Epithelial and Mesenchymal Contribution to the Niche: A Safeguard for Intestinal Stem Cell Homeostasis

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The intestinal stem cell (ISC) niche is a highly complex microenvironment that supports stem cell maintenance and precisely orchestrates the balance between proliferation and differentiation. Here, multiple signaling molecules emanating from both the underlying mesenchyme and crypt-based epithelial cells cooperate to govern stem cell homeostasis (Figure 1). Understanding the cellular and molecular constituents of the niche is of critical importance to harness stem cells for tissue regeneration and to elucidate disease mechanisms. The conserved Wnt, Notch and epidermal growth factor (EGF) signaling pathways are identified regulators of stem cell behavior, however resolution of the cellular players and the impact of signaling molecules on different progenitor populations residing within the niche remain poorly understood. In this issue of Gastroenterology, a group led by Hans Clevers (Farin et al.)[1] specifically address the niche requirement of Paneth cell (PC)-derived Wnt3 in mediating intestinal homeostasis. Analysis of Wnt3-null epithelia in both in vivo, and in vitro cultures resulted in no apparent effect within the intact small intestine, but lack of growth in the culture system. While PCs have been defined to express Wnt6 and 9b in vivo, PCs did not express adequate levels to rescue the phenotype in vitro; instead, addition of the mesenchymally-expressed Wnt2b ligand supported enteroid growth. These findings highlight the robust compensatory signaling support provided by the underlying mesenchymal niche cells despite loss of an epithelial Wnt source. Figure 1 Comparison of in vivo (left) and in vitro (right) signaling support to the intestinal stem cell. Signaling networks between the Paneth cell and stem cell appear to be broadly conserved. However, disruption on one element of a single pathway highlights ...