The overall goal of this proposal is to identify means for improving ?-cell regeneration in the adult pancreas. With previous BCBC funding we have developed a transgenic model of inducible total or partial ?-cell ablation (RIP-DTR). In these mice, ?-cell regeneration occurs after near total ?-cell loss, and this relies on the transdifferentiation of adult mature ?-cells to ?-cells. In this proposal we will test, among different aspects, i) whether ?-cell regeneration in RIP-DTR mice can be enhanced by promoting the observed spontaneous ?-to-?-cell conversion. ?-cell regeneration occurs by ?-cell replication in other diabetes models of less severe ?-cell ablation. Regeneration in RIP-DTR mice is less efficient than in these mouse models probably because DT treatment leaves almost no ?-cells (DT stands for diphtheria toxin, the agent used to induce ?-cell ablation in these mice). Accordingly, ?-cell repopulation principally occurs in RIP-DTR mice by a mechanism of ?-cell reprogramming. One of our objectives will be ii) to determine if age plays a role in ?-cell regeneration / ?-cell reprogramming , since proliferation in islets has been shown to profoundly decline in older rodents and humans. In addition, we will examine the molecular mechanisms controlling ?- to ?-cell transdifferentiation in RIP-DTR mice. These analyses will be performed in parallel with studies aimed at iii) exploring whether cell fate reprogramming is a common feature of different adult pancreatic cell types, and is not restricted to ? - cells only. The heterologous origin of new ?-cells is particularly interesting, since the almost complete ?-cell depletion achieved in RIP-DTR mice recreates a condition very similar to the situation found in Type 1 diabetic patients.

Public Health Relevance

Understanding the mechanisms of ?-cell regeneration and identifying the cells and factor(s) that enhance the formation and/or growth and/or survival of ?-cells should have a high impact on the development of new treatments for human T1D.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Project--Cooperative Agreements (U01)
Project #
Application #
Study Section
Special Emphasis Panel (ZDK1-GRB-G (M3))
Program Officer
Sato, Sheryl M
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
University of Geneva
Zip Code
Cigliola, Valentina; Ghila, Luiza; Thorel, Fabrizio et al. (2018) Pancreatic islet-autonomous insulin and smoothened-mediated signalling modulate identity changes of glucagon+ ?-cells. Nat Cell Biol 20:1267-1277
Damond, Nicolas; Thorel, Fabrizio; Kim, Seung K et al. (2017) Dnmt1 activity is dispensable in ?-cells but is essential for ?-cell homeostasis. Int J Biochem Cell Biol 88:226-235
Matsuoka, Taka-Aki; Kawashima, Satoshi; Miyatsuka, Takeshi et al. (2017) Mafa Enables Pdx1 to Effectively Convert Pancreatic Islet Progenitors and Committed Islet ?-Cells Into ?-Cells In Vivo. Diabetes 66:1293-1300
Cigliola, V; Thorel, F; Chera, S et al. (2016) Stress-induced adaptive islet cell identity changes. Diabetes Obes Metab 18 Suppl 1:87-96
Chera, Simona; Herrera, Pedro L (2016) Regeneration of pancreatic insulin-producing cells by in situ adaptive cell conversion. Curr Opin Genet Dev 40:1-10
Chera, Simona; Baronnier, Delphine; Ghila, Luiza et al. (2014) Diabetes recovery by age-dependent conversion of pancreatic ?-cells into insulin producers. Nature 514:503-7
Schaffer, Ashleigh E; Taylor, Brandon L; Benthuysen, Jacqueline R et al. (2013) Nkx6.1 controls a gene regulatory network required for establishing and maintaining pancreatic Beta cell identity. PLoS Genet 9:e1003274