Ultra-High-Frequency Reprogramming of Individual Long-Term Hematopoietic Stem Cells Yields Low Somatic Variant Induced Pluripotent Stem Cells

Cell Rep. 2019 Mar 5;26(10):2580-2592.e7. doi: 10.1016/j.celrep.2019.02.021.

Abstract

Efficiency of reprogramming of human cells into induced pluripotent stem cells (iPSCs) has remained low. We report that individual adult human CD49f+ long-term hematopoietic stem cells (LT-HSCs) can be reprogrammed into iPSCs at close to 50% efficiency using Sendai virus transduction. This exquisite sensitivity to reprogramming is specific to LT-HSCs, since it progressively decreases in committed progenitors. LT-HSC reprogramming can follow multiple paths and is most efficient when transduction is performed after the cells have exited G0. Sequencing of 75 paired skin fibroblasts/LT-HSC samples collected from nine individuals revealed that LT-HSCs contain a lower load of somatic single-nucleotide variants (SNVs) and indels than skin fibroblasts and accumulate about 12 SNVs/year. Mutation analysis revealed that LT-HSCs and fibroblasts have very different somatic mutation signatures and that somatic mutations in iPSCs generally exist prior to reprogramming. LT-HSCs may become the preferred cell source for the production of clinical-grade iPSCs.

Keywords: induced pluripotent stem cells; long-term hematopoietic stem cells; reprogramming; skin fibroblasts; somatic mutation.

Publication types

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

MeSH terms

  • Adolescent
  • Adult
  • Cellular Reprogramming
  • Female
  • Healthy Volunteers
  • Hematopoietic Stem Cells / metabolism*
  • Humans
  • Induced Pluripotent Stem Cells / metabolism*
  • Male
  • Middle Aged
  • Young Adult