Forced transcription factor expression can transdifferentiate somatic cells into other specialized cell types or reprogram them into induced pluripotent stem cells (iPSCs) with variable efficiency. To better understand the heterogeneity of these processes, we used single-cell RNA sequencing to follow the transdifferentation of murine pre-B cells into macrophages as well as their reprogramming into iPSCs. Even in these highly efficient systems, there was substantial variation in the speed and path of fate conversion. We predicted and validated that these differences are inversely coupled and arise in the starting cell population, with Mychigh large pre-BII cells transdifferentiating slowly but reprogramming efficiently and Myclow small pre-BII cells transdifferentiating rapidly but failing to reprogram. Strikingly, differences in Myc activity predict the efficiency of reprogramming across a wide range of somatic cell types. These results illustrate how single cell expression and computational analyses can identify the origins of heterogeneity in cell fate conversion processes.
Single cell gene expression data have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) under accession number GSE112004
Single cell expression analysis uncouples transdifferentiation and reprogrammingNCBI Gene Expression Omnibus, GSE112004.
- Thomas Graf
- Ben Lehner
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Animal experimentation: The protocol was approved by the Committee on the Ethics of Animal Experiments of the Generalitat de Catalunya (Permit Number: JMC-071001P3). All surgery was performed under sodium pentobarbital anesthesia, and every effort was made to minimize suffering.
- Chris P Ponting, University of Edinburgh, United Kingdom
© 2019, Francesconi et al.
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