Hedgehog fuels gut regeneration

The intestinal epithelia rely on resident stem cells to undergo homeostatic growth as well as tissue repair upon injury. In response to insults elicited by pathological bacterial infection or tissue damaging chemicals such as dextran sodium sulfate (DSS), intestinal stem cells (ISCs) speed up their proliferation and differentiation to effectively replenish lost cells. Despite numerous studies, the regulatory mechanisms underlying the control of stem cell activity during homeostasis and regeneration still remain poorly understood. The Hedgehog (Hh) pathway governs animal development in species ranging from fruit fly to human. In additional to their role as morphogen to control cell differentiation and pattern formation in embryonic development, the secreted Hh glycoproteins also function as mitogen to regulate cell proliferation in adult tissue homeostasis and tumorigenesis [1]. Hh signaling has been implicated in tissue repair in organs including lung, prostate, pancreas, liver, bladder, skin, and bone. With few exceptions, the precise locations where Hh signaling acts and the downstream genes mediating the effect of Hh signaling have remained largely unknown. Drosophila adult midgut provides a powerful system to address these problems because sophisticated genetic tools are available to allow the manipulation of gene function in any cell types within the intestinal epithelia as well as in surrounding tissues. Our recent study, which was published in The Journal of Cell Biology, established a critical role of Hh signaling in the regulation of regenerative stem cell proliferation in Drosophila adult midguts [2]. Similar to mammalian intestines, Drosophila midguts constantly turn over and are replaced by new cells derived from ISCs localized at the base of the epithelia. ISCs divide to produce themselves and enteroblasts (EBs) that subsequently differentiate into more specialized cell types. Previous studies revealed that ISC proliferation was elevated upon intestinal injury caused by DSS feeding [3]. Here we found that DSS increased the production of Hh ligand in multiple cell types including precursor cells (ISCs plus EBs) and enterocytes but Hh pathway activity was only elevated in precursor cells. Depleting Hh from the precursor cells but not from the enterocytes blocked DSS-stimulated ISC proliferation, suggesting that local Hh production is critical for stimulating ISC proliferation. Surprisingly, we found that blocking Hh pathway activity in EBs but not in ISCs affected DSS-induced ISC proliferation, suggesting that Hh signaling didn't drive ISC proliferation by acting directly on the stem cells themselves but rather by acting on the neighboring EBs. In corroborating with this …