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Single cell expression analysis uncouples transdifferentiation and reprogramming

By Mirko Francesconi, Bruno Di Stefano, Clara Berenguer, Marisa de Andres, Maria Mendez Lago, Amy Guillaumet-Adkins, Gustavo Rodriguez-Esteban, Marta Gut, Ivo Glynne Gut, Holger Heyn, Ben Lehner, Thomas Graf

Posted 20 Jun 2018
bioRxiv DOI: 10.1101/351957 (published DOI: 10.7554/eLife.41627)

Many somatic cell types are plastic, having the capacity to convert into other specialized cells (transdifferentiation)(1) or into induced pluripotent stem cells (iPSCs, reprogramming)(2) in response to transcription factor over-expression. To explore what makes a cell plastic and whether these different cell conversion processes are coupled, we exposed bone marrow derived pre-B cells to two different transcription factor overexpression protocols that efficiently convert them either into macrophages or iPSCs and monitored the two processes over time using single cell gene expression analysis. We found that even in these highly efficient cell fate conversion systems, cells differ in both their speed and path of transdifferentiation and reprogramming. This heterogeneity originates in two starting pre-B cell subpopulations, large pre-BII and the small pre-BII cells they normally differentiate into. The large cells transdifferentiate slowly but exhibit a high efficiency of iPSC reprogramming. In contrast, the small cells transdifferentiate rapidly but are highly resistant to reprogramming. Moreover, the large B cells induce a stronger transient granulocyte/macrophage progenitor (GMP)-like state, while the small B cells undergo a more direct conversion to the macrophage fate. The large cells are cycling and exhibit high Myc activity whereas the small cells are Myc low and mostly quiescent. The observed heterogeneity of the two cell conversion processes can therefore be traced to two closely related cell types in the starting population that exhibit different types of plasticity. These data show that a somatic cell's propensity for either transdifferentiation and reprogramming can be uncoupled.

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