{"database":"biostudies-literature","file_versions":[],"scores":null,"additional":{"omics_type":["Unknown"],"submitter":["Kalashyan M"],"funding":["NIDDK NIH HHS"],"pubmed_abstract":["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 <sup>+</sup> /H <sup>+</sup> 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. Inhibition of Notch signaling with the γ-secretase inhibitor, DAPT, recovered apical brush border structure and functional Na <sup>+</sup> /H <sup>+</sup> 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.<h4>Conflict-of-interest statement</h4>The authors have declared that no conflict of interest exists."],"journal":["bioRxiv : the preprint server for biology"],"pagination":["2023.01.28.526036"],"full_dataset_link":["https://www.ebi.ac.uk/biostudies/studies/S-EPMC9900906"],"repository":["biostudies-literature"],"pubmed_title":["Therapy Development for Microvillus Inclusion Disease using Patient-derived Enteroids."],"pmcid":["PMC9900906"],"funding_grant_id":["R01 DK128190","RC2 DK118640","P30 DK034854"],"pubmed_authors":["Goldsmith JD","Thiagarajah JR","Shub MD","Kalashyan M","Roland JT","Kolobova E","Goldenring JR","Theres MB","Hagen SJ","Jimenez L","Kaji I","Raghunathan K","Oller H"],"additional_accession":[]},"is_claimable":false,"name":"Therapy Development for Microvillus Inclusion Disease using Patient-derived Enteroids.","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 <sup>+</sup> /H <sup>+</sup> 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. Inhibition of Notch signaling with the γ-secretase inhibitor, DAPT, recovered apical brush border structure and functional Na <sup>+</sup> /H <sup>+</sup> 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.<h4>Conflict-of-interest statement</h4>The authors have declared that no conflict of interest exists.","dates":{"release":"2023-01-01T00:00:00Z","publication":"2023 Jan","modification":"2025-04-05T11:27:56.147Z","creation":"2025-04-05T11:27:56.147Z"},"accession":"S-EPMC9900906","cross_references":{"pubmed":["36747680"],"doi":["10.1101/2023.01.28.526036"]}}