Helminths hijack the TGFβ receptor to promote a pro-regenerative program in the intestinal stem cell compartment

The intestine is a multifunctional tissue relying on multipotent stem cells to establish a repertoire of epithelial cell lineages. We have previously shown that the enteric parasitic nematode Heligmosomoides polygyrus bakeri (Hpb) directly regulates the intestinal stem cell compartment, tuning the epithelium to a regenerative fetal-like state, marked by the expansion of Clusterin-expressing revival stem cells (revSCs) and inhibiting goblet and tuft cell differentiation. However, the host signaling pathway driving this response remained obscure. Here, we demonstrate that TGFβ receptor (TGFβR) engagement is critical for helminth-induced epithelial reprogramming. Specifically, we show that Hpb induces potent epithelial TGFβR signaling in both mouse and human intestinal epithelium and that Hpb-mediated revSC expansion is TGFβR-dependent. In addition, we show that the loss of TGFβR signaling in the intestinal epithelium enhances goblet cell expansion while compromising Hpb egg production. Finally, we identify the TGFβ mimic, TGM, as the Hpb-secreted protein responsible for the induction of the fetal-like transcriptional program and revSC expansion. Collectively, our study reveals how a parasitic helminth hijacks epithelial TGFβR signaling to expand a pro-regenerative stem cell population and support host-helminth mutualism.