Takahiro Ohara

  • Torrance, CA

  • California-Los Angeles, U. of (2012)

  • Immunology

  • Thaddeus S. Stappenbeck, Ph.D., M.D.

  • Dynamics of epithelial differentiation following intestinal villus injury

  • oharat@wustl.edu

Research

Millions of finger-like structures called villi line the small intestine, providing an enormous


surface area for rapid and efficient nutrient absorption. Collapse of the villus architecture, known


as villus atrophy, is often observed in response to pathogen invasion, inflammation, medications,


and ischemia due to loss of intestinal epithelial cells, resulting in symptoms of diarrhea and


malabsorption. Though removal of the inciting agent generally allows for near complete tissue


recovery, some individuals take longer to restore their villi, a condition known as persistent


villus atrophy, for reasons that are unknown. How intestinal villi cope with tissue damage and re-


establish their structure remains poorly understood, yet their capacity to do so is vital for


survival. For my thesis work, I developed a robust and highly reproducible injury-repair model that specifically targets the villus compartment of the small intestine. This system, which entails a single intraperitoneal injection of the double-stranded RNA analog poly(I:C) in mice, mimics key aspects of acute viral gastroenteritis and displays a consistent repair and regeneration pattern


following injury. Using this model, I identified a transient, damage-induced epithelial cell type


covering the surface of atrophic villi. Intriguingly, these atrophy-induced villus epithelial cells (aVECs) possessed a fetal-like transcriptional profile, yet were terminally differentiated and lineage-committed. The primary function of aVECs was to quickly re-establish the intestinal barrier after villus damage. I further determined yes-associated protein (YAP), one of the major transcriptional mediators of the Hippo signaling pathway, as a crucial regulator of aVEC function. In the absence of YAP, aVECs were unable to properly restore the intestinal barrier post-injury. As a result, villus regeneration was markedly hampered in YAP-deficient mice. Finally, I found evidence of aVEC-like cells in human disease states with villus injury, such as Crohn’s and celiac disease. Given that aVECs were derived from progenitor cells in the crypt, I defined a key repair mechanism involving the activation of a fetal-like program during injury- induced differentiation, a process I term “adaptive differentiation”. Thus, I propose adaptive differentiation as an important healing mechanism in high turnover tissues such as the intestine.

Graduate Publications:

Murray E, Cheng X, Krishna A, Jin X, Ohara TE, Stappenbeck TS, Bose R. 2021 HER2 and APC mutations promote altered crypt-villus morphology and marked hyperplasia in the intestinal epithelium. Cell Mol Gastroenterol Hepatol, ():S2352-345X(21)00083-7.

Verma MS, Fink MJ, Salmon GL, Fornelos N, Ohara TE, Ryu SH, Vlamakis H, Xavier RJ, Stappenbeck TS, Whitesides GM. 2018 A Common Mechanism Links Activities of Butyrate in the Colon. ACS Chem Biol, 13(5):1291-1298.

Last Updated: 5/31/2018 4:07:05 PM

Back to top