CD41 expression marks myeloid-biased adult hematopoietic stem cells and increases with age

Abstract

Key Points• Integrin CD41, thought to absent on adult HSCs, marks a novel subset of myeloidbiased long-term HSCs that becomes prevalent with age.• Loss of CD41 leads to transplantable hematopoietic defects that affect HSC survival and maintenance and are, in part, mediated by platelet loss.The hematopoietic stem cell (HSC) compartment is heterogeneous, yet our understanding of the identities of different HSC subtypes is limited. Here we show that platelet integrin CD41 (aIIb), currently thought to only transiently mark fetal HSCs, is expressed on an adult HSC subtype that accumulates with age. CD411 HSCs were largely quiescent and exhibited myeloerythroid and megakaryocyte gene priming, governed by Gata1, whereas CD412 HSCs were more proliferative and exhibited lymphoid gene priming. When isolated without the use of blocking antibodies, CD411 HSCs possessed long-term repopulation capacity on serial transplantations and showed a marked myeloid bias compared with CD412 HSCs, which yielded a more lymphoid-biased progeny. CD41-knockout (KO) mice displayed multilineage hematopoietic defects coupled with decreased quiescence and survival of HSCs, suggesting that CD41 is functionally relevant for HSC maintenance and hematopoietic homeostasis. Transplantation experiments indicated that CD41-KOassociated defects are long-term transplantable, HSC-derived and, in part, mediated through the loss of platelet mass leading to decreases in HSC exposure to important platelet released cytokines, such as transforming growth factor b1. In summary, our data provide a novel marker to identify a myeloid-biased HSC subtype that becomes prevalent with age and highlights the dogma of HSC regulation by their progeny. (Blood. 2013;121(22):4463-4472) Introduction Hematopoietic stem cells (HSCs) are responsible for the production of all blood lineages for the duration of an individual's life span. During the aging of mice, HSCs undergo cell-intrinsic and cellextrinsic alterations characterized by attenuated lymphoid-cell production and a decline in their functional potential.1-3 These changes were originally envisioned to take place within a homogeneous HSC population that changes over time.2 However, several recent studies indicate that even phenotypically well-defined HSC subsets are functionally heterogeneous, differing in their life span, cycling status, and lineage bias.4-8 Intriguingly, the proportions and numbers of these subtypes change with time throughout fetal, young, and old life stages.9 Thus, hematopoietic aging can be viewed as the outcome of gradual changes in the clonal composition of the HSC compartment with respect to distinct HSC subtypes.9-12 However, the cell surface phenotypes of the different subtypes and the mechanisms behind these shifts remain poorly understood. Here we identify integrin CD41 as a novel marker for adult and aging HSCs and as functionally relevant for hematopoiesis.Integrins are a/b heterodimeric transmembrane receptors mediating broad effects on cytoskeletal organization, motility, and survival ...

Hematopoietic stem cells count and remember self-renewal divisions

“…CD41 has been reported to mark myeloid and megakaryocyte progenitors within the HSC compartment (Haas et al, 2015;Yamamoto et al, 2013), and it's expression increases with age (Gekas and Graf, 2013). Given that myeloid-restricted repopulating cells accumulate in aged mice (Dykstra et al, 2011;Sudo et al, 2000), we hypothesized that by examining CD41 expression we would better understand both the heterogeneity and the myeloid potential within aging HSC compartments.…”

“…CD41 + cells do not function as LT-HSCs at the clonal level in young adult mice (Yamamoto et al, 2013), but in the aging HSC compartment CD41 + HSCs have been shown to reside at the top of the hematopoietic hierarchy (Gekas and Graf, 2013). In order to understand how CD41 + cells develop LT-HSC potential with aging, we compared the H2BGFP label dilution of CD41 − and CD41 + cells within the GFP Hi LR-HSC fractions of young and aging mice.…”

Hematopoietic stem/progenitor cell commitment to the megakaryocyte lineage

“…46 Previous studies have also reported that CD41 expression marks myeloid-biased adult hematopoietic stem cells and increases with age. 47 Unfortunately, none of these studies [42][43][44][45][46][47] evaluated megakaryocyte or erythroid output from these functionally defined HSC subsets. The identification of LMPPs suggested that a committed MegEprogenitor arises directly from an ST-HSC or early MPP without passing through a requisite CMP intermediate.…”

Haematopoietic and immune defects associated with GATA2 mutation

“…The gradual and progressive decline in stem cell function in humans is reflected in the results of several model systems in which GATA2 is required to maintain stem cell selfrenewal capacity Nottingham et al, 2007;de Pater et al, 2013). The absence of MLP/LMPP, loss of lymphoid and monocyte/DC haematopoiesis, with relative sparing of erythropoiesis and granulopoiesis, resembles an accelerated ageing phenotype (Gekas & Graf, 2013). It will be of interest to determine whether objective signs of this can be detected prematurely in GATA2 patients (Bakker & Passegue, 2013).…”