Project description:Remarkable progress has been made in cell fate reprogramming by forced expression of a small number of transcription factors. Major challenges remain, however, in regenerative medicine regarding how to target multiple cell types and direct them to form a functional organ in vivo. Here, we demonstrate that, by changing their stromal microenvironment, adult differentiated cells of endodermal origin can be reprogrammed to generate a functional ectodermal organ. The process of organ regeneration is highly efficient and complete, and depends on epithelial-stromal interactions that lead to successful remodeling of the extracellular matrix and stromal cells that are essential for organ function. Furthermore, it is a multistep process consisting of changes in cell fate, where dedifferentiation occurs more rapidly than redifferentiation, and subsequent morphogenetic reprogramming. Remarkably, neither direct transdifferentiation nor a complete reversion to the pluripotency state is involved in the reprogramming process; instead it features dynamic activities of essential genes that regulate pluripotency and lineage development. Our data have important implications for stem cell biology, cancer biology, and regenerative medicine.
Project description:Remarkable progress has been made in cell fate reprogramming by forced expression of a small number of transcription factors. Major challenges remain, however, in regenerative medicine regarding how to target multiple cell types and direct them to form a functional organ in vivo. Here, we demonstrate that, by changing their stromal microenvironment, adult differentiated cells of endodermal origin can be reprogrammed to generate a functional ectodermal organ. The process of organ regeneration is highly efficient and complete, and depends on epithelial-stromal interactions that lead to successful remodeling of the extracellular matrix and stromal cells that are essential for organ function. Furthermore, it is a multistep process consisting of changes in cell fate, where dedifferentiation occurs more rapidly than redifferentiation, and subsequent morphogenetic reprogramming. Remarkably, neither direct transdifferentiation nor a complete reversion to the pluripotency state is involved in the reprogramming process; instead it features dynamic activities of essential genes that regulate pluripotency and lineage development. Our data have important implications for stem cell biology, cancer biology, and regenerative medicine.
Project description:Some mammalian tissues can replace lost cells within one lineage, but organ-level regeneration—restoring diverse cell types across lineages—remains rare. Here we show that late embryonic full-thickness skin injuries heal by regenerating epithelial, mesenchymal, neuronal, and vascular lineages with proper connectivity. However, this ability is lost soon after birth, leading to a failure to restore most cell types and hyperinnervation of the wound bed. Single-cell sequencing identified a postnatal wound-specific fibroblast (PWF) population absent after embryonic wounding. Through an in vivo screen, we discovered three PWF-enriched genes—Timp1, Cxcl12, and Ccl7—that inhibit organ-level regeneration and cause hyperinnervation when overexpressed in embryonic wounds. Reducing hyperinnervation by depleting Cxcl12 in fibroblasts or inhibiting synaptic release enables postnatal skin to regenerate diverse lineages after injury. Our study identifies mechanisms transitioning an organ from regenerative to non-regenerative, discovers fibroblast-driven hyperinnervation as a key barrier, and demonstrates removing this barrier unlocks organ-level regeneration.