Dual role of BMP signaling in the regulation of Drosophila intestinal stem cell self-renewal

Abstract

Many adult organs including Drosophila adult midguts rely on resident stem cells to replenish damaged cells during tissue homeostasis and regeneration. Previous studies have shown that, upon injury, intestinal stem cells (ISCs) in the midguts can increase proliferation and lineage differentiation to meet the demand for tissue repair. Our recent study has demonstrated that, in response to certain injury, midguts can expand ISC population size as an additional regenerative mechanism. We found that injury elicited by bleomycin feeding or bacterial infection increased the production of two BMP ligands (Dpp and Gbb) in enterocytes (ECs), leading to elevated BMP signaling in progenitor cells that drove an expansion of ISCs by promoting their symmetric self-renewing division. Interestingly, we also found that BMP signaling in ECs inhibits the production of Dpp and Gbb, and that this negative feedback mechanism is required to reset ISC pool size to the homeostatic state. Our findings suggest that BMP signaling exerts two opposing influences on stem cell activity depending on where it acts: BMP signaling in progenitor cells promotes ISC self-renewal while BMP signaling in ECs restricts ISC self-renewal by preventing excessive production of BMP ligands. Our results further suggest that transient expansion of ISC population in conjunction with increasing ISC proliferation provides a more effective strategy for tissue regeneration.

Keywords: BMP; Dpp; Gbb; ISC; N; Niche; Smad; adult stem cell; asymmetric division; differentiation; injury; midgut; proliferation; regeneration; self-renewal; signaling; symmetric division.

Figure 1.

Injury stimulated and self-restrained BMP signaling regulates stem cell pool size by antagonizing N. (A) Dpp and Gbb are produced by ECs. Basal secretion coupled with basement membrane (BM) trapping sets up an apical-basal BMP activity gradient consisting of Dpp-Gbb heterodimers. (B) After an apical basal division, the two ISC daughter cells are initially equivalent with respect to N signaling. However, the basally localized cell transduces higher level of BMP signaling activity than the apical one to inhibit N and upregulate Dl. The initial small difference in N pathway activity is amplified by feedback mechanisms, leading to unidirectional N signaling and bistable cell choice with the basal cell sending the N signal and becoming ISC whereas the apical one transducing N signal and differentiating into EB. (C) Injury stimulates the production of BMP in ECs that activates Mad in progenitor cells to promote symmetric self-renewal division, leading to an expansion of ISC pool size. Elevated BMP signaling in ECs inhibits ligand production to reset ISC homeostasis. (D) Transient expansion of ISC by increasing the symmetric self-renewing division followed by excessive symmetric differentiation division (plastic division mode) produces more new cells in given rounds of division compared with the condition where ISCs undergo strictly asymmetric division (fixed division mode). BM, basement membrane; VM, visceral muscle. Adapted from Tian et al.