Single cell RNA-seq identifies the origins of heterogeneity in efficient cell transdifferentiation and reprogramming
- Centre for Genomic Regulation (CRG), The Barcelona Institute of Science and Technology (BIST), Spain
- Harvard University, United States
Abstract
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.
Data availability
Single cell gene expression data have been deposited in the National Center for Biotechnology Information Gene Expression Omnibus (GEO) under accession number GSE112004
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Single cell expression analysis uncouples transdifferentiation and reprogrammingNCBI Gene Expression Omnibus, GSE112004.
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Murine bone marrow B cell precursorsNCBI Gene Expression Omnibus, GSE13.
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Immunological Genome Project data Phase 1NCBI Gene Expression Omnibus, GSE15907.
Article and author information
Author details
Marcos Plana-Carmona
Funding
H2020 European Research Council
- Thomas Graf
H2020 European Research Council
- Ben Lehner
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Chris P Ponting, University of Edinburgh, United Kingdom
Ethics
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.
Version history
- Received: September 1, 2018
- Accepted: March 11, 2019
- Accepted Manuscript published: March 12, 2019 (version 1)
- Accepted Manuscript updated: March 21, 2019 (version 2)
- Version of Record published: March 26, 2019 (version 3)
Copyright
© 2019, Francesconi et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Single cell RNA-seq identifies the origins of heterogeneity in efficient cell transdifferentiation and reprogramming
eLife 8:e41627.
https://doi.org/10.7554/eLife.41627
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