Human organs and tissues can be irreversibly damaged by aging, disease, and trauma, reducing lifespan and leading to exorbitant health care costs. Although humans' ability to regenerate damaged tissues is limited, some animals possess extensive regenerative capacity, and can repair or completely replace injured limbs and organs. Successful regeneration requires the early and dramatic upregulation of proliferation by progenitor cells responsible for new tissue production. However, the identities of signals that promote proliferation, their roles in homeostatic maintenance and activation of progenitor cells, and the mechanisms that modulate expression of these pro-regenerative cues in response to injury, are poorly understood. The freshwater flatworm (planarian) Schmidtea mediterranea is an ideal, tractable model in which to address these problems, because of its rapid regeneration time, and available functional genomics tools (e.g., a sequenced genome and RNA interference). In planarians, surgical amputation induces proliferation of pluripotent somatic stem cells called neoblasts, which completely regenerate damaged organs within ten days, even in small tissue fragments. Recently, while investigating intestinal regeneration, we identified a conserved, intestine-enriched transcription factor, nkx2.2, that was unexpectedly required not only for intestinal regeneration, but also for neoblast proliferation and regeneration of other organs. Subsequently, we have identified ~70 intestine- enriched, nkx2.2-dependent transcripts encoding secreted proteins, solute carriers, ion channels, and metabolic factors, including paralogs of apolipoprotein B (apoB), a regulator of lipoprotein particle secretion. Based on these observations, we hypothesize that the intestine non-autonomously controls regeneration via Nkx2.2-dependent regulation of secreted paracrine factors and transcriptional injury responses required for neoblast proliferation.
In Aim 1, we will test whether ApoB delivers lipids to neoblasts as a requirement for proliferation and tissue repair.
In Aim 2, we will determine if paracrine regulation of proliferation is homeostatic or regeneration-specific, and identify novel regulators of neoblast proliferation.
In Aim 3, we will determine whether Nkx2.2 coordinates early injury-responsive gene expression programs in the intestine. Our long-term goal is to understand the mechanisms that drive successful tissue regeneration. Our work capitalizes on planarians' unique biology, and couples functional genomics resources with innovative tissue isolation strategies developed by our laboratory to understand how paracrine cues control tissue repair, and how tissue damage is transduced into gene expression changes required for regeneration. Long term, these insights are expected to provide avenues for improving regeneration of human organs, and for controlling dysregulated proliferation in human diseases like cancer.
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