Colonic CD90+ Crypt Fibroblasts Secrete Semaphorins to Support Epithelial Growth

Abstract

Summary: Intestinal epithelial cells have a defined hierarchy with stem cells located at the bottom of the crypt and differentiated cells more at the top. Epithelial cell renewal and differentiation are strictly controlled by various regulatory signals provided by epithelial as well as surrounding cells. Although there is evidence that stromal cells contribute to the intestinal stem cell niche, their markers and the soluble signals they produce have been incompletely defined. Using a number of established stromal cell markers, we phenotypically and functionally examined fibroblast populations in the colon. CD90+ fibroblasts located in close proximity to stem cells in vivo support organoid growth in vitro and express crucial stem cell growth factors, such as Grem1, Wnt2b, and R-spondin3. Moreover, we found that CD90+ fibroblasts express a family of proteins—class 3 semaphorins (Sema3)—that are required for the supportive effect of CD90+ fibroblasts on organoid growth. : Stem cell proliferation is dependent on regulatory signals from surrounding cells, including stromal cells. Karpus et al. identify a membrane marker, CD90, that specifically marks stem cell niche fibroblasts in the colon. CD90+ fibroblasts produce class 3 semaphorins that promote stem cell proliferation via the Nrp2 receptor. Keywords: colon, intestine, stem cell, niche, fibroblast, stroma, Gli1, CD90, semaphorin, Nrp2