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

Abstract

Key Points• Hematopoietic stem cell aging associates with stable transcriptional alterations.• Somatic cell reprogramming reverses functional defects associated with hematopoietic aging.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. (Blood. 2013;121(21):4257-4264)

Human and murine hematopoietic stem cell aging is associated with functional impairments and intrinsic megakaryocytic/erythroid bias

“…Murine BM-derived hematopoietic stem and progenitor cells were identified and isolated as previously described [13,[32][33][34]. In short, BM cells were incubated with a cocktail of antibodies against lineage markers B220, CD4, CD8a, CD11b, Gr-1, Ly6c and Ter119, followed by incubation with antibodies recognizing cKit, Sca1, CD48, CD150, Flt3 and IL7Ra (HSC/CLP stain), or antibodies recognizing cKit, Sca1, CD150, CD41 and CD105 (myeloerythroid stain).…”

“…However, in mice, ample evidence points to intrinsic alterations in the hematopoietic stem cells (HSCs) themselves as the main drivers of hematological aging. These include functional, genetic, and epigenetic modifications [10][11][12][13][14][15][16]. In mice, HSCs increase in frequency that however is paralleled by a decreased proliferative capacity on a per-cell basis [10][11][12]17].…”

“…These observations are presumably coupled to an age-related clonal shift within the aged HSC compartment towards increased My-bi HSC frequency at the expense of lymphoid-biased (Ly-bi) HSCs [18][19][20], although these alterations to some extent can also be strain-specific [18]. Regardless, the lineage skewing with murine HSC aging has been linked to an upregulation of myeloid-specific genes and a downregulation of lymphoid-specific genes [11][12][13][14][15]18], although many of previous transcriptome analyses were based on a selection and manual curation of lineage-associated genes. By contrast, recent global transcriptome analysis of single HSCs based on more objectively defined lineage-affiliated transcription programs revealed a molecular and functional platelet bias, rather than a My-bi, in aged murine HSC [21].…”

Role of regeneration in tissue repairing and therapies

“…New molecular insights are needed for developing new strategies for generation of HSCs from pluripotent stem cells [49]. Like other body cells, HSCs also show ageing that leads to several functional changes which affect self-renewal and differentiation of cells [58]. All age-induced changes are intrinsic to HSCs but it is unknown that how does HSCs aging is driven by the acquisition of permanent genetic mutations.…”

“…All age-induced changes are intrinsic to HSCs but it is unknown that how does HSCs aging is driven by the acquisition of permanent genetic mutations. Though reversible, epigenetic component is a hallmark of HSC aging [58]. However, by employing induced pluripotent stem (iPS) cell reprogramming of aged hematopoietic progenitors all age related effects can be slow down that may provide longevity.…”