Re-expression of YAP for beta-cell regeneration; beta-reYAP

• Applicant: Kathrin Maedler, Ph.D.
• Subject Area: Endocrinology, Diabetology, Metabolism
• Term: since 2023
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 529558957

Both type 1 diabetes (T1D) and type 2 diabetes (T2D) result from a decline in functional pancreatic β-cells. A major objective is to develop therapeutic targets to regain, restore and maintain functional β-cell mass in patients with diabetes. Establishing the β-cell regenerative capacity represents an attractive therapeutic approach. In this project, we aim to establish YAP, a regulator within the Hippo signaling pathway, as tool to promote β-cell regeneration and to restore functional pancreatic β-cells. As suggested by its name “Hippo”potamus, this pathway regulates cell and organ size during development. YAP is highly expressed in pre-pancreatic cells during development, which have a high capacity to grow and proliferate. However, at the time when the β-cell arises, YAP is switched OFF, which correlates with an extremely low rate of proliferation of endocrine cells in pancreatic islets. We have shown the robust pro-proliferative and anti-apoptotic function of YAP in human β-cells, which is accompanied with full preservation of insulin secretory function and β-cell identity genes. Consistently, β-cell specific YAP-overexpressing mice showed dramatic induction in β-cell proliferation, together with a remarkable β-cell mass expansion. In this project, we 1stly aim to establish the specific stages and timing of YAP induced β-cell regeneration/ functionality in vitro (human isolated islets) and in vivo. We will determine whether YAP re-expression is able to induce β-cell proliferation and islet mass expansion and correct glucose homeostasis in vivo in mice with a severely diabetic background. 2ndly, on the basis of our findings, we will establish a pharmaceutical tool, namely by the YAP/TAZ-TEAD activator TT-10, which has already shown great potential for rodent and human β-cell proliferation in vitro. This effect will be further mechanistically characterized in vitro and in vivo in order to establish a β-cell regeneration therapy. 3rdly, in order to tackle YAP as safe β-cell regenerative tool in mature β-cell, one needs to understand its mechanisms when re-expressed in the mature β-cell and thus identify the “transcriptional signature” of YAP-expressing β-cells; to correlate levels of cellular YAP expression with cell cycle and survival genes and -on the other hand- functionality and maturity of β-cells within the pancreatic islets, which is of utmost importance for the safety of a potential pharmacologic target. With our strategy of transient YAP expression in mature β-cells, we anticipate and hope -at the end of this project- to have an efficient tool for tunable, controllable and adjustable regeneration of mature β-cells for diabetes therapy. YAP expression will turn β-cells for a short time into a rare pro-β-like cell type, still with remaining functionality, but capable of proliferation. With these investigations we hope to restore the β-cells in the pancreas, insulin secretion and normoglycemia in T1D and T2D.

• DFG Programme: Research Grants
• International Connection: Israel
• International Co-Applicant: Professor Dr. Dan Mishmar