Cellular reprogramming: a small molecule perspective

Abstract

The discovery that somatic cells can be reprogrammed to induced pluripotent stem cells (iPSCs) by the expression of a few transcription factors has attracted enormous interest in biomedical research and the field of regenerative medicine. iPSCs nearly identically resemble embryonic stem cells (ESCs) and can give rise to all cell types in the body, and thus have opened new opportunities for personalized regenerative medicine and new ways of modeling human diseases. Although some studies have raised concerns about genomic stability and epigenetic memory in the resulting cells, better understanding and control of the reprogramming process should enable enhanced efficiency and higher fidelity in reprogramming. Therefore, small molecules regulating reprogramming mechanisms are valuable tools to probe the process of reprogramming and harness cell fate transitions for various applications.

Figure 1. Schematic model of cellular reprogramming and the regulation pathways

Pluripotency reprogramming is a slow and stochastic process that is regulated by several interconnected mechanisms. Transient overexpression of reprogramming factors in fibroblasts leads to the rapid generation of epigenetically “activated” cells (unstable intermediate), which can be coaxed to various cell states by using lineage-specific conditions. iPSCs are one of the outcomes. Besides iPSCs, many lineage-specific cells and progenitor cells can be obtained. Only some representative small molecules and transcription factors are shown here.