RSPO1, a potent inducer of pancreatic β cell neogenesis

Abstract

Inducing the neogenesis of pancreatic insulin-producing β cells holds great promise for diabetes research. However, non-toxic compounds with such activities remain to be discovered. Herein, we report the identification of RSPO1, a key agonist of the Wnt/β-catenin pathway, as an inducer of β cell replication. Specifically, we provide evidence that RSPO1 promotes a significant increase in β cell neogenesis in vitro, ex vivo, and in vivo. Importantly, RSPO1 administration is sufficient to activate Wnt/β-catenin signaling in β cells and counter chemically induced or autoimmune-mediated diabetes. Similarly, an optimized analog of RSPO1, allowing for weekly administration, also prevents diabetes in vivo. Lastly, the treatment of transplanted human islets with RSPO1 induces a significant 2.78-fold increase in human β cell numbers in only 60 days, these cells being functional. Such activities of RSPO1 to promote β cell neogenesis could therefore represent an unprecedented hope in the continued search for diabetes alternative therapies.

Keywords: Rspo1; Wnt/β-catenin signaling; diabetes; endocrine pancreas; islets of Langerhans; β cell replication.