title: An epigenetic component of hematopoietic stem cell aging amenable to reprogramming into a young state.
abstract: Aging of hematopoietic stem cells (HSCs) leads to several functional changes, including alterations affecting self-renewal and differentiation. Although it is well established that many of the age-induced changes are intrinsic to HSCs, less is known regarding 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 after 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.
authors.affiliation: Immunology Section, Lund University, Medical Faculty, Institution for Experimental Medical Science, Lund, Sweden.
authors.forename: Martin
authors.initials: M
authors.lastname: Wahlestedt
authors.forename: Gudmundur L
authors.initials: GL
authors.lastname: Norddahl
authors.forename: Gerd
authors.initials: G
authors.lastname: Sten
authors.forename: Amol
authors.initials: A
authors.lastname: Ugale
authors.forename: Mary-Ann Micha
authors.initials: MA
authors.lastname: Frisk
authors.forename: Ragnar
authors.initials: R
authors.lastname: Mattsson
authors.forename: Tomas
authors.initials: T
authors.lastname: Deierborg
authors.forename: Mikael
authors.initials: M
authors.lastname: Sigvardsson
authors.forename: David
authors.initials: D
authors.lastname: Bryder
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D016922:Cellular Senescence / Q000235:genetics / Q000502:physiology*; D044127:Epigenesis, Genetic / Q000502:physiology*; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D055106:Genome-Wide Association Study; D018380:Hematopoietic Stem Cell Transplantation; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000502:physiology*; D051379:Mice; D008810:Mice, Inbred C57BL; D016615:Telomere / Q000235:genetics; D039901:Totipotent Stem Cells / Q000166:cytology / Q000502:physiology; D014158:Transcription, Genetic / Q000502:physiology