Blood Journal
Leading the way in experimental and clinical research in hematology

An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state

  1. Martin Wahlestedt1,
  2. Gudmundur L. Norddahl1,
  3. Gerd Sten1,
  4. Amol Ugale1,
  5. Mary-Ann Micha Frisk2,
  6. Ragnar Mattsson2,
  7. Tomas Deierborg3,
  8. Mikael Sigvardsson4, and
  9. David Bryder1,*
  1. 1 Lund University, Medical Faculty, Institution for Experimental Medical Science, Immunology Section, Lund, Sweden;
  2. 2 Lund University, Medical Faculty, Institution for Experimental Medical Science, Transgenic Core Facility, Lund, Sweden;
  3. 3 Lund University, Medical Faculty, Institution for Experimental Medical Science, Neuronal Survival Unit, Lund, Sweden;
  4. 4 Linkoping University, Institution of Clinical and Experimental Medicine, Linkoping, Sweden
  1. * Corresponding author; email: david.bryder{at}med.lu.se

Key points

  • Hematopoietic stem cell aging associate with stable transcriptional alterations that persist through transplantation.

  • Somatic cell reprogramming of aged hematopoietic stem and progenitor cells reverses functional defects associated with hematopoietic aging.

Abstract

Aging of hematopoietic stem cells (HSCs) leads to several functional changes, including alterations affecting self-renewal and differentiation. While it is well established that many of the age-induced changes are intrinsic to HSCs, less is known about the stability of this state. Here, we entertained the hypothesis that HSC aging is driven by the acquisition of permanent genetic mutations. To examine this issue at a functional level in vivo, we applied induced pluripotent stem (iPS) cell reprogramming of aged hematopoietic progenitors and allowed the resulting aged-derived iPS cells to reform hematopoiesis via blastocyst complementation. Next, we functionally characterized iPS-derived HSCs in primary chimeras and following the transplantation of 're-differentiated' HSCs into new hosts; the gold standard to assess HSC function. Our data demonstrate remarkably similar functional properties of iPS-derived and endogenous blastocyst-derived HSCs, despite the extensive chronological and proliferative age of the former. Our results therefore favor a model in which an underlying, but reversible, epigenetic component is a hallmark of HSC aging rather than being driven by an increased DNA mutation burden.

  • Submitted November 26, 2012.
  • Accepted March 1, 2013.