Discovery and characterization of novel cell reprogramming compounds for treating degenerative diseases

Abstract

In mammals, adult somatic cells can’t be differentiated into other cell types because they are terminally differentiated. For this reason, cell therapy utilizes induced pluripotent stem cells (iPSCs) from patients for the potential treatment of degenerative diseases. iPSCs were obtained by genetic modification. However, iPSCs can be derived at a low rate and show propensity for tumorigenesis that makes these cells challenging to be used for cell therapy in humans. For these reasons, new approaches are needed to manipulate cell pluripotency. Chemical-based methods have numerous advantages compared to genetic manipulation. In the previous study in our lab, a novel indazole derivative compound, termed LDD-1821, was identified as an inducer of cell reprogramming, which differentiates into various cell types. Along with the previous results, LDD-1821 was studied to induce myoblasts and fibroblasts, terminally differentiated cells, into cardiocytes or myocytes-like cells by treating LDD-1821 and appropriate differentiation culture media. Additionally, a derivative of LDD-1821, termed LDD-1692 that has superior chemico-physical properties than LDD-1821, was also investigated as a reprogramming agent. It was demonstrated that LDD-1692 is an RNA methyl-transferase inhibitor, similar to LDD-1821. Two compounds were compared by adipogenic differentiation assay. As a result, more adipogenic droplets were observed in LDD-1692 treated group in microscopic images. Furthermore, to identify the synergetic effect on cell reprogramming, LDD-1692 single treated group and LDD-1692 co-treated group with other reprogramming molecules were compared. C2C12 myoblasts were induced into adipocytes or osteocytes-like cells to confirm the best combination for cell reprogramming. According to the results, LDD-1692 with TSA treated group showed the highest effect on adipogenic conversion and LDD-1692 with reversine treated group showed the impact on osteogenic conversion.