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

Abstract

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 b-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 b-cells can be derived from hepatocyte reprogramming remains low. Here we demonstrated that the combination of Pdx1 and Ngn3 can trigger reprogramming of mouse and human liver cells to insulin-producing cells that exhibit the characteristics of pancreatic b-cells. Treatment with PDGF-AA was found to facilitate Pdx1 and Ngn3-induced reprogramming of hepatocytes to b-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 b-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 b-like cells derived from autologous hepatocyte reprogramming.

Diversity of dermal fibroblasts as major determinant of variability in cell reprogramming

“…Notably, the release of the EGF, proved to be an enhancer of fibroblast proliferation and, as consequence, of impairing cell reprogramming, was significantly lower in culture of slow‐proliferating dermal fibroblast from abdominal skin and significantly higher in culture of fast‐proliferating fibroblasts from arm skin. On the contrary, the release of growth factors known to be inducers of cell reprogramming, like GM‐CSF, HGF, PDGF and VEGF resulted significantly higher in dermal fibroblasts from abdominal skin (Figure ). Furthermore, as reprogramming of fibroblasts to iPSCs requires a mesenchymal to epithelial transition (MET), factors involved in the activation of MET or inhibition of the opposite process, the epithelial‐to‐mesenchymal transition (EMT), have potential critical role in reprogramming.…”

In Vitro and In Vivo Improvement of Islet Quality and Transplantation Successes following Islet Treatment with Biomaterials in Diabetic Rats

“…Our study demonstrated that expression of pancreatic pdx 1 and insulin was upregulated in diabetic animals transplanted with islet with PRP and biomaterial combination therapy. Several studies have indicated that treatment INS-1 with TGF- β [ 60 ] and pancreatic β -cell with PDGF-AA [ 61 ] or ECM proteins (28) could increase pdx 1 and insulin mRNA expressions. The other study showed that laminin could increase the expression levels of islet-specific genes such as pdx1 and insulin [ 62 ].…”

Traditional and emerging strategies using hepatocytes for pancreatic regenerative medicine

“…Coexpression of PDX1 and Ngn3 induces the expression of various islet cell‐specific genes to initiate a series of events that induce a small number of hepatocytes into β‐like cells. Chang et al showed that PDX1 and Ngn3 combined can reprogram hepatocytes into platelet‐derived growth factor receptor A (PDGFRα)‐positive β‐like cells 31 . The addition of PDGF‐AA to glucagon‐like peptide‐1/exendin‐4‐containing medium promotes the expansion of β‐like cells, and the cells can secrete insulin in response to glucose stimulation, enabling the treatment of diabetic mice after transplantation.…”

“…Chang et al showed that PDX1 and Ngn3 combined can reprogram hepatocytes into platelet‐derived growth factor receptor A (PDGFRα)‐positive β‐like cells. 31 The addition of PDGF‐AA to glucagon‐like peptide‐1/exendin‐4‐containing medium promotes the expansion of β‐like cells, and the cells can secrete insulin in response to glucose stimulation, enabling the treatment of diabetic mice after transplantation. Compared to previous work using PDX1 alone to reprogram hepatocytes into insulin‐producing cells, the improved strategy developed based on the current work not only improves the efficiency of reprogramming hepatocytes into β‐like cells but also enhances the ability of reprogrammed cells to secrete insulin.…”