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Myosin VB is Critical for Progenitor Cell Function in the intestine

ABSTRACT: Microvillus inclusion disease (MVID) is a congenital diarrheal disorder, caused by inactivating mutations in myosin Vb (MYO5B). MYO5B deficient mice and cell lines have demonstrated the importance of MYO5B in enterocyte brush border development; however, the previous MYO5B knockout models lacked specificity to the stem cell function. To address the direct impact of MYO5B loss on the epithelial stemness, we investigated the effects of progressive MYO5B deficiency originating in mouse intestinal crypt cells. Our transcriptomic and multi-plex immunostaining datasets demonstrate that MYO5B is critical for intestinal stem cell identity. MYO5B-deficient crypts acquire a hyperproliferative phenotype and lack the ability of proper cell lineage differentiation. An evident disruption in mitochondrial structure and fatty acid metabolism likely underlies these crypt deficits. Consistent with mouse models, MVID patient biopsies demonstrate abnormal expansion of proliferative zone besides villus blunting. These data reveal the direct impacts of MYO5B loss on intestinal epithelial cell progenitor functions.

ORGANISM(S): Mus musculus

PROVIDER: GSE300032 | GEO | 2026/03/10

REPOSITORIES: GEO

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Similar Datasets

Loss-of-function of MYO5B induces epithelial cell scattering in enterocytes

Project description:A non-functional myosin Vb motor in duodenal enterocytes results in disruption of epithelial cell polarity characterized by complete loss of microvilli and mislocalization of apical brush border proteins in the cytoplasm which finally cause a devastating disease in neonates with severe malabsorption defects accompanied by protracted diarrhea during infancy, classified as microvillus inclusion disease (MVID). The exact mechanisms how loss-of-function of MYO5B induces polarity loss are not completely understood in MVID pathogenesis. Obtaining better insights in cell polarity defects caused by loss of MYO5B, we performed microarray- in combination with protein expression-analysis in an inducible CaCo2 MYO5B RNAi cell system. Surprisingly, in MYO5B-depleted CaCo2 cells, CDH1 coding for the cell adhesion protein E-Cadherin and important for cell adhesion and therefore maintenance of cell polarity, was significantly downregulated. Interestingly, mesenchymal cell markers, specifically Vimentin and N-Cadherin, physiologically not expressed in differentiated epithelium, were upregulated and accompanied by increased phospho-c-jun levels in the nucleus. Importantly phospho-c-jun was also found in nuclei of duodenal enterocytes in MVID patients, indicating loss of MYO5B induces epithelial cell scattering in enterocytes. 3 Myosin 5B KD versus 3 control samples

2013-03-14 | E-GEOD-45134 | biostudies-arrayexpress

Lysophosphatidic acid treatment improves brush border maturation and apical SGLT1 activity in Myo5b deficient mice, a model of MVID

Project description:Myosin Vb (Myo5b) is an essential trafficking protein for membrane recycling in gastrointestinal (GI) epithelial cells and its inactivating mutation causes the congenital diarrheal disease, microvillus inclusion disease (MVID). We previously reported that Myo5b deficiency in mice causes mislocalization of SGLT1 and NHE3, but retained apical function of CFTR, resulting in malabsorption and secretory diarrhea. Activation of lysophosphatidic acid (LPA) receptors can improve diarrhea, but the effects of LPA on MVID symptoms is unclear. We therefore tested whether LPA treatment can ameliorate the epithelial deficits in Myo5b knockout (KO) mice. Methods: Adult tamoxifen-induced, intestine-specific, Myo5b KO (VillinCreERT2;Myo5bflox/flox) and littermate control mice were treated with LPA, an LPAR2 agonist (GRI977143), or vehicle for 4 days after a single tamoxifen injection. Apical SGLT1 and CFTR activities were measured in Üssing chambers. The localization of membrane transporters was evaluated by immunostaining in mouse tissues and enteroids. RNA sequencing and enrichment analysis were performed with isolated jejunal epithelial cells. Results: Daily treatment with LPA decreased the frequency of multivesicular bodies and the expression of cathepsins, but did not affect the formation of microvillus inclusions in Myo5b KO mice. LPA partially restored the brush border height and the localization of SGLT1 and NHE3 in Myo5b KO small intestine and enteroids. SGLT1-dependent short-circuit current (Isc) was increased and abnormal CFTR activities were suppressed in LPA-treated jejunum compared to that of vehicle-treated Myo5b KO mice. Conclusions: Cell autonomous LPA signaling may modulate a Myo5b-independent trafficking mechanism and the brush border maturation, demonstrating a therapeutic potential for LPA in the treatment of MVID.

2019-10-24 | GSE139302 | GEO

Patient-derived Enteroids provide a Platform for the Development of Therapeutic Approaches in Microvillus Inclusion Disease

Project description:Microvillus Inclusion Disease (MVID), caused by loss-of-function mutations in the motor protein Myosin Vb (MYO5B), is a severe infantile disease characterized by diarrhea, malabsorption, and acid-base instability, requiring intensive parenteral support for nutritional and fluid management. Human patient-derived enteroids represent a model for investigation of monogenic epithelial disorders but are a rare resource from MVID patients. We developed human enteroids with different loss-of function MYO5B variants and showed that they recapitulated the structural changes found in native MVID enterocytes. Multiplex Immunofluorescence imaging of patient duodenal tissues revealed patient-specific changes in localization of brush border transporters. Functional analysis of electrolyte transport revealed profound loss of Na+/H+ exchange (NHE) activity in MVID patient enteroids with near-normal chloride secretion. The chloride channel-blocking anti-diarrheal drug, Crofelemer, dose-dependently inhibited agonist-mediated fluid secretion. MVID enteroids exhibited altered differentiation and maturation versus healthy enteroids. Gamma-secretase inhibition with DAPT recovered apical brush border structure and functional Na+/H+ exchange activity in MVID enteroids. Transcriptomic analysis revealed potential pathways involved in the rescue of MVID cells including serum- and glucocorticoid-induced protein kinase 2 (SGK2), and NHE regulatory factor 3 (NHERF3). These results demonstrate the utility of patient-derived enteroids for developing therapeutic approaches to MVID.

2023-08-16 | GSE240928 | GEO

Alterations in cellular metabolic pathway and epithelial cell maturation induced by MYO5B defects are partially reversible by LPAR5 activation

Project description:Functional loss of the motor protein, Myosin Vb (MYO5B), induces various defects in intestinal epithelial function and causes a congenital diarrheal disorder, microvillus inclusion disease (MVID). Utilizing the MVID model mice, Vil1-CreERT2;Myo5bflox/flox (MYO5B∆IEC) and Vil1-CreERT2;Myo5bflox/G519R (MYO5B(G519R)), we previously reported that functional MYO5B loss disrupts progenitor cell differentiation and enterocyte maturation that result in villus blunting and deadly malabsorption symptoms. In this study, we determined that both absence and a point mutation of MYO5B impair lipid metabolism and alter mitochondrial structure, which may underlie the progenitor cell malfunction observed in MVID intestine. Along with a decrease in fatty acid oxidation, the lipogenesis pathway was enhanced in the MYO5B∆IEC small intestine. Consistent with these observations in vivo, RNA-sequencing of enteroids generated from the two MVID mouse strains showed similar downregulation of energy metabolic enzymes, including mitochondrial oxidative phosphorylation genes. In our previous studies, lysophosphatidic acid (LPA) signaling ameliorates epithelial cell defects in MYO5B∆IEC tissues and enteroids. The present study demonstrated that the highly soluble LPAR5-preferred agonist, Compound-1, improved sodium transporter localization and absorptive function, and tuft cell differentiation in patient-modeled MVID animals that carry independent mutations in MYO5B. Body weight loss in male MYO5B(G519R) mice was ameliorated by Compound-1. These observations suggest that Compound-1 treatment has a trophic effect on intestine with MYO5B functional loss through epithelial cell-autonomous pathways that can accelerate the differentiation of progenitor cells and the maturation of enterocytes. Targeting LPAR5 may represent an effective therapeutic approach for treatment of MVID symptoms induced by different point mutations in MYO5B.

2024-09-24 | GSE260706 | GEO

Loss-of-function of MYO5B induces epithelial cell scattering in enterocytes

2013-03-14 | GSE45134 | GEO

Myosin 5b Deficiency Alters Liver Proliferation, Zonation and Bile Acid Composition

Project description:Background: Myosin 5b (Myo5b) is a motor protein critical for trafficking proteins to the apical surface of intestinal epithelial cells. Inactivating mutations in MYO5B cause Microvillus Inclusion Disease (MVID), a congenital diarrhea disorder that often leads to liver cholestasis. While Myo5b’s role in the intestine is well characterized, its function in the liver remains unclear. Methods & Results: To define the hepatic consequences of Myo5b loss, we analyzed germline Myo5b knockout (KO) mice. Bulk RNA-seq of KO livers revealed significant transcriptomic alterations, notably downregulation of genes linked to cell proliferation. Immunostaining confirmed reduced Ki67, phospho-histone H3, and cyclin D1 expression, along with impaired growth of liver organoids in Myo5b deficient mice. Histology and lipid staining showed steatosis and enlarged lipid droplets, with gene signatures favoring lipogenesis and ketogenesis in mice lacking Myo5b. Myo5b KO livers also displayed disrupted zonated gene expression and loss of zone 1 and zone 3 markers. Bile acid profiling revealed reduced hepatic bile acid levels, decreased expression of classical pathway genes (Cyp7a1, Cyp7b1), and compensatory upregulation of Cyp27a1. In the ileum, we observed mislocalization of the apical bile acid transporter ASBT and decreased levels of basolateral OSTβ, leading to impaired enterohepatic recycling and increased luminal bile acids. Conclusions: These findings reveal a previously unrecognized role for Myo5b in liver proliferation, metabolic zonation, and bile acid homeostasis, highlighting its importance in maintaining hepatobiliary function.

2026-01-11 | GSE315772 | GEO

Lysophosphatidic acid treatment improves brush border maturation and apical SGLT1 activity in Myo5b deficient mice, a model of MVID

Project description:Lysophosphatidic acid treatment improves brush border maturation and apical SGLT1 activity in Myo5b deficient mice, a model of MVID

| PRJNA579150 | ENA

Ileal Enterocyte Brush Border Abnormalities Associate with Progressive Disease Course in Pediatric Crohn’s Disease

Project description:Objective: There is a critical need for biomarkers to predict prognosis and guide clinical care in pediatric Crohn’s disease (CD). Our previous studies of adult CD indicated ileal microvillus length as a potential prognostic biomarker for therapy response. Here, we tested if short microvillus length predicted progression of disease behavior or bowel resection surgery in pediatric CD. Design: We obtained H&E-stained ileal histology samples from 3 pediatric CD cohorts. Average microvillus length was determined for 59 Control and 377 CD samples and tested for associations with patient demographic and clinical data, RNA-seq molecular profiles, histological inflammation scores, and clinical outcomes. Results: Relative to Controls, the average microvillus length was shorter in CD samples collected at diagnostic or follow-up colonoscopy procedures. Microvillus length was generally not associated with demographic data or clinical activity indices. The CD molecular signature was functionally enriched for transporter activity and brush border membrane among the genes positively associated with microvillus length and for extracellular matrix, inflamed macrophages, and fibroblasts among the genes negatively associated with microvillus length. Microvillus length negatively correlated with histologic inflammation score, but short microvillus length phenotype could cooccur with low histologic inflammation. There was a higher likelihood of stricturing disease behavior or bowel resection surgery, but not fistulizing disease behavior, in follow-up CD samples with short microvillus length. Conclusion: Short microvillus length can predict the development of stricturing disease behavior and bowel resection surgery in pediatric CD, further supporting the potential use of this histological phenotype as a biomarker for CD prognosis.

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2025-08-08 | PXD062684 | Pride

Isthmus progenitor cells contribute to homeostatic cellular turnover and support regeneration following intestinal injury

Project description:The currently accepted intestinal epithelial cell organization model equates crypt base columnar (CBC) cells, marked by high levels of Lgr5 expression, with the intestinal stem cell (ISC). However, recent intestinal regeneration studies have uncovered limitations of the ‘Lgr5-CBC’ model, leading to two major views: one favoring the presence of a quiescent reserve stem cell population, the other calling for differentiated cell plasticity. To test if an alternative model may help reconcile these perspectives, we studied the hierarchical organization of crypt epithelial cells in an unbiased fashion, by combining high-resolution, single-cell profiling and lineage tracing in multiple transgenic mouse models. These show that Lgr5 is not a specific ISC marker; rather, cells located in the crypt isthmus, which include Lgr5low cells, comprise the ISCs that sustain tissue homeostasis. Following irradiation or intestinal injury, surviving ISCs and progenitors, but not differentiated cells, participate in intestinal regeneration, suggesting that neither de-differentiation nor reserve stem cell populations are drivers of intestinal regeneration. Our results provide a novel viewpoint for the intestinal crypt epithelium, in which ISCs localize to the crypt isthmus, and ISC potential is restricted to stem and progenitor cells.

2024-03-24 | GSE205229 | GEO

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