The induced pluripotent stem cells (iPSCs) resemble embryonic stem cells (ESCs) and are considered as a prominent source for cell replacement therapy and drug screening. Many efforts have been taken to make iPSCs more amendable in clinical applications by using non-integrating gene delivery approaches, or cell membrane permeable proteins to induce the reprogramming. Small molecule compounds have also been found to be extremely useful in facilitating iPSC generation and replacing several reprogramming factors. However, full-chemical mediated reprogramming of somatic cells into pluripotent state has been proved to be extremely difficult.

Prof.XIE’s group from Shanghai Institute of Materia Medica (SIMM) have established a 96-well-plate-based chemical screening system for OSKM-induced reprogramming in MEFs, and LiCl and high osmotic pressure were identified to enhance transcription factor-mediated reprogramming. Recently, they discovered that the commonly used biological reagent bromodeoxyuridine (BrdU) is able to enhance Yamanaka factor-mediated reprogramming. More interestingly, BrdU can replace Oct4, the most critical factor in iPSC generation. Further studies demonstrate that BrdU enables full-chemical induction of mouse iPSCs (CiPSCs) with several chemical cocktails, and the minimal combination being BrdU, CHIR99021, Repsox, and Forskolin. The CiPSCs resemble ESCs in terms of their gene expression, epigenetic status, in vivo differentiation and chimera generation. Although the mechanisms underlying BrdU-mediated reprogramming remain to be elucidated, this combination may lay a foundation for full-chemical induction of human iPSCs and may eventually provide a safer strategy to generate clinically applicable iPSCs.

This study was recently published online in Cell Research. LONG Yuan, a PhD candidate from SIMM was the first author. This work was supervised by Prof. XIE Xin, a principle investigator of SIMM, the deputy director of the National Center for Drug Screening, and an adjunct professor of Tongji University. Her research is mainly focused on GPCR-based drug discovery and chemical biology of stem cells.

This work was supported by the Chinese Academy of Sciences, the Ministry of Science and Technology of China, and the National Natural Science Foundation of China.