Reprogramming of Fibroblasts into Pancreatic-like Betacells

Faster way to reprogram fibroblasts to bypass pancreatic-pluripotent state shown in mouse models….

New strategies of healthy islet and beta cell transplantation may represent a "cure" for type 1 diabetes. Transplantation via direct reprogramming has been used to generate pancreatic beta-like cells. The challenge with transplantation of islets is the scarcity of functional, glucose-responsive beta cells.

 

Previous studies used conventional direct beta-cell reprogramming; this method is faster than preparing induced pluripotent stem cells (iPSCs). Previously, there was not an approach to convert nonendoderm cells toward endoderm beta cell lineage. The cell types derived from the endoderm lineage may be easier to reprogram into the beta cell lineage due to their similarity. Previous studies were challenged by the practicality of starting cells and the limited ability to regenerate.

 

This study used doxycycline-inducible secondary mouse embryonic fibroblasts to enable expression of four iPSC factors with precise temporal control. It was hypothesized that transcriptional activity downstream of lineage-specific signals may help set up lineage-specific transcriptional programs. Results from this study showed that pancreatic beta-like cells can be differentiated in a process similar to previously observed endoderm cells. Despite the success, the efficiency of generating pancreatic-like cells was low. The results indicated that the lineage induction conditions could be further improved. From the results, the next step was to focus and optimize inductive conditions by small molecules. By using small molecules the results showed a 7-fold increase over the initial approach. These results suggest that overlapping lineage-specific patterning conditions with early reprogramming based on small molecules enhances pancreatic induction.

 

In conclusion, this study found that pancreatic progenitor-like cells (PPLCs) generated from fibroblasts could mature into cells of all three pancreatic lineages and can functionally ameliorate hyperglycemia in vivo. The approach used in this study may be faster and potentially safer than previous methods.