PDGF Facilitates Direct Lineage Reprogramming of Hepatocytes to Functional beta-Like Cells Induced by Pdx1 and Ngn3

摘要

Islet transplantation has been proven to be an effective treatment for patients with type 1 diabetes, but a lack of islet donors limits the use of transplantation therapies. It has been previously demonstrated that hepatocytes can be converted into insulin-producing beta-like cells by introducing pancreatic transcription factors, indicating that direct hepatocyte reprogramming holds potential as a treatment for diabetes. However, the efficiency at which functional beta-cells can be derived from hepatocyte reprogramming remains low. Here we demonstrated that the combination of Pdxl and Ngn3 can trigger reprogramming of mouse and human liver cells to insulin-producing cells that exhibit the characteristics of pancreatic beta-cells. Treatment with PDGF-AA was found to facilitate Pdxl and Ngn3-induced reprogramming of hepatocytes to beta-like cells with the ability to secrete insulin in response to glucose stimulus. Importantly, this reprogramming strategy could be applied to adult mouse primary hepatocytes, and the transplantation of beta-like cells derived from primary hepatocyte reprogramming could ameliorate hyperglycemia in diabetic mice. These findings support the possibility of developing transplantation therapies for type 1 diabetes through the use of beta-like cells derived from autologous hepatocyte reprogramming.