Islet neogenesis: a possible pathway for beta-cell replenishment

Susan Bonner-Weir, Lili Guo, Wan-Chun Li, Limor Ouziel-Yahalom, Philippe Lysy, Gordon C. Weir, Arun Sharma

Joslin Diabetes Center, Department of Medicine, Harvard Medical School Boston, MA, USA

Abstract

Diabetes, particularly type 1 diabetes, results from the lack of pancreatic beta-cells. Beta-cell replenishment can functionally reverse diabetes but two critical challenges face the field: 1) the immunological one of protecting the new beta-cells from autoimmunity and allo-rejection, and 2) developing a supply of beta-cells that are readily available and reliably functional. This chapter will examine the potential of endogenous replenishment of pancreatic beta-cells as a possible tool therapeutically if the autoimmunity could be blunted. Two pathways for endogenous replenishment exist in the pancreas: replication and neogenesis (defined as the formation of new islet cells from pancreatic progenitor/stem cells). These pathways of beta-cell expansion are not mutually exclusive and both occur in embryonic development, in postnatal growth, and in response to some injuries. Since the beta-cell population is dramatically reduced in the pancreas of type 1 diabetes with only a small fraction of the beta-cells surviving years after onset, replication of preexisting beta-cells would not be a reasonable start for replenishment. However induction of neogenesis could provide a starting population that could be further expanded by replication. Neogenesis is widely accepted as occurring for the initial embryonic formation of the endocrine pancreas but its occurrence anytime after birth has become controversial due to discordant data from lineage tracing experiments. However, the concept was built upon many observations from different models and species over many years. Herein we discuss the role of neogenesis in normal growth and regeneration as learned from rodent models, followed by an analysis of what has been found in humans.