Integrated time-lapse and single-cell transcription studies highlight the variable and dynamic nature of human hematopoietic cell fate commitment

PLoS Biol. 2017 Jul 27;15(7):e2001867. doi: 10.1371/journal.pbio.2001867. eCollection 2017 Jul.

Abstract

Individual cells take lineage commitment decisions in a way that is not necessarily uniform. We address this issue by characterising transcriptional changes in cord blood-derived CD34+ cells at the single-cell level and integrating data with cell division history and morphological changes determined by time-lapse microscopy. We show that major transcriptional changes leading to a multilineage-primed gene expression state occur very rapidly during the first cell cycle. One of the 2 stable lineage-primed patterns emerges gradually in each cell with variable timing. Some cells reach a stable morphology and molecular phenotype by the end of the first cell cycle and transmit it clonally. Others fluctuate between the 2 phenotypes over several cell cycles. Our analysis highlights the dynamic nature and variable timing of cell fate commitment in hematopoietic cells, links the gene expression pattern to cell morphology, and identifies a new category of cells with fluctuating phenotypic characteristics, demonstrating the complexity of the fate decision process (which is different from a simple binary switch between 2 options, as it is usually envisioned).

Publication types

  • Comparative Study

MeSH terms

  • AC133 Antigen / genetics
  • AC133 Antigen / metabolism
  • Antigens, CD34 / genetics
  • Antigens, CD34 / metabolism
  • Biomarkers / metabolism
  • Cell Differentiation
  • Cell Lineage
  • Cell Proliferation
  • Cell Shape
  • Cell Tracking
  • Cells, Cultured
  • Fetal Blood / cytology
  • Gene Expression Profiling
  • Gene Expression Regulation, Developmental*
  • Hematopoietic Stem Cells / cytology
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Image Processing, Computer-Assisted
  • Microscopy, Confocal
  • Multipotent Stem Cells / cytology
  • Multipotent Stem Cells / metabolism*
  • Principal Component Analysis
  • Single-Cell Analysis
  • Thy-1 Antigens / genetics
  • Thy-1 Antigens / metabolism
  • Time-Lapse Imaging
  • Transcription, Genetic*

Substances

  • AC133 Antigen
  • Antigens, CD34
  • Biomarkers
  • PROM1 protein, human
  • Thy-1 Antigens

Grant support

Ecole Pratique des Hautes Etudes www.ephe.fr (grant number 11REC/BIMO). Received by AP. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Agence Nationale de la Recherche www.anr.fr (grant number BSV6 014 02 « Stochagene »). Received by AP and OG. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Genethon www.genethon.fr. Received by AP and DS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.