Methods for repopulating the pancreas with new insulin-producing cells have strong potential for therapy in diabetes. Recently, we have found that inhibition of serpinB13 - a protease inhibitor of cathepsin L (catL) - with mAb in mouse embryos leads to a robust increase in the number of pancreatic Ngn3+ progenitor cells, significant expansion of islet mass, and improved resistance to severe diabetes in adulthood. To unveil the molecular mechanism of the augmented Ngn3+ cell response following inhibition of serpinB13 during gestation, we focused on the Notch communication system - a critical signaling pathway for pancreatic development. We found that serpinB13 is expressed and secreted by epithelial cells in murine embryonic pancreases. Moreover, in vivo and in vitro inhibition of serpinB13 during embryogenesis caused protease-dependent cleavage of the extracellular domain of Notch1 receptor in the pancreas (p<0.0001). This partial loss of the extracellular Notch was followed by decreased translocation to the nucleus of active Notch intracellular domain (aNICD), a fragment of Notch that is critical for restraining endocrine cell development. Finally, embryonic pancreases of mice with genetic deficiency of catL had significantly fewer Ngn3+ cells compared with wild type controls. Together, our data point to a novel function of serpinB13 in maintaining Notch receptor-mediated repression of pancreatic endocrine progenitors. Consequently, the perturbation of this effect of serpinB13 enables protease activity to partially dismantle Notch signaling, thereby allowing for more efficient development of Ngn3+ progenitors cells and a subsequent increase in islet mass.


Y. Kryvalap: None. C. Hendrickson: None. J. Czyzyk: None.


American Diabetes Association (1-17-ICTS-083 to J.C.)

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