus smooth muscle cells during adult life. We further found that the NOTCH3-DLL4 signaling axis governs the assembly of villus smooth muscles alongside their adjacent lacteal, and we show that this is necessary for gut absorptive function. Overall, our data shed light on the genesis of a poorly defined class of intestinal smooth muscle and pave the way for new opportunities to accelerate recovery of digestive function by stimulating muscle repair.
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Affiliation(s)
- Bhargav D. Sanketi
- Department of Molecular Medicine, College of Veterinary Medicine, Cornell University; Ithaca, NY 14853, USA
| | - Madhav Mantri
- Department of Biomedical Engineering, Cornell University; Ithaca, NY 14850, USA
| | - Liqing Huang
- Department of Molecular Medicine, College of Veterinary Medicine, Cornell University; Ithaca, NY 14853, USA
| | - Mohammad A. Tavallaei
- Department of Molecular Medicine, College of Veterinary Medicine, Cornell University; Ithaca, NY 14853, USA
| | - Shing Hu
- Department of Molecular Medicine, College of Veterinary Medicine, Cornell University; Ithaca, NY 14853, USA
| | - Michael F. Z. Wang
- Department of Biomedical Engineering, Cornell University; Ithaca, NY 14850, USA
| | - Iwijn De Vlaminck
- Department of Biomedical Engineering, Cornell University; Ithaca, NY 14850, USA
| | - Natasza A. Kurpios
- Department of Molecular Medicine, College of Veterinary Medicine, Cornell University; Ithaca, NY 14853, USA
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35
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Wu H, Mu C, Xu L, Yu K, Shen L, Zhu W. Host-microbiota interaction in intestinal stem cell homeostasis. Gut Microbes 2024; 16:2353399. [PMID: 38757687 PMCID: PMC11110705 DOI: 10.1080/19490976.2024.2353399] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/02/2024] [Accepted: 05/06/2024] [Indexed: 05/18/2024] Open
Abstract
Intestinal stem cells (ISCs) play a pivotal role in gut physiology by governing intestinal epithelium renewal through the precise regulation of proliferation and differentiation. The gut microbiota interacts closely with the epithelium through myriad of actions, including immune and metabolic interactions, which translate into tight connections between microbial activity and ISC function. Given the diverse functions of the gut microbiota in affecting the metabolism of macronutrients and micronutrients, dietary nutrients exert pronounced effects on host-microbiota interactions and, consequently, the ISC fate. Therefore, understanding the intricate host-microbiota interaction in regulating ISC homeostasis is imperative for improving gut health. Here, we review recent advances in understanding host-microbiota immune and metabolic interactions that shape ISC function, such as the role of pattern-recognition receptors and microbial metabolites, including lactate and indole metabolites. Additionally, the diverse regulatory effects of the microbiota on dietary nutrients, including proteins, carbohydrates, vitamins, and minerals (e.g. iron and zinc), are thoroughly explored in relation to their impact on ISCs. Thus, we highlight the multifaceted mechanisms governing host-microbiota interactions in ISC homeostasis. Insights gained from this review provide strategies for the development of dietary or microbiota-based interventions to foster gut health.
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Affiliation(s)
- Haiqin Wu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
| | - Chunlong Mu
- Food Informatics, AgResearch, Te Ohu Rangahau Kai, Palmerston North, New Zealand
| | - Laipeng Xu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
| | - Kaifan Yu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
| | - Le Shen
- Department of Surgery, The University of Chicago, Chicago, IL, USA
| | - Weiyun Zhu
- Laboratory of Gastrointestinal Microbiology, Jiangsu Key Laboratory of Gastrointestinal Nutrition and Animal Health, College of Animal Science and Technology, Nanjing Agricultural University, Nanjing, Jiangsu, China
- National Center for International Research on Animal Gut Nutrition, Nanjing Agricultural University, Nanjing, China
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36
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Li J, Liu J, Xia W, Yang H, Sha W, Chen H. Deciphering the Tumor Microenvironment of Colorectal Cancer and Guiding Clinical Treatment With Patient-Derived Organoid Technology: Progress and Challenges. Technol Cancer Res Treat 2024; 23:15330338231221856. [PMID: 38225190 PMCID: PMC10793199 DOI: 10.1177/15330338231221856] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 11/10/2023] [Accepted: 11/30/2023] [Indexed: 01/17/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most prevalent malignant tumors of the digestive tract worldwide. Despite notable advancements in CRC treatment, there is an urgent requirement for preclinical model systems capable of accurately predicting drug efficacy in CRC patients, to identify more effective therapeutic options. In recent years, substantial strides have been made in the field of organoid technology, patient-derived organoid models can phenotypically replicate the original intra-tumor and inter-tumor heterogeneity of CRC, reflecting cellular interactions of the tumor microenvironment. Patient-derived organoid models have become an indispensable tool for investigating the pathogenesis of CRC and facilitating translational research. This review focuses on the application of organoid technology in CRC modeling, tumor microenvironment, and guiding clinical treatment, particularly in drug screening and personalized medicine. It also examines the existing challenges encountered in clinical organoid research and provides a prospective outlook on the future development directions of clinical organoid research, encompassing the standardization of organoid culture technology and the application of tissue engineering technology.
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Affiliation(s)
- Jingwei Li
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Jianhua Liu
- The Second School of Clinical Medicine, Southern Medical University, Guangzhou, China
| | - Wuzheng Xia
- Department of Organ Transplantation, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Hongwei Yang
- Department of Obstetrics and Gynecology, The First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Weihong Sha
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
| | - Hao Chen
- Department of Gastroenterology, Guangdong Provincial People's Hospital (Guangdong Academy of Medical Sciences), Southern Medical University, Guangzhou, China
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Gall L, Duckworth C, Jardi F, Lammens L, Parker A, Bianco A, Kimko H, Pritchard DM, Pin C. Homeostasis, injury, and recovery dynamics at multiple scales in a self-organizing mouse intestinal crypt. eLife 2023; 12:e85478. [PMID: 38063302 PMCID: PMC10789491 DOI: 10.7554/elife.85478] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2022] [Accepted: 12/07/2023] [Indexed: 01/16/2024] Open
Abstract
The maintenance of the functional integrity of the intestinal epithelium requires a tight coordination between cell production, migration, and shedding along the crypt-villus axis. Dysregulation of these processes may result in loss of the intestinal barrier and disease. With the aim of generating a more complete and integrated understanding of how the epithelium maintains homeostasis and recovers after injury, we have built a multi-scale agent-based model (ABM) of the mouse intestinal epithelium. We demonstrate that stable, self-organizing behaviour in the crypt emerges from the dynamic interaction of multiple signalling pathways, such as Wnt, Notch, BMP, ZNRF3/RNF43, and YAP-Hippo pathways, which regulate proliferation and differentiation, respond to environmental mechanical cues, form feedback mechanisms, and modulate the dynamics of the cell cycle protein network. The model recapitulates the crypt phenotype reported after persistent stem cell ablation and after the inhibition of the CDK1 cycle protein. Moreover, we simulated 5-fluorouracil (5-FU)-induced toxicity at multiple scales starting from DNA and RNA damage, which disrupts the cell cycle, cell signalling, proliferation, differentiation, and migration and leads to loss of barrier integrity. During recovery, our in silico crypt regenerates its structure in a self-organizing, dynamic fashion driven by dedifferentiation and enhanced by negative feedback loops. Thus, the model enables the simulation of xenobiotic-, in particular chemotherapy-, induced mechanisms of intestinal toxicity and epithelial recovery. Overall, we present a systems model able to simulate the disruption of molecular events and its impact across multiple levels of epithelial organization and demonstrate its application to epithelial research and drug development.
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Affiliation(s)
- Louis Gall
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZenecaCambridgeUnited Kingdom
| | - Carrie Duckworth
- Institute of Systems, Molecular and Integrative Biology, University of LiverpoolLiverpoolUnited Kingdom
| | - Ferran Jardi
- Preclinical Sciences and Translational Safety, JanssenBeerseBelgium
| | - Lieve Lammens
- Preclinical Sciences and Translational Safety, JanssenBeerseBelgium
| | - Aimee Parker
- Gut Microbes and Health Programme, Quadram InstituteNorwichUnited Kingdom
| | - Ambra Bianco
- Clinical Pharmacology and Safety Sciences, AstraZenecaCambridgeUnited Kingdom
| | - Holly Kimko
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZenecaCambridgeUnited Kingdom
| | - David Mark Pritchard
- Institute of Systems, Molecular and Integrative Biology, University of LiverpoolLiverpoolUnited Kingdom
| | - Carmen Pin
- Clinical Pharmacology and Quantitative Pharmacology, Clinical Pharmacology and Safety Sciences, R&D, AstraZenecaCambridgeUnited Kingdom
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38
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Zhou W, Yan K, Xi Q. BMP signaling in cancer stemness and differentiation. CELL REGENERATION (LONDON, ENGLAND) 2023; 12:37. [PMID: 38049682 PMCID: PMC10695912 DOI: 10.1186/s13619-023-00181-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/09/2023] [Accepted: 11/06/2023] [Indexed: 12/06/2023]
Abstract
The BMP (Bone morphogenetic protein) signaling pathway plays a central role in metazoan biology, intricately shaping embryonic development, maintaining tissue homeostasis, and influencing disease progression. In the context of cancer, BMP signaling exhibits context-dependent dynamics, spanning from tumor suppression to promotion. Cancer stem cells (CSCs), a modest subset of neoplastic cells with stem-like attributes, exert substantial influence by steering tumor growth, orchestrating therapy resistance, and contributing to relapse. A comprehensive grasp of the intricate interplay between CSCs and their microenvironment is pivotal for effective therapeutic strategies. Among the web of signaling pathways orchestrating cellular dynamics within CSCs, BMP signaling emerges as a vital conductor, overseeing CSC self-renewal, differentiation dynamics, and the intricate symphony within the tumor microenvironment. Moreover, BMP signaling's influence in cancer extends beyond CSCs, intricately regulating cellular migration, invasion, and metastasis. This multifaceted role underscores the imperative of comprehending BMP signaling's contributions to cancer, serving as the foundation for crafting precise therapies to navigate multifaceted challenges posed not only by CSCs but also by various dimensions of cancer progression. This article succinctly encapsulates the diverse roles of the BMP signaling pathway across different cancers, spanning glioblastoma multiforme (GBM), diffuse intrinsic pontine glioma (DIPG), colorectal cancer, acute myeloid leukemia (AML), lung cancer, prostate cancer, and osteosarcoma. It underscores the necessity of unraveling underlying mechanisms and molecular interactions. By delving into the intricate tapestry of BMP signaling's engagement in cancers, researchers pave the way for meticulously tailored therapies, adroitly leveraging its dualistic aspects-whether as a suppressor or promoter-to effectively counter the relentless march of tumor progression.
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Affiliation(s)
- Wei Zhou
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Kun Yan
- Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Qiaoran Xi
- State Key Laboratory of Molecular Oncology, MOE Key Laboratory of Protein Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China.
- Joint Graduate Program of Peking-Tsinghua-NIBS, Tsinghua University, Beijing, China.
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39
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Manieri E, Tie G, Malagola E, Seruggia D, Madha S, Maglieri A, Huang K, Fujiwara Y, Zhang K, Orkin SH, Wang TC, He R, McCarthy N, Shivdasani RA. Role of PDGFRA + cells and a CD55 + PDGFRA Lo fraction in the gastric mesenchymal niche. Nat Commun 2023; 14:7978. [PMID: 38042929 PMCID: PMC10693581 DOI: 10.1038/s41467-023-43619-y] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2023] [Accepted: 11/15/2023] [Indexed: 12/04/2023] Open
Abstract
PDGFRA-expressing mesenchyme supports intestinal stem cells. Stomach epithelia have related niche dependencies, but their enabling mesenchymal cell populations are unknown, in part because previous studies pooled the gastric antrum and corpus. Our high-resolution imaging, transcriptional profiling, and organoid assays identify regional subpopulations and supportive capacities of purified mouse corpus and antral PDGFRA+ cells. Sub-epithelial PDGFRAHi myofibroblasts are principal sources of BMP ligands and two molecularly distinct pools distribute asymmetrically along antral glands but together fail to support epithelial growth in vitro. In contrast, PDGFRALo CD55+ cells strategically positioned beneath gastric glands promote epithelial expansion in the absence of other cells or factors. This population encompasses a small fraction expressing the BMP antagonist Grem1. Although Grem1+ cell ablation in vivo impairs intestinal stem cells, gastric stem cells are spared, implying that CD55+ cell activity in epithelial self-renewal derives from other subpopulations. Our findings shed light on spatial, molecular, and functional organization of gastric mesenchyme and the spectrum of signaling sources for epithelial support.
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Affiliation(s)
- Elisa Manieri
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
| | - Guodong Tie
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Ermanno Malagola
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY, 10032, USA
| | - Davide Seruggia
- Department of Hematology, Boston Children's Hospital, Boston, MA, 02115, USA
- St. Anna Children's Cancer Research Institute, Vienna, Austria
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Shariq Madha
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Adrianna Maglieri
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Kun Huang
- Molecular Imaging Core and Department of Cancer Immunology and Virology, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Yuko Fujiwara
- Department of Hematology, Boston Children's Hospital, Boston, MA, 02115, USA
- Howard Hughes Medical Institute, Boston, MA, 02115, USA
| | - Kevin Zhang
- Department of Hematology, Boston Children's Hospital, Boston, MA, 02115, USA
| | - Stuart H Orkin
- Department of Hematology, Boston Children's Hospital, Boston, MA, 02115, USA
- Howard Hughes Medical Institute, Boston, MA, 02115, USA
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA
| | - Timothy C Wang
- Division of Digestive and Liver Diseases, Department of Medicine and Irving Cancer Research Center, Columbia University Medical Center, New York, NY, 10032, USA
| | - Ruiyang He
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
| | - Neil McCarthy
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA
| | - Ramesh A Shivdasani
- Department of Medical Oncology and Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, 02215, USA.
- Department of Medicine, Harvard Medical School, Boston, MA, 02115, USA.
- Harvard Stem Cell Institute, Cambridge, MA, 02138, USA.
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40
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Liu J, Yang L, Lu Z, Wang Q. Tmem88 plays an essential role in pharyngeal pouch progenitor specification by inhibiting Wnt/β-catenin signaling. LIFE MEDICINE 2023; 2:lnad044. [PMID: 39872065 PMCID: PMC11749258 DOI: 10.1093/lifemedi/lnad044] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 11/15/2023] [Indexed: 01/29/2025]
Abstract
Pharyngeal pouches, which are endodermal outpockets that segment the pharyngeal arches, play a crucial role in the development of craniofacial skeletons in vertebrate embryos. Our previous study successfully identified pharyngeal pouch progenitors (PPPs) in zebrafish embryos and emphasized the significance of BMP2b signaling in their specification. However, the specific mechanism by which these progenitors originate from endodermal cells remains largely unknown. Here we found that the pharmacological activation of Wnt signaling pathway disrupts the emergence of PPPs and subsequently hinders the formation of pharyngeal pouches. Moreover, we have identified the expression of tmem88a and tmem88b (collectively known as tmem88a/b) in PPPs during the early-somite stages. Furthermore, the deficiency of tmem88a/b leads to an excessive accumulation of β-catenin in both the cytoplasm and nucleus of endodermal cells that are intended to differentiate into PPPs. Importantly, suppressing the hyperactivation of Wnt/β-catenin signaling through pharmacological treatment, the defects in PPP specification in tmem88a/b -/- mutants are successfully rescued. In summary, our findings establish a clear connection between the specification of PPPs and the regulation of Wnt signaling mediated by Tmem88. These results underscore the pivotal role of Tmem88 in the development of pharyngeal pouches.
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Affiliation(s)
- Jingwen Liu
- State Key Laboratory of Membrane Biology, Institute of Zoology, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Beijing 100101, China
| | - Liping Yang
- Innovation Centre of Ministry of Education for Development and Diseases, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, China
| | - Zidong Lu
- Innovation Centre of Ministry of Education for Development and Diseases, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, China
| | - Qiang Wang
- Innovation Centre of Ministry of Education for Development and Diseases, The Sixth Affiliated Hospital, School of Medicine, South China University of Technology, Guangzhou 510006, China
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41
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Vermeulen S, Knoops K, Duimel H, Parvizifard M, van Beurden D, López-Iglesias C, Giselbrecht S, Truckenmüller R, Habibović P, Tahmasebi Birgani Z. An in vitro model system based on calcium- and phosphate ion-induced hMSC spheroid mineralization. Mater Today Bio 2023; 23:100844. [PMID: 38033367 PMCID: PMC10682137 DOI: 10.1016/j.mtbio.2023.100844] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2023] [Revised: 10/15/2023] [Accepted: 10/23/2023] [Indexed: 12/02/2023] Open
Abstract
A challenge in regenerative medicine is creating the three-dimensional organic and inorganic in vitro microenvironment of bone, which would allow the study of musculoskeletal disorders and the generation of building blocks for bone regeneration. This study presents a microwell-based platform for creating spheroids of human mesenchymal stromal cells, which are then mineralized using ionic calcium and phosphate supplementation. The resulting mineralized spheroids promote an osteogenic gene expression profile through the influence of the spheroids' biophysical environment and inorganic signaling and require less calcium or phosphate to achieve mineralization compared to a monolayer culture. We found that mineralized spheroids represent an in vitro model for studying small molecule perturbations and extracellular mediated calcification. Furthermore, we demonstrate that understanding pathway signaling elicited by the spheroid environment allows mimicking these pathways in traditional monolayer culture, enabling similar rapid mineralization events. In sum, this study demonstrates the rapid generation and employment of a mineralized cell model system for regenerative medicine applications.
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Affiliation(s)
- Steven Vermeulen
- Department of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, the Netherlands
| | - Kèvin Knoops
- Microscopy CORE Lab, M4I Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | - Hans Duimel
- Microscopy CORE Lab, M4I Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | - Maryam Parvizifard
- Department of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, the Netherlands
| | - Denis van Beurden
- Department of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, the Netherlands
| | - Carmen López-Iglesias
- Microscopy CORE Lab, M4I Faculty of Health, Medicine and Life Sciences, Maastricht University, Maastricht, the Netherlands
| | - Stefan Giselbrecht
- Department of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, the Netherlands
| | - Roman Truckenmüller
- Department of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, the Netherlands
| | - Pamela Habibović
- Department of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, the Netherlands
| | - Zeinab Tahmasebi Birgani
- Department of Instructive Biomaterials Engineering, MERLN Institute for Technology-Inspired Regenerative Medicine, Maastricht University, Maastricht, the Netherlands
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42
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Cui Z, Wei H, Goding C, Cui R. Stem cell heterogeneity, plasticity, and regulation. Life Sci 2023; 334:122240. [PMID: 37925141 DOI: 10.1016/j.lfs.2023.122240] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2023] [Revised: 10/30/2023] [Accepted: 10/31/2023] [Indexed: 11/06/2023]
Abstract
As a population of homogeneous cells with both self-renewal and differentiation potential, stem cell pools are highly compartmentalized and contain distinct subsets that exhibit stable but limited heterogeneity during homeostasis. However, their striking plasticity is showcased under natural or artificial stress, such as injury, transplantation, cancer, and aging, leading to changes in their phenotype, constitution, metabolism, and function. The complex and diverse network of cell-extrinsic niches and signaling pathways, together with cell-intrinsic genetic and epigenetic regulators, tightly regulate both the heterogeneity during homeostasis and the plasticity under perturbation. Manipulating these factors offers better control of stem cell behavior and a potential revolution in the current state of regenerative medicine. However, disruptions of normal regulation by genetic mutation or excessive plasticity acquisition may contribute to the formation of tumors. By harnessing innovative techniques that enhance our understanding of stem cell heterogeneity and employing novel approaches to maximize the utilization of stem cell plasticity, stem cell therapy holds immense promise for revolutionizing the future of medicine.
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Affiliation(s)
- Ziyang Cui
- Department of Dermatology and Venerology, Peking University First Hospital, Beijing 100034, China.
| | - Hope Wei
- Department of Biology, Boston University, 5 Cummington Mall, Boston, MA 02215, United States of America
| | - Colin Goding
- Ludwig Institute for Cancer Research, Nuffield Department of Clinical Medicine, University of Oxford, Headington, Oxford OX37DQ, UK
| | - Rutao Cui
- Skin Disease Research Institute, The 2nd Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China
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43
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Brügger MD, Basler K. The diverse nature of intestinal fibroblasts in development, homeostasis, and disease. Trends Cell Biol 2023; 33:834-849. [PMID: 37080817 DOI: 10.1016/j.tcb.2023.03.007] [Citation(s) in RCA: 29] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2022] [Revised: 02/28/2023] [Accepted: 03/13/2023] [Indexed: 04/22/2023]
Abstract
Only in recent years have we begun to appreciate the involvement of fibroblasts in intestinal development, tissue homeostasis, and disease. These insights followed the advent of single-cell transcriptomics that allowed researchers to explore the heterogeneity of intestinal fibroblasts in unprecedented detail. Since researchers often defined cell types and their associated function based on the biological process they studied, there are a plethora of partially overlapping markers for different intestinal fibroblast populations. This ambiguity complicates putting different research findings into context. Here, we provide a census on the function and identity of intestinal fibroblasts in mouse and human. We propose a simplified framework consisting of three colonic and four small intestinal fibroblast populations to aid navigating the diversity of intestinal fibroblasts.
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Affiliation(s)
- Michael David Brügger
- Department of Molecular Life Sciences, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
| | - Konrad Basler
- Department of Molecular Life Sciences, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland.
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44
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Yousafzai MS, Hammer JA. Using Biosensors to Study Organoids, Spheroids and Organs-on-a-Chip: A Mechanobiology Perspective. BIOSENSORS 2023; 13:905. [PMID: 37887098 PMCID: PMC10605946 DOI: 10.3390/bios13100905] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/26/2023] [Revised: 09/13/2023] [Accepted: 09/19/2023] [Indexed: 10/28/2023]
Abstract
The increasing popularity of 3D cell culture models is being driven by the demand for more in vivo-like conditions with which to study the biochemistry and biomechanics of numerous biological processes in health and disease. Spheroids and organoids are 3D culture platforms that self-assemble and regenerate from stem cells, tissue progenitor cells or cell lines, and that show great potential for studying tissue development and regeneration. Organ-on-a-chip approaches can be used to achieve spatiotemporal control over the biochemical and biomechanical signals that promote tissue growth and differentiation. These 3D model systems can be engineered to serve as disease models and used for drug screens. While culture methods have been developed to support these 3D structures, challenges remain to completely recapitulate the cell-cell and cell-matrix biomechanical interactions occurring in vivo. Understanding how forces influence the functions of cells in these 3D systems will require precise tools to measure such forces, as well as a better understanding of the mechanobiology of cell-cell and cell-matrix interactions. Biosensors will prove powerful for measuring forces in both of these contexts, thereby leading to a better understanding of how mechanical forces influence biological systems at the cellular and tissue levels. Here, we discussed how biosensors and mechanobiological research can be coupled to develop accurate, physiologically relevant 3D tissue models to study tissue development, function, malfunction in disease, and avenues for disease intervention.
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Affiliation(s)
- Muhammad Sulaiman Yousafzai
- Cell and Developmental Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - John A. Hammer
- Cell and Developmental Biology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD 20892, USA
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45
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Frum T, Hsu PP, Hein RFC, Conchola AS, Zhang CJ, Utter OR, Anand A, Zhang Y, Clark SG, Glass I, Sexton JZ, Spence JR. Opposing roles for TGFβ- and BMP-signaling during nascent alveolar differentiation in the developing human lung. NPJ Regen Med 2023; 8:48. [PMID: 37689780 PMCID: PMC10492838 DOI: 10.1038/s41536-023-00325-z] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Accepted: 08/31/2023] [Indexed: 09/11/2023] Open
Abstract
Alveolar type 2 (AT2) cells function as stem cells in the adult lung and aid in repair after injury. The current study aimed to understand the signaling events that control differentiation of this therapeutically relevant cell type during human development. Using lung explant and organoid models, we identified opposing effects of TGFβ- and BMP-signaling, where inhibition of TGFβ- and activation of BMP-signaling in the context of high WNT- and FGF-signaling efficiently differentiated early lung progenitors into AT2-like cells in vitro. AT2-like cells differentiated in this manner exhibit surfactant processing and secretion capabilities, and long-term commitment to a mature AT2 phenotype when expanded in media optimized for primary AT2 culture. Comparing AT2-like cells differentiated with TGFβ-inhibition and BMP-activation to alternative differentiation approaches revealed improved specificity to the AT2 lineage and reduced off-target cell types. These findings reveal opposing roles for TGFβ- and BMP-signaling in AT2 differentiation and provide a new strategy to generate a therapeutically relevant cell type in vitro.
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Affiliation(s)
- Tristan Frum
- Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Peggy P Hsu
- Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
- Rogel Cancer Center, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Renee F C Hein
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Ansley S Conchola
- Program in Cell and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Charles J Zhang
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Olivia R Utter
- Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Abhinav Anand
- Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Yi Zhang
- Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Sydney G Clark
- Program in Cell and Molecular Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
| | - Ian Glass
- Department of Pediatrics, Genetic Medicine, University of Washington, Seattle, WA, 98195, USA
| | - Jonathan Z Sexton
- Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA
- Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, MI, 48109, USA
- Center for Drug Repurposing, University of Michigan, Ann Arbor, MI, 48109, USA
- Michigan Institute for Clinical and Health Research, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Jason R Spence
- Department of Internal Medicine, Gastroenterology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
- Department of Cell and Developmental Biology, University of Michigan Medical School, Ann Arbor, MI, 48109, USA.
- Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, 48109, USA.
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46
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Shimizu S, Kondo J, Onuma K, Coppo R, Ota K, Kamada M, Harada Y, Tanaka Y, Nakazawa MA, Tamada Y, Okuno Y, Kawada K, Obama K, Coffey RJ, Fujiwara Y, Inoue M. Inhibition of the bone morphogenetic protein pathway suppresses tumor growth through downregulation of epidermal growth factor receptor in MEK/ERK-dependent colorectal cancer. Cancer Sci 2023; 114:3636-3648. [PMID: 37357017 PMCID: PMC10475764 DOI: 10.1111/cas.15882] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2022] [Revised: 05/22/2023] [Accepted: 05/27/2023] [Indexed: 06/27/2023] Open
Abstract
The bone morphogenetic protein (BMP) pathway promotes differentiation and induces apoptosis in normal colorectal epithelial cells. However, its role in colorectal cancer (CRC) is controversial, where it can act as context-dependent tumor promoter or tumor suppressor. Here we have found that CRC cells reside in a BMP-rich environment based on curation of two publicly available RNA-sequencing databases. Suppression of BMP using a specific BMP inhibitor, LDN193189, suppresses the growth of select CRC organoids. Colorectal cancer organoids treated with LDN193189 showed a decrease in epidermal growth factor receptor, which was mediated by protein degradation induced by leucine-rich repeats and immunoglobulin-like domains protein 1 (LRIG1) expression. Among 18 molecularly characterized CRC organoids, suppression of growth by BMP inhibition correlated with induction of LRIG1 gene expression. Notably, knockdown of LRIG1 in organoids diminished the growth-suppressive effect of LDN193189. Furthermore, in CRC organoids, which are susceptible to growth suppression by LDN193189, simultaneous treatment with LDN193189 and trametinib, an FDA-approved MEK inhibitor, resulted in cooperative growth inhibition both in vitro and in vivo. Taken together, the simultaneous inhibition of BMP and MEK could be a novel treatment option in CRC cases, and evaluating in vitro growth suppression and LRIG1 induction by BMP inhibition using patient-derived organoids could offer functional biomarkers for predicting potential responders to this regimen.
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Affiliation(s)
- Shota Shimizu
- Department of Clinical Bioresource Research and DevelopmentKyoto University Graduate School of MedicineKyotoJapan
- Division of Gastrointestinal and Pediatric Surgery, Department of Surgery, School of MedicineTottori University Faculty of MedicineTottoriJapan
| | - Jumpei Kondo
- Department of Clinical Bioresource Research and DevelopmentKyoto University Graduate School of MedicineKyotoJapan
- Department of BiochemistryOsaka International Cancer InstituteOsakaJapan
- Department of Molecular Biochemistry and Clinical Investigation, Division of Health ScienceOsaka University Graduate School of MedicineOsakaJapan
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Kunishige Onuma
- Department of Clinical Bioresource Research and DevelopmentKyoto University Graduate School of MedicineKyotoJapan
| | - Roberto Coppo
- Department of Clinical Bioresource Research and DevelopmentKyoto University Graduate School of MedicineKyotoJapan
| | - Kasumi Ota
- Graduate School of Medicine and Faculty of MedicineKyoto UniversityKyotoJapan
| | - Mayumi Kamada
- Graduate School of Medicine and Faculty of MedicineKyoto UniversityKyotoJapan
| | - Yohei Harada
- Graduate School of Medicine and Faculty of MedicineKyoto UniversityKyotoJapan
| | - Yoshihisa Tanaka
- Graduate School of Pharmaceutical SciencesKyoto UniversityKyotoJapan
- RIKEN Center for Computational Science(R‐CCS)HPC/HPC‐ and AI‐driven Drug Development Platform DivisionKobeJapan
| | - Mai Adachi Nakazawa
- Graduate School of Medicine and Faculty of MedicineKyoto UniversityKyotoJapan
- Department of Medical Data Intelligence and Data Analysis Division, Innovation Center for Health PromotionHirosaki UniversityHirosakiJapan
| | - Yoshinori Tamada
- Department of Medical Data Intelligence and Data Analysis Division, Innovation Center for Health PromotionHirosaki UniversityHirosakiJapan
| | - Yasushi Okuno
- Graduate School of Medicine and Faculty of MedicineKyoto UniversityKyotoJapan
- RIKEN Center for Computational Science(R‐CCS)HPC/HPC‐ and AI‐driven Drug Development Platform DivisionKobeJapan
| | - Kenji Kawada
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Kazutaka Obama
- Department of Surgery, Graduate School of MedicineKyoto UniversityKyotoJapan
| | - Robert J. Coffey
- Epithelial Biology CenterVanderbilt University Medical CenterNashvilleTennesseeUSA
| | - Yoshiyuki Fujiwara
- Division of Gastrointestinal and Pediatric Surgery, Department of Surgery, School of MedicineTottori University Faculty of MedicineTottoriJapan
| | - Masahiro Inoue
- Department of Clinical Bioresource Research and DevelopmentKyoto University Graduate School of MedicineKyotoJapan
- Department of BiochemistryOsaka International Cancer InstituteOsakaJapan
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47
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Xiang J, Guo J, Zhang S, Wu H, Chen YG, Wang J, Li B, Liu H. A stromal lineage maintains crypt structure and villus homeostasis in the intestinal stem cell niche. BMC Biol 2023; 21:169. [PMID: 37553612 PMCID: PMC10408166 DOI: 10.1186/s12915-023-01667-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 07/24/2023] [Indexed: 08/10/2023] Open
Abstract
BACKGROUND The nutrient-absorbing villi of small intestines are renewed and repaired by intestinal stem cells (ISCs), which reside in a well-organized crypt structure. Genetic studies have shown that Wnt molecules secreted by telocytes, Gli1+ stromal cells, and epithelial cells are required for ISC proliferation and villus homeostasis. Intestinal stromal cells are heterogeneous and single-cell profiling has divided them into telocytes/subepithelial myofibroblasts, myocytes, pericytes, trophocytes, and Pdgfralow stromal cells. Yet, the niche function of these stromal populations remains incompletely understood. RESULTS We show here that a Twist2 stromal lineage, which constitutes the Pdgfralow stromal cell and trophocyte subpopulations, maintains the crypt structure to provide an inflammation-restricting niche for regenerating ISCs. Ablating Twist2 lineage cells or deletion of one Wntless allele in these cells disturbs the crypt structure and impairs villus homeostasis. Upon radiation, Wntless haplo-deficiency caused decreased production of anti-microbial peptides and increased inflammation, leading to defective ISC proliferation and crypt regeneration, which were partially rescued by eradication of commensal bacteria. In addition, we show that Wnts secreted by Acta2+ subpopulations also play a role in crypt regeneration but not homeostasis. CONCLUSIONS These findings suggest that ISCs may require different niches for villus homeostasis and regeneration and that the Twist2 lineage cells may help to maintain a microbe-restricted environment to allow ISC-mediated crypt regeneration.
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Affiliation(s)
- Jinnan Xiang
- The Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, 200024, China
| | - Jigang Guo
- The Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, 200024, China
| | - Shaoyang Zhang
- The Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, 200024, China
| | - Hongguang Wu
- The Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, 200024, China
| | - Ye-Guang Chen
- State Key Laboratory of Membrane Biology, Tsinghua-Peking Center for Life Sciences, School of Life Sciences, Tsinghua University, Beijing, 100084, China
| | - Junping Wang
- Chongqing Engineering Research Center for Nanomedicine, College of Preventive Medicine, Third Military Medical University, Chongqing, China
| | - Baojie Li
- The Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, 200024, China.
| | - Huijuan Liu
- The Bio-X Institutes, Shanghai Jiao Tong University, Shanghai, 200024, China.
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48
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Kolev HM, Kaestner KH. Mammalian Intestinal Development and Differentiation-The State of the Art. Cell Mol Gastroenterol Hepatol 2023; 16:809-821. [PMID: 37507088 PMCID: PMC10520362 DOI: 10.1016/j.jcmgh.2023.07.011] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 07/19/2023] [Accepted: 07/20/2023] [Indexed: 07/30/2023]
Abstract
The development of the mammalian intestine, from its earliest origins as a morphologically uniform sheet of endoderm cells during gastrulation into the complex organ system that is essential for the life of the organism, is a truly fascinating process. During midgestation development, reciprocal interactions between endoderm-derived epithelium and mesoderm-derived mesenchyme enable villification, or the conversion of a radially symmetric pseudostratified epithelium into the functional subdivision of crypts and villi. Once a mature crypt-villus axis is established, proliferation and differentiation of new epithelial cells continue throughout life. Spatially localized signals including the wingless and Int-1, fibroblast growth factor, and Hippo systems, among others, ensure that new cells are being born continuously in the crypt. As cells exit the crypt compartment, a gradient of bone morphogenetic protein signaling limits proliferation to allow for the specification of multiple mature cell types. The first major differentiation decision is dependent on Notch signaling, which specifies epithelial cells into absorptive and secretory lineages. The secretory lineage is subdivided further into Paneth, goblet, tuft, and enteroendocrine cells via a complex network of transcription factors. Although some of the signaling molecules are produced by epithelial cells, critical components are derived from specialized crypt-adjacent mesenchymal cells termed telocytes, which are marked by Forkhead box l1, GLI Family Zinc Finger 1, and platelet-derived growth factor receptor α. The crucial nature of these processes is evidenced by the multitude of intestinal disorders such as colorectal cancer, short-bowel syndrome, and inflammatory bowel disease, which all reflect perturbations of the development and/or differentiation of the intestine.
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Affiliation(s)
- Hannah M Kolev
- Department of Genetics and Center for Molecular Studies in Digestive and Liver Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Klaus H Kaestner
- Department of Genetics and Center for Molecular Studies in Digestive and Liver Diseases, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania.
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49
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Xie Z, Zhou G, Zhang M, Han J, Wang Y, Li X, Wu Q, Li M, Zhang S. Recent developments on BMPs and their antagonists in inflammatory bowel diseases. Cell Death Discov 2023; 9:210. [PMID: 37391444 DOI: 10.1038/s41420-023-01520-z] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/15/2023] [Accepted: 06/22/2023] [Indexed: 07/02/2023] Open
Abstract
Inflammatory bowel diseases (IBDs), including ulcerative colitis, and Crohn's disease, are intestinal disorders characterized by chronic relapsing inflammation. A large proportion of patients with IBD will progress to develop colitis-associated colorectal cancer due to the chronic intestinal inflammation. Biologic agents that target tumour necrosis factor-α, integrin α4β7, and interleukin (IL)12/23p40 have been more successful than conventional therapies in treating IBD. However, drug intolerance and loss of response are serious drawbacks of current biologics, necessitating the development of novel drugs that target specific pathways in IBD pathogenesis. One promising group of candidate molecules are bone morphogenetic proteins (BMPs), members of the TGF-β family involved in regulating morphogenesis, homeostasis, stemness, and inflammatory responses in the gastrointestinal tract. Also worth examining are BMP antagonists, major regulators of these proteins. Evidence has shown that BMPs (especially BMP4/6/7) and BMP antagonists (especially Gremlin1 and follistatin-like protein 1) play essential roles in IBD pathogenesis. In this review, we provide an updated overview on the involvement of BMPs and BMP antagonists in IBD pathogenesis and in regulating the fate of intestinal stem cells. We also described the expression patterns of BMPs and BMP antagonists along the intestinal crypt-villus axis. Lastly, we synthesized available research on negative regulators of BMP signalling. This review summarizes recent developments on BMPs and BMP antagonists in IBD pathogenesis, which provides novel insights into future therapeutic strategies.
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Affiliation(s)
- Zhuo Xie
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Gaoshi Zhou
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Mudan Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Jing Han
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Ying Wang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Xiaoling Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Qirui Wu
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Manying Li
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China
| | - Shenghong Zhang
- Division of Gastroenterology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, P. R. China.
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50
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Pontarollo G, Kollar B, Mann A, Khuu MP, Kiouptsi K, Bayer F, Brandão I, Zinina VV, Hahlbrock J, Malinarich F, Mimmler M, Bhushan S, Marini F, Ruf W, Belheouane M, Baines JF, Endres K, Reba SM, Raker VK, Deppermann C, Welsch C, Bosmann M, Soshnikova N, Chassaing B, Bergentall M, Sommer F, Bäckhed F, Reinhardt C. Commensal bacteria weaken the intestinal barrier by suppressing epithelial neuropilin-1 and Hedgehog signaling. Nat Metab 2023; 5:1174-1187. [PMID: 37414930 PMCID: PMC10365997 DOI: 10.1038/s42255-023-00828-5] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/14/2022] [Accepted: 05/24/2023] [Indexed: 07/08/2023]
Abstract
The gut microbiota influences intestinal barrier integrity through mechanisms that are incompletely understood. Here we show that the commensal microbiota weakens the intestinal barrier by suppressing epithelial neuropilin-1 (NRP1) and Hedgehog (Hh) signaling. Microbial colonization of germ-free mice dampens signaling of the intestinal Hh pathway through epithelial Toll-like receptor (TLR)-2, resulting in decreased epithelial NRP1 protein levels. Following activation via TLR2/TLR6, epithelial NRP1, a positive-feedback regulator of Hh signaling, is lysosomally degraded. Conversely, elevated epithelial NRP1 levels in germ-free mice are associated with a strengthened gut barrier. Functionally, intestinal epithelial cell-specific Nrp1 deficiency (Nrp1ΔIEC) results in decreased Hh pathway activity and a weakened gut barrier. In addition, Nrp1ΔIEC mice have a reduced density of capillary networks in their small intestinal villus structures. Collectively, our results reveal a role for the commensal microbiota and epithelial NRP1 signaling in the regulation of intestinal barrier function through postnatal control of Hh signaling.
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Affiliation(s)
- Giulia Pontarollo
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Bettina Kollar
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- Department of Chemistry, Biochemistry, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Amrit Mann
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - My Phung Khuu
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Klytaimnistra Kiouptsi
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, Mainz, Germany
| | - Franziska Bayer
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Inês Brandão
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Valeriya V Zinina
- Institute of Molecular Medicine, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Jennifer Hahlbrock
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Frano Malinarich
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Maximilian Mimmler
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- Department of Chemistry, Biochemistry, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Sudhanshu Bhushan
- Institute of Anatomy and Cell Biology, Unit of Reproductive Biology, Justus-Liebig-University of Giessen, Giessen, Germany
| | - Federico Marini
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- Institute of Medical Biostatistics, Epidemiology and Informatics (IMBEI), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Wolfram Ruf
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, Mainz, Germany
| | - Meriem Belheouane
- Institute for Experimental Medicine, Kiel University and Max Planck Institute for Evolutionary Biology, Plön, Germany
| | - John F Baines
- Institute for Experimental Medicine, Kiel University and Max Planck Institute for Evolutionary Biology, Plön, Germany
| | - Kristina Endres
- Department of Psychiatry and Psychotherapy, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Scott M Reba
- Department of Medicine, Case Western Reserve University and University Hospitals Cleveland Medical Center, Cleveland, OH, USA
| | - Verena K Raker
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Carsten Deppermann
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, Mainz, Germany
| | - Christoph Welsch
- Department of Internal Medicine 1, Goethe University Hospital Frankfurt, Frankfurt am Main, Germany
| | - Markus Bosmann
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
- Pulmonary Center, Department of Medicine, Boston University School of Medicine, Boston, MA, USA
| | - Natalia Soshnikova
- Institute of Molecular Medicine, University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany
| | - Benoit Chassaing
- INSERM U1016, Team 'Mucosal microbiota in chronic inflammatory diseases', CNRS UMR 8104, Université de Paris, Paris, France
| | - Mattias Bergentall
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
| | - Felix Sommer
- Institute of Clinical Molecular Biology, Christian-Albrechts-University, Kiel, Germany
| | - Fredrik Bäckhed
- Department of Molecular and Clinical Medicine, Wallenberg Laboratory, Institute of Medicine, University of Gothenburg, Gothenburg, Sweden
- Novo Nordisk Foundation Center for Basic Metabolic Research, Section for Metabolic Receptology and Enteroendocrinology, Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Physiology, Region Västra Götland, Sahlgrenska University Hospital, Gothenburg, Sweden
| | - Christoph Reinhardt
- Center for Thrombosis and Hemostasis (CTH), University Medical Center Mainz, Johannes Gutenberg-University Mainz, Mainz, Germany.
- German Center for Cardiovascular Research (DZHK), Partner Site RhineMain, Mainz, Germany.
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