The mechanisms of regeneration and their evolution
Most animals are able to repair wounds and many can regenerate extensively, re-growing organs or even entire body plans from small fragments. A full understanding of the mechanisms, i.e., how wounding results in this “whole-body” regeneration, is lacking. Further, it is unknown whether regeneration mechanisms are conserved or independently evolved across diverse animal species. Thus, our lab seeks to: 1) identify cellular and genetic mechanisms for whole-body regeneration, and 2) understand how regeneration has evolved by comparing mechanisms across distantly-related animals.
The model system
Our work focuses on a new model system that enables deep mechanistic insights into the process of regeneration and facilitates comparisons of distantly related animal lineages. Our model, the acoel worm, Hofstenia miamia, a.k.a. the three-banded panther worm, belongs to a lineage (Phylum: Xenacoelomorpha) that represents the likely sister-group to all other animals with bilateral symmetry (bilaterians). Despite some debate surrounding the placement of acoels (one study placed them as closely related to echinoderms), all phylogenetic analyses agree in placing acoels as distantly-related to traditional regenerative model invertebrates such as planarians (550 mya) and hydra (650 mya).
Hofstenia presents many advantages as a model regenerative species. Adult Hofstenia regenerate robustly and harbor a large population of pluripotent stem cells call "neoblasts". Adult tissues and structures can be visualized via in situ hybridization, RNAi can be administered by injection or by soaking in dsRNA, stem cells can be isolated by FACS, and a high-quality genome assembly enables functional genomics. Hofstenia also produces accessible embryos that enable comparisons of regeneration and development, and provide a unique opportunity to use gene-delivery and genome-editing tools.
The questions and approaches
Regeneration: Whole-body regeneration in Hofstenia hinges upon several crucial events including signaling from the wound site (i.e., the wound response), proliferation of stem cells, and patterning of the newly formed cells to correctly integrate new tissue into the existing animal body plan. Seeking to understand these major aspects of regeneration, we 1) utilize functional epigenomics approaches in Hofstenia to build gene regulatory networks for launched upon the initiation of regeneration, 2) utilize single-cell RNA-sequencing data from developing embryos and adult worms to identify regulators of stem cells in Hofstenia, and 3) investigate pathways that reestablish patterning information in regenerating worms and direct the correct differentiation of new tissue.
Development: The accessible embryos of Hofstenia provide an opportunity to assess how similar or different regenerative pathways are to developmental ones. Further, as acoels, Hofstenia embryos are relevant for many questions in the field of evolutionary developmental biology, such as the evolution of bilateral symmetry, mesoderm, or centralization of the nervous system. We are studying embryonic development in Hofstenia using a multitude of approaches, including lineage tracing, in situ hybridization, and single-cell sequencing.