Retrospective identification of cell-intrinsic factors that mark pluripotency potential in rare somatic cells

Naveen Jain, Yogesh Goyal, Margaret C. Dunagin, Christopher J. Cote, Ian A. Mellis, Benjamin Emert, Connie L. Jiang, Ian P. Dardani, Sam Reffsin, Miles Arnett, Wenli Yang, Arjun Raj*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

Abstract

Pluripotency can be induced in somatic cells by the expression of OCT4, KLF4, SOX2, and MYC. Usually only a rare subset of cells reprogram, and the molecular characteristics of this subset remain unknown. We apply retrospective clone tracing to identify and characterize the rare human fibroblasts primed for reprogramming. These fibroblasts showed markers of increased cell cycle speed and decreased fibroblast activation. Knockdown of a fibroblast activation factor identified by our analysis increased the reprogramming efficiency. We provide evidence for a unified model in which cells can move into and out of the primed state over time, explaining how reprogramming appears deterministic at short timescales and stochastic at long timescales. Furthermore, inhibiting the activity of LSD1 enlarged the pool of cells that were primed for reprogramming. Thus, even homogeneous cell populations can exhibit heritable molecular variability that can dictate whether individual rare cells will reprogram or not.

Original languageEnglish (US)
Pages (from-to)109-133.e10
JournalCell Systems
Volume15
Issue number2
DOIs
StatePublished - Feb 21 2024

Keywords

  • cellular barcoding
  • iPSC reprogramming
  • lineage tracing
  • systems biology

ASJC Scopus subject areas

  • Pathology and Forensic Medicine
  • Cell Biology
  • Histology

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