Institute of Molecular Biology
We are interested in discovering why select animals, unlike humans, exhibit a truly remarkable capacity for organ and tissue regeneration. For instance, although human bone can imperfectly repair itself, we cannot replace lost or severely fractured bones and bone repair capacity greatly diminishes with age. In contrast, zebrafish completely regenerate damaged or lost bones, regardless of age, providing an example of innate, perfect bone regeneration that could be recapitulated as a therapeutic strategy. A major focus of our current research is a detailed understanding of the molecular and cellular mechanisms that underlie the ability of zebrafish to regenerate bone. We use an array of cellular and molecular approaches to tackle these problems.
Our recent work in collaboration with the Stankunas lab demonstrated zebrafish bone regeneration is driven by lineage-restricted osteoblast progenitors (pObs) generated by dedifferentiation of mature osteoblasts at the site of injury. Following dedifferentiation, coordinated Wnt and Bone Morphogenetic Protein (BMP) signaling directs pObs to self-renew and redifferentiate, respectively, to progressively re-form the bony fin rays. BMP-dependent osteoblast re-epithelialization and maturation is lineage-intrinsic while the Wnt ligands that maintain pObs are lineage-extrinsic, produced by a specialized group of neighboring non-osteoblast cells, the Regenerating Fin Progenitor Niche (RPN). Therefore, supplying damaged human bone with an RPN-like niche or recapitulating its activities are attractive strategies to enhance bone healing. However, the cells, transcriptional regulators, and signaling networks that comprise and control the RPN are unknown. Further, it is unknown how Wnt mechanistically maintains a pOb progenitor pool. Current projects in the lab include: 1) Determining the cellular origins, organization, and fate of the RPN. 2) Determining transcription factor networks that define the RPN, and 3) Identifying how Wnt maintains pObs as a self-renewing, mesenchymal population.
Zebrafish bone regeneration. Runx2+ osteoblasts (in pink) are maintained in a self-renewing mesenchymal state by Wnt signals secreted by niche cells (RPN, green cells). BMPs induce differentiation of proximal Runx2+ cells to Runx2+/sp7+ cells, and finally mature sp7+ cells. Adapted from Stewart, 2014.
(pulled from pubmed)