Abstract
Aging is associated with reduced fitness and increased myeloid bias of the hematopoietic stem cell (HSC) compartment, causing increased risk of immune compromise, anemia, and malignancy. We show that mitochondrial membrane potential (MMP) can be used to prospectively isolate chronologically old HSCs with transcriptional features and functional attributes characteristic of young HSCs, including a high rate of transcription and balanced lineage-affiliated programs. Strikingly, MMP is a stronger determinant of the quantitative and qualitative transcriptional state of HSCs than chronological age, and transcriptional consequences of manipulation of MMP in HSCs within their native niche suggest a causal relationship. Accordingly, we show that pharmacological enhancement of MMP in old HSCs invivo increases engraftment potential upon transplantation and reverses myeloid-biased peripheral blood output at steady state. Our results demonstrate that MMP is a source of heterogeneity in old HSCs, and its pharmacological manipulation can alter transcriptional programs with beneficial consequences for function.
Highlights
Hematopoietic stem cells (HSCs) are a rare population of bone marrow (BM) resident cells that sit at the apex of the hematopoietic hierarchy and are capable of self-renewal and lifelong replenishment of all blood lineages (Orkin and Zon, 2008)
We show that despite the decrease in membrane potential (MMP) of aging HSCs at the population level, a fraction of HSCs exist in old mice that are similar in MMP to the bulk of HSCs from young mice, thereby identifying MMP as a source of heterogeneity in chronologically old HSCs
In line with published literature, we observed a significant increase in the frequency of immunophenotypic HSCs with age, at the expense of the hematopoietic progenitor cell compartment-1 (HPC1) population (Figure 1A)
Summary
Hematopoietic stem cells (HSCs) are a rare population of bone marrow (BM) resident cells that sit at the apex of the hematopoietic hierarchy and are capable of self-renewal and lifelong replenishment of all blood lineages (Orkin and Zon, 2008). With respect to metabolic state, several studies have linked differences in mitochondrial activity or content to differences in HSC state and fate, including cell-cycle status, lineage potential, and engraftment upon transplantation (Luchsinger et al, 2016; Ito et al, 2016; Liang et al, 2020; Umemoto et al, 2018). Such studies reported that HSCs have low mitochondrial membrane potential (MMP) and low mitochondrial mass, and these attributes are supportive of stem cell function (Simsek et al, 2010; Rimmeleet al., 2015; Sukumar et al, 2016; Vannini et al., 2016). This becomes important in the mitochondrial analysis of HSCs and progenitors that express such efflux pumps to a much higher degree than mature BM populations (Chaudhary and Roninson, 1991; Norddahl et al, 2011; de Almeida et al, 2017; Morganti et al, 2019b)
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