Interspecies chimeric conditions affect the developmental rate of human pluripotent stem cells

PLoS Comput Biol. 2021 Mar 1;17(3):e1008778. doi: 10.1371/journal.pcbi.1008778. eCollection 2021 Mar.

Abstract

Human pluripotent stem cells hold significant promise for regenerative medicine. However, long differentiation protocols and immature characteristics of stem cell-derived cell types remain challenges to the development of many therapeutic applications. In contrast to the slow differentiation of human stem cells in vitro that mirrors a nine-month gestation period, mouse stem cells develop according to a much faster three-week gestation timeline. Here, we tested if co-differentiation with mouse pluripotent stem cells could accelerate the differentiation speed of human embryonic stem cells. Following a six-week RNA-sequencing time course of neural differentiation, we identified 929 human genes that were upregulated earlier and 535 genes that exhibited earlier peaked expression profiles in chimeric cell cultures than in human cell cultures alone. Genes with accelerated upregulation were significantly enriched in Gene Ontology terms associated with neurogenesis, neuron differentiation and maturation, and synapse signaling. Moreover, chimeric mixed samples correlated with in utero human embryonic samples earlier than human cells alone, and acceleration was dose-dependent on human-mouse co-culture ratios. The altered gene expression patterns and developmental rates described in this report have implications for accelerating human stem cell differentiation and the use of interspecies chimeric embryos in developing human organs for transplantation.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cells, Cultured
  • Chimerism*
  • Computational Biology
  • Human Embryonic Stem Cells* / cytology
  • Human Embryonic Stem Cells* / physiology
  • Humans
  • Mice
  • Neurogenesis* / genetics
  • Neurogenesis* / physiology
  • Pluripotent Stem Cells* / cytology
  • Pluripotent Stem Cells* / physiology
  • Species Specificity
  • Transcriptome / genetics