Mechanisms underlying establishment of regeneration competence

Division Of Basic Sciences - Nci

Investigators

Abstract

Planarian regeneration requires adult pluripotent stem cells, the source of all new tissues, and instructive cues from pre-existing tissues to re-establish polarity, patterning, and orchestrate differentiation of missing cell types. When and how embryos acquire regenerative abilities was not known. We discovered that regeneration competence emerges gradually during embryogenesis, and that development of somatic tissue(s) necessary for context-dependent regulation of stem cell dynamics after injury is rate-limiting establishment of regenerative abilities. We observe stage- and axial position-dependent effects on regenerative abilities late in embryogenesis, culminating in the production of a fully regeneration-competent animal immediately after hatching. Regeneration-incompetent animals, while able to regenerate posterior body structures, were incapable of regenerating new anterior (head) tissue. Ongoing work suggests that stem cell specification is not rate-limiting for establishment of regeneration competence: stem cells were present, cycling, and capable of producing differentiating progeny for pre-existing tissues in regeneration-incompetent animals. We discovered that failure to reset the anterior-posterior axis underlies the head regeneration defect. RNAi knock-down of the Wnt pathway effector Beta-catenin-1 induced precocious head formation in regeneration-incompetent embryos, suggesting that high Wnt pathway activity inhibits anterior regeneration. Consistent with this result and in contrast to what was observed in regeneration-competent embryos, regeneration-incompetent embryos did not express Wnt pathway inhibitors, like notum, in anterior-facing blastemas. We are currently investigating how development of tissues that are transcriptionally responsive to wounding, including the body wall musculature, impinge on axial polarity re-establishment and acquisition of regeneration competence. Our results suggest that regeneration is regulated hierarchically, with master regulators of axial polarity governing regional patterning and organogenesis.