No "Master Genes" Needed: Scientists Generate iPSCs with Small Molecules
It was considered a major breakthrough when scientists first transformed adult fibroblasts into pluripotent stem cells with a few genetic manipulations in 2006. But genetic manipulations can be tricky and expensive.
Writing in Science this week, researchers at Peking University and Beijing Vitalstar Biotechnology demonstrate their generation of induced pluripotent stem cells (iPSCs) from mouse somatic cells using a combination of seven small-molecule compounds. The team dubbed its research products chemically induced pluripotent stem cells, or CiPSCs.
Importantly, CiPSCs “resemble embryonic stem cells in terms of their gene expression profiles, epigenetic status, and potential for differentiation and germline transmission,” the researchers note.
To identify which small molecules might induce pluripotency, Peking’s Hongkui Deng, Ph.D., and colleagues focused on those that enabled reprogramming in the absence of Oct4—a critical genetic factor— using Oct4 promoter-driven GFP expression mouse embryonic fibroblasts with viral expression of Sox2, Klf4, and c-Myc—the three other factors normally required for making iPSCs.
All told, the researchers screened more than 10,000 small molecules. Narrowing down the potential hits, the researchers sought to determine which were critical for inducing CiPSCs. Of these, four small molecules stood out as essential: CHIR, glycogen synthase kinase 3 inhibitor; 616452, a transforming growth factor-beta inhibitor; the cAMP agonist FSK; and DZNep, an S-adenosylhomocysteine hydrolase inhibitor.
“By using small molecules, exogenous ‘master genes’ are dispensable for cell fate reprogramming,” Dr. Deng et al. wrote. “This chemical reprogramming strategy has potential use in generating functional desirable cell types for clinical applications.”
“Pluripotent stem cells induced from mouse somatic cells by small-molecule compounds” appeared online in Science July 18.