Functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion

Abstract

Aging of the hematopoietic stem cell compartment is believed to contribute to the onset of a variety of age-dependent blood cell pathophysiologies. Mechanistic drivers of hematopoietic stem cell (HSC) aging include DNA damage accumulation and induction of tumor suppressor pathways that combine to reduce the regenerative capacity of aged HSCs. Such mechanisms do not however account for the change in lymphoid and myeloid lineage potential characteristic of HSC aging, which is believed to be central to the decline of immune competence and predisposition to myelogenous diseases in the elderly. Here we have prospectively isolated functionally distinct HSC clonal subtypes, based on cell surface phenotype, bearing intrinsically different capacities to differentiate toward lymphoid and myeloid effector cells mediated by quantitative differences in lineage priming. Finally, we present data supporting a model in which clonal expansion of a class of intrinsically myeloid-biased HSCs with robust self-renewal potential is a central component of hematopoietic aging.

Epigenetic regulation of aging stem cells

“…However, modest increased cycling of lymphoid-biased clones relative to myeloid-biased clones has been reported (Challen et al, 2010). Aged clones also maintain their surface phenotype and differentiation bias during serial transplantation (Cho et al, 2008;Beerman et al, 2010a;Challen et al, 2010), suggesting that conversion between clonal types does not contribute to age-dependent fluctuations in clonal subtype. However, the enhanced expansion of myeloid-biased clones with age in the DB/2 strain compared with C57BL/6 indicates a genetic component for clonal regulation (Cho et al, 2008).…”

“…Aged HSCs also give rise to more cells of myeloid lineage at the expense of lymphoid fates (Sudo et al, 2000;Kim et al, 2003;Rossi et al, 2005;Cho et al, 2008;Guerrettaz et al, 2008). This myeloid bias in aging HSC populations has been explained by alterations in the subcomposition of the HSC pool, which is thought to contain clones with pre-determined differentiation bias (Dykstra et al, 2007;Cho et al, 2008;Beerman et al, 2010a;Morita et al, 2010). The frequency of myeloid-biased HSC clones, distinguished by their high expression of marker SLAMF1/CD150 (Beerman et al, 2010a;Challen et al, 2010;Morita et al, 2010), increases with age, although the mechanism of this expansion is not yet fully understood.…”

“…This myeloid bias in aging HSC populations has been explained by alterations in the subcomposition of the HSC pool, which is thought to contain clones with pre-determined differentiation bias (Dykstra et al, 2007;Cho et al, 2008;Beerman et al, 2010a;Morita et al, 2010). The frequency of myeloid-biased HSC clones, distinguished by their high expression of marker SLAMF1/CD150 (Beerman et al, 2010a;Challen et al, 2010;Morita et al, 2010), increases with age, although the mechanism of this expansion is not yet fully understood. Myeloidbiased cells do not appear to cycle more rapidly than clones giving rise to balanced numbers of lymphoid and myeloid cells (Beerman et al, 2010a).…”

“…The frequency of myeloid-biased HSC clones, distinguished by their high expression of marker SLAMF1/CD150 (Beerman et al, 2010a;Challen et al, 2010;Morita et al, 2010), increases with age, although the mechanism of this expansion is not yet fully understood. Myeloidbiased cells do not appear to cycle more rapidly than clones giving rise to balanced numbers of lymphoid and myeloid cells (Beerman et al, 2010a). However, modest increased cycling of lymphoid-biased clones relative to myeloid-biased clones has been reported (Challen et al, 2010).…”

“…However, the enhanced expansion of myeloid-biased clones with age in the DB/2 strain compared with C57BL/6 indicates a genetic component for clonal regulation (Cho et al, 2008). Notably, although HSC subclones maintain many of their properties, defects of both myeloid and balanced HSC clones in competitive transplantation assays suggest that there may also be functional alterations within clonal subtypes during aging (Beerman et al, 2010a).…”