Cellular reprogramming can manipulate the identity of cells to generate the desired cell types. The use of cell intrinsic components, including oocyte cytoplasm and transcription factors, can enforce somatic cell reprogramming to pluripotent stem cells. By contrast, chemical stimulation by exposure to small molecules offers a novel approach that can manipulate cell fate in a simple and highly controllable manner. However, human somatic cells are refractory to chemical stimulation owing to their stable epigenome and reduced plasticity; it is therefore challenging to induce human pluripotent stem cells by chemical reprogramming.  

Recently, we achieved the chemical reprogramming of human somatic cells to pluripotent stem cells, and identified crucial steps and pathways that act as barriers to chemically induced reprogramming of human cells.

Most interestingly, human cells undergoing chemical reprogramming transit a unique intermediate plastic state, showing the activation of a regeneration-like program resembling that in axolotl blastema cells arising during limb regeneration. Single-cell transcriptomic and histone modification profiling unveiled an epigenome remodeling process in which proinflammatory pathways and enhancer silence are crucial intrinsic barriers to the chemical manipulation of human cells. Targeting cell metabolic state also facilitated a reproducible, rapid, and efficient pathway for chemical reprogramming and the generation of pluripotent stem cells. Collectively, our work provides insights into human cell fate regulation through a chemical lens, which is promising for future development of pharmacological approaches for regeneration.