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Scott Stewart

Scott Stewart

Research Assistant Professor, Biology
Associate Member, IMB

Ph.D., Biological Chemistry, University of Michigan
B.S., Biochemistry, University of Washington

Email
Office: 269A Klamath Hall
Office Phone: 541-346-9180

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Research Interests

Our long-term goals are to understand the molecular mechanisms that enable zebrafish to regenerate tissues and organs after severe damage, thereby gaining knowledge to rationally design new therapeutics to treat bone maladies. Bone disease and fractures are among the most common, debilitating, and costly human health concerns. While human bone can imperfectly repair, we cannot regenerate lost or severely fractured bones and our capacity for bone repair greatly diminishes with age and disease, such as diabetes. In contrast, throughout their life zebrafish completely regenerate damaged or lost bones after caudal fin amputation, providing an example of innate, perfect bone regeneration that could be recapitulated as a therapeutic strategy. Adult fins comprise multiple cell types, including bone-producing osteoblasts, fibroblasts, endothelial cells, neurons, and epidermal cells (Fig. 1). Following amputation, regeneration of the lost tissue is driven by lineage-restricted progenitors generated by dedifferentiation of mature cells near the injury site. Each of these cell types, and their derived tissues, then regenerate in concert after amputation resulting in a new fin. Though significant progress in the field has been made over the last decade, we still lack answers to the oldest, most basic and pressing questions: A) what triggers regeneration, B) how does the fin “know” when to stop regenerating, and C) why don’t humans regenerate appendages like zebrafish?
Stewart research: zebrafish fin regeneration
Fig. 1. Zebrafish fin regeneration. After fin amputation, epidermal cells migrate to seal the wound. At 24 hours post amputation (hpa), cells near the site of damage dedifferentiate to lineage-restricted progenitors, and by 48 hpa, these cells populate the tissue distal to the amputation site forming the blastema. During regenerative outgrowth (4- 14 days), a balance of cell proliferation, progenitor maintenance, and redifferentiation results in regeneration of the lost tissue.
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 (Fig. 2). 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.
 Wnt produced by the RPN orchestrates bone regeneration
Fig. 2. Wnt produced by the RPN orchestrates bone regeneration. Following fin amputation, mature osteoblasts dedifferentiate resulting in the generation of Runx2+ pObs (in pink) that are maintained in a self-renewing mesenchymal state by Wnt signals produced by Dach+ RPN cells (green). BMP2b induces differentiation of proximal Runx2+ cells to Runx2+/sp7+ cells (orange), and finally mature sp7+ cells (blue). Dkk1b produced by differentiating osteoblasts in response to BMP serves as negative feedback to further inhibit Wnt.

Recent publications

(pulled from pubmed)

Recent publications

(pulled from pubmed)

Spatial and temporal control of transgene expression in zebrafish.
Akerberg AA, Stewart S, Stankunas K
PloS one 2014
Sequential and opposing activities of Wnt and BMP coordinate zebrafish bone regeneration.
Stewart S, Gomez AW, Armstrong BE, Henner A, Stankunas K
Cell reports 2014
A histone demethylase is necessary for regeneration in zebrafish.
Stewart S, Tsun ZY, Izpisua Belmonte JC
Proceedings of the National Academy of Sciences of the United States of America 2009
Bioelectricity and epimorphic regeneration.
Stewart S, Rojas-Muñoz A, Izpisúa Belmonte JC
BioEssays : news and reviews in molecular, cellular and developmental biology 2007