A Molecular Roadmap for Induced Multi-lineage Trans-differentiation of Fibroblasts by Chemical Combinations [gene expression]

Recent advances highlight the power of small molecules for promoting cellular reprogramming. Yet, the full potential of such chemicals in cell fate manipulation and the underlying mechanisms needs further characterization. Through functional screening assays, we found that mouse embryonic fibroblast can be induced to trans-differentiate into a wide range of somatic lineages simultaneously by treatment with a combination of four chemicals. Genomic analysis of the process indicates activation of multi-lineage modules and relaxation of epigenetic silencing programs. In addition, we identify Sox2 as an important regulator within the induced network. Single cell analysis uncovers a priming state that enables transition from fibroblast cells to diverse somatic lineages. Finally, we demonstrate that modification of the culture system enables directional trans-differentiation towards cardiac, neuronal or adipocytic lineages. Our study describes a cell fate control system that may be harnessed for regenerative medicine.

12

Han X, Yu H, Huang D, Xu Y, Saadatpour A, Li X, Wang L, Yu J, Pinello L, Lai S, Jiang M, Tian X, Zhang F, Cen Y, Fujiwara Y, Zhu W, Zhou B, Zhou T, Ouyang H, Wang J, Yuan GC, Duan S, Orkin SH, Guo G