Andreanna Burman; Monica E. Brown; Yilin Yang; Michael Momoh; Francisca Adeniran; Cynthia Ramos; Ken S. Lau; Linda C. Samuelson; Mitchell D. Shub; Joseph T. Roland; Izumi Kaji (2026).听.听Stem Cell Reports, 21(3), 102820.听
This study investigates the role of a protein called听MYO5B (myosin Vb)听in the intestine, particularly in early-stage cells that give rise to the intestinal lining, known as听intestinal stem and progenitor cells. Mutations in MYO5B cause a rare genetic condition called听microvillus inclusion disease (MVID), which leads to severe, lifelong diarrhea because the intestine cannot properly absorb nutrients. While previous research showed that MYO5B is important for forming the brush border (the surface of intestinal cells that helps with absorption), its specific role in stem cells was not well understood.
To explore this, the researchers created specialized mouse models in which MYO5B was gradually lost in intestinal crypt cells鈥攖he regions where stem cells reside and continuously produce new intestinal cells. They found that without MYO5B, these stem cells lost their normal identity and instead shifted toward a听transit-amplifying (TA) state, meaning they multiplied rapidly but did not fully mature into functional cells. As a result, the intestinal tissue showed excessive cell growth (hyperproliferation) but poor differentiation (incomplete development into specialized cell types). The study also found disruptions in听mitochondria听(the cell鈥檚 energy producers) and听fatty acid metabolism, suggesting that energy processing problems may contribute to these abnormalities.
Importantly, similar patterns were observed in tissue samples from patients with MVID, including an expanded region of rapidly dividing cells and shortened intestinal structures (villus blunting), which impair nutrient absorption. Overall, the findings show that MYO5B plays a crucial role in maintaining healthy intestinal stem cell function, including proper cell growth, maturation, and metabolism, helping explain how its loss leads to disease.
Figure 1听Lrig1螖惭驰翱5叠听mice are a model of progressive MYO5B deficiency originating in the small intestinal crypt
(A) Experimental timeline of tamoxifen administration (TMX) on day 0 to induce the听Lrig1-Cre recombinase and the collection of intestinal tissues on days 3 and 5. MYO5B loss and corresponding YFP+ lineage cells are depicted in green.
(B) Changes in mouse body weight following TMX administration. Daily results are presented as mean 卤 SEM;听N听= 5鈥�9 mice per group.听鈭椻垪鈭椻垪p听< 0.0001 by two-way ANOVA with Tukey鈥檚 test. Asterisk colors depict significances between Lrig1螖惭驰翱5叠and M5B f/f (black) or听Lrig1-CreERT2;听M5B fl/+听(gray).
(C) Gastrointestinal tract from day 5 control and Lrig1螖惭驰翱5叠听mice. Scale bars, 1 cm.
(D) Duodenal histology with Alcian blue-PAS (AB-PAS) staining and MYO5B immunostaining (inverted). Immunostaining illustrates a decrease in targeted epithelial MYO5B expression, and unclassified non-epithelial signal is evident in MYO5B-deficient lamina propria tissues. Example crypts outlined in yellow dashes. Scale bars, 50 渭m.
(E) Quantification of crypt and villus lengths from AB-PAS-stained mouse tissues. Mean 卤 SEM;听N听= 5鈥�10 mice per group.听鈭椻垪p听< 0.01,听鈭椻垪鈭�p听< 0.001,听鈭椻垪鈭椻垪p听< 0.0001 by two-way ANOVA with Dunnett鈥檚 test vs. control. Asterisk colors indicate significances in villus (gray) or crypt (yellow) values.
(F) Immunostaining for SGLT1, YFP, and ACTG1 in the mouse duodenum. Scale bars, 50 渭m.
(G) Control (adult and pediatric) and pediatric MVID patient small intestinal tissues with multiplexed immunostaining for PCNA (proliferative marker), ACTG1 or Ezrin (brush border), CTNNB1 (basolateral membrane), DEF5A (Paneth cell), and nuclei. Scale bars, 50 渭m.