Distinct Hematopoietic Stem Cell Subtypes Are Differentially Regulated by TGF-β1

Abstract

Summary The traditional view of hematopoiesis has been that all the cells of the peripheral blood are the progeny of a unitary homogeneous pool of hematopoietic stem cells (HSCs). Recent evidence suggests that the hematopoietic system is actually maintained by a consortium of HSC subtypes with distinct functional characteristics. We show here that myeloid-biased HSCs (My-HSCs) and lymphoid-biased (Ly-HSCs) can be purified according to their capacity for Hoechst dye efflux in combination with canonical HSC markers. These phenotypes are stable under natural (aging) or artificial (serial transplantation) stress and are exacerbated in the presence of competing HSCs. My- and Ly-HSCs respond differently to TGFβ1, presenting a possible mechanism for differential regulation of HSC subtype activation. This study demonstrates definitive isolation of lineage-biased HSC subtypes and contributes to the fundamental change in view that the hematopoietic system is maintained by a continuum of HSC subtypes, rather than a functionally uniform pool.

Epigenetic regulation of aging stem cells

“…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).…”

“…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). 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, 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).…”

“…However, HSC clonal subtypes are differentially responsive to a key factor involved in paracrine signaling, transforming growth factor-b1 (TGF-b1). TGF-b1 stimulates myeloid-biased HSC clones while inhibiting lymphoidbiased clones (Challen et al, 2010), indicating that mechanisms of clonal expansion may also be environmentally controlled.…”

Evidence that β7 Integrin Regulates Hematopoietic Stem Cell Homing and Engraftment Through Interaction with MAdCAM-1

“…Recent evidence suggests that the primitive HSC pool is comprised of several distinct HSC subtypes that functionally differ in their lineage potential and self-renewal capacity [24,25]. According to the expression patterns of CD150 and b7 integrin in the LSK cell population, we identified a subset of b7 + HSCs (LSK CD150 + ) in the BM at steady state (Fig.…”