A molecular roadmap for induced multi-lineage trans-differentiation of fibroblasts by chemical combinations

Abstract

Recent advances have demonstrated the power of small molecules in promoting cellular reprogramming. Yet, the full potential of such chemicals in cell fate manipulation and the underlying mechanisms require further characterization. Through functional screening assays, we find that mouse embryonic fibroblast cells 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 novel 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 myocytic, glial or adipocytic lineages. Our study describes a cell fate control system that may be harnessed for regenerative medicine.

Chemicals orchestrate reprogramming with hierarchical activation of master transcription factors primed by endogenous Sox17 activation

“…Unexpectedly, although cells in the priming phase had already expressed some of the XEN master TFs, they were still fibroblast-like with a high level of the fibroblasts program, as well as the high expression of fibroblast master genes. This was rather different from an intermediate multipotent cell type that was presumed in previous reports 34 , 35 and from the other possible intermediates that were speculated before this study (Fig. 1a ).…”

Mapping the Mouse Cell Atlas by Microwell-Seq

“…Recent advances in single-cell gene expression analysis offer an opportunity to greatly enhance cell identification and classification. Emerging methods, such as high-throughput single-cell qPCR (Dalerba et al, 2011;Guo et al, 2010;Han et al, 2017), single-cell mass cytometry (Bendall et al, 2011), and singlecell mRNA-seq (Hashimshony et al, 2012;Ramskö ld et al, 2012;Shalek et al, 2013;Tang et al, 2009;Treutlein et al, 2014) allow for dissection of cell heterogeneity at high resolution.…”

Maturity of associating liver partition and portal vein ligation for staged hepatectomy-derived liver regeneration in a rat model

“…A rational possibility is that volumetric assessment overestimates the functional proliferation. Given the development of induced pluripotent stem cell technique and the illustration of the roadmap determining the fate of diverse cells, the mechanism of hepatocyte differentiation has been elucidated gradually through the lineage tracing method[ 13 ]. Basic research has elucidated that it takes about 8 to 10 d for a hepatoblast to mature into a hepatocyte[ 14 ].…”