Susan Bonner-Weir, Ph.D.
The main goal of our group is to understand the mechanisms of pancreatic growth after birth in order to regulate generation of new beta cells and expansion of beta cells for regenerative purposes. Over the years our research has focused on the endocrine pancreas (the islets of Langerhans) in three main areas: 1) the architecture of the islet and its implications for function; 2) the in vivo regulation of beta-cell mass; and 3) the factors involved in islet growth and differentiation. We provided the first strong evidence of multipotent progenitor cells in the adult pancreatic ducts, first in transgenic mice over-expressing transforming growth factor-alpha, second in the partial pancreatectomy model, and third in cultured islet-depleted human pancreatic tissue, and more recently, lineage tracing experiments showing the ductal origin of the new islets formed after birth. This pathway of pancreatic growth after birth has important implications for understanding the mechanisms of response to injury and neoplasia of the pancreas as well as providing possible new insights into the pathogenesis of diabetes and new directions for therapy.
The current areas of interest include:
1. Defining the cells in the duct that can give rise postnatally to new islets.
Our studies on the pancreatic regeneration after partial pancreatectomy in the adult rat defined two pathways of new β cell formation in postnatal life: replication of preexisting beta cells and differentiation from progenitors/stem cells (neogenesis). Focusing on the progenitors for the neogenesis, our hypothesis has been that in the adult pancreas duct cells act as progenitors, such that with replication the mature duct cell regresses to a less differentiated cell (perhaps equivalent to a embryonic pancreatic duct cell) and regains its potential to differentiate into islet, acinar or mature duct cell, and that this differentiation is directed by external signals or morphogens. We are defining the cells that are involved and the factors that are carefully orchestrated in vivo to stimulate the growth and differentiation of the beta cells. This project entails the use of duct specific Cre mice, surgical models of regeneration, characterization of different subpopulations of ductal cells from rodents and humans and determining their potential to differentiate into islet cells.
2. Understanding the phenotypic basis of functional heterogeneity among beta cells whether normal, immature or dysfunction due to glucose toxicity.
We have been interested in the specializations that determine the beta cell phenotype. Recently we have shown that neonatal beta cells have a very different phenotype than adult beta cells and are functionally immature and that the transcription factor MafA is key to their functional maturation. Consistent with this, beta cells can be made dysfunctional by knocking down MafA. We are defining the physiological factors that regulate the maturation process in vivo so that we can mimic the maturation process in vitro for use with human ES/iPS derived cells. Additionally we are examining how the repression of selected genes modulates this maturation process.
3. Understanding how the human pancreas responds to the demand for more beta cells.
As we learn more about the mechanism of growth and differentiation in the rodent pancreas, it is critical that we assess whether the same mechanisms are involved in human tissue. We study pancreas from non-diabetic and long-term diabetic humans to answer to such questions.
Dr. Bonner-Weir is Senior Investigator in the Section on Islet Transplantation and Cell Biology at Joslin and Professor of Medicine at Harvard Medical School. Dr. Bonner-Weir received her doctorate in biology at Case Western Reserve University and then completed postdoctoral training in islet morphology at Harvard Medical School. She serves or has served on the editorial boards of the American Journal of Physiology, Journal of Biological Chemistry, Endocrinology, Cell Transplant, and Diabetes. She is or has been a member of the grant review panels for the NIH, Juvenile Diabetes Research Foundation, the American Diabetes Association, the California Institute of Regenerative Medicine, and the European Research Council.