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Yamashita, M. Clonal Behavior of Hematopoietic Stem Cells. Encyclopedia. Available online: https://encyclopedia.pub/entry/20432 (accessed on 19 June 2024).
Yamashita M. Clonal Behavior of Hematopoietic Stem Cells. Encyclopedia. Available at: https://encyclopedia.pub/entry/20432. Accessed June 19, 2024.
Yamashita, Masayuki. "Clonal Behavior of Hematopoietic Stem Cells" Encyclopedia, https://encyclopedia.pub/entry/20432 (accessed June 19, 2024).
Yamashita, M. (2022, March 10). Clonal Behavior of Hematopoietic Stem Cells. In Encyclopedia. https://encyclopedia.pub/entry/20432
Yamashita, Masayuki. "Clonal Behavior of Hematopoietic Stem Cells." Encyclopedia. Web. 10 March, 2022.
Clonal Behavior of Hematopoietic Stem Cells
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Hematopoietic stem cells (HSCs) are the only cell population that possesses both a self-renewing capacity and multipotency, and can give rise to all lineages of blood cells throughout an organism’s life. However, the self-renewal capacity of HSCs is not infinite, and cumulative evidence suggests that HSCs alter their function and become less active during organismal aging, leading ultimately to the disruption of hematopoietic homeostasis, such as anemia, perturbed immunity and increased propensity to hematological malignancies. Thus, understanding how HSCs alter their function during aging is a matter of critical importance to prevent or overcome these age-related changes in the blood system. Recent advances in clonal analysis have revealed the functional heterogeneity of murine HSC pools that is established upon development and skewed toward the clonal expansion of functionally poised HSCs during aging. In humans, next-generation sequencing has revealed age-related clonal hematopoiesis that originates from HSC subsets with acquired somatic mutations, and has highlighted it as a significant risk factor for hematological malignancies and cardiovascular diseases. 

hematopoietic stem cells aging clones

1. Introduction

Hematopoietic stem cells (HSCs) are blood-forming stem cells that can clonally expand by self-renewing cell division, and that disseminate their clonal progeny by differentiating to all lineages of the blood and immune cells, such as leukocytes, erythrocytes and platelets [1]. Although some exceptions have been identified recently, such as tissue-resident macrophages [2][3] and innate-like B and T lymphocytes [4], HSCs are an important source for the vast majority of the blood and immune cells throughout an organism’s life, during steady-state hematopoiesis and hematopoietic regeneration after injury, thus being attractive targets for preventing or curing hematopoietic disorders. Even after the establishment and sophistication of efficient HSC purification methods, single-cell-based analyses have revealed a remarkable phenotypic and functional heterogeneity in the HSC pool [5]. Of note, recent advances in the clonal tracking methods, referred to as “fate mapping”, provided evidence that HSC heterogeneity can originate from individual clones that emerge during the developmental process [6][7]. Moreover, clonal analyses have revealed an age-related expansion of functionally skewed HSCs, which is associated with an imbalanced production between blood lineages, and reduced clonal diversity in hematopoiesis [6][8][9].

2. Hematopoietic Stem Cell Development and Clonal Expansion

Cumulative evidence indicates that HSCs emerge mainly from the endothelial cells of the dorsal aorta in the aorta-gonad-mesonephros (AGM) region around E10.5 in mice and E30-42 in humans [10][11]. Upon budding into blood vessels, HSCs firstly migrate to the fetal liver, where they transiently amplify their numbers by self-renewing cell divisions. They then migrate to the bone marrow, where they continue to undergo self-renewing cell division until the end of the organism’s life. Of note, the majority of HSCs stop or slow down their cell cycle at around 4 weeks old in mice, and enter into quiescence, the G0 state of the cell cycle [12]. Thus, HSCs expand their clones from emerging during development, until they become quiescent in the adult bone marrow. How HSCs transition from the active to the quiescent state has not been clarified yet, but a recent single-cell RNA-sequencing (scRNA-seq) study suggests that the transition from fetal to adult HSCs occurs in a gradual, niche-independent, and stochastic manner and appears, at least in part, mediated by the type I interferon [13].
In the classical model, adult HSCs reside at the apex of a differentiation hierarchy and give rise to multipotent progenitors (MPPs), which do not possess a robust self-renewing capacity like HSCs, but still maintain the capacity to differentiate into all lineages of the hematopoietic cells. Along the course of differentiation, MPPs transiently amplify themselves and differentiate into more lineage-restricted progenitors, such as common myeloid progenitors (CMPs) and common lymphoid progenitors (CLPs), which undergo further amplification and commitments to become one of the mature blood cell types. Of note, recent transplantation analyses revealed remarkable functional heterogeneity within the phenotypically defined murine MPP subsets. Passegué and colleagues have shown that MPP2, MPP3 and MPP4 are already lineage-biased towards the erythro-megakaryocyte, myeloid and lymphoid lineages, respectively [14]. Cabezas-Wallscheid and colleagues have further demonstrated that MPP5 are functionally located between HSCs and the more committed MPP2-4, and are capable of stably contributing to both myeloid and lymphoid cell production upon transplantation [15]. Moreover, rather than the classical step-by-step decision making model depicted by the differentiation hierarchy, scRNA-seq studies demonstrated a continuum of the lineage commitment from HSCs to each mature cell type, with the majority of the decision making processes being initiated at the hematopoietic stem and multipotent progenitor cell (HSPC) level [16][17][18][19][20]. These findings have led to the development of a revised model of adult HSC differentiation (Figure 1), the details of which have been discussed elsewhere [21].
Figure 1. A revised model of adult HSC differentiation. In both humans and mice, recent scRNA-seq analyses predicted a revised model of adult HSC differentiation, where rather than the classical step-by-step progression through discrete cell states, HSCs undergo a continuous progression of lineage commitment toward individual mature blood cell types. In mice, HSCs first give rise to MPPs with no or little lineage commitment (MPP1, 5), and then lineage-biased MPPs, such as erythro-megakaryocyte-biased MPP2, myeloid-biased MPP3 and lymphoid-biased MPP4. These lineage-biased MPP subsets preferentially make further commitment to the corresponding lineage but can be instructed to commit towards others by external cues (e.g., inflammation). Surface markers that can be used to identify each murine HSPC and committed progenitor subset are also shown. It is noteworthy that in the revised model, a phenotypically defined progenitor subset (e.g., CMP) should represent a mixture of cells that are located within a certain range of the continuous differentiation path. CMP, common myeloid progenitors; GMP, granulocyte-monocyte progenitors; MEP, megakaryocyte-erythrocyte progenitors; CLP, common lymphoid progenitors; Meg, megakaryocytes; Plt, platelets; EB, erythroblasts; Ery, erythrocytes; Gr, granulocytes; Mφ, macrophages; DC, dendritic cells; NK, natural killer cells; B, B cells; T, T cells.
Quiescence is considered as an important mechanism to compensate for HSCs’ incomplete self-renewal ability, and for reserving as many functional HSCs as possible throughout life. This concept is supported by the fact that HSCs often lose their self-renewal ability if they are forced to undergo cell division by ex vivo cell culture [22] or in vivo serial transplantation [23], massive loss of blood cells by traumatic injury [24] and other insults to the bone marrow, such as myeloablative drugs [25]. In addition, by using a molecule that is diluted by half upon cell division, such as Bromodeoxyuridine (BrdU) and the histone H2B-GFP fusion protein, quiescent, label-retaining HSCs are shown to possess a more durable self-renewal capacity compared to actively cycling, non-labeled HSCs [23][26]. Interestingly, the label-retaining assay using H2B-GFP mice suggested that HSCs lose their self-renewal capacity after four cycles of self-renewing cell division [27]. This indicates that HSCs can remember their divisional history through certain molecular mechanisms, which restrict their self-renewal ability. The same group suggested in the following paper that a switch from EZH1 to EZH2, the two catalytic subunits of polycomb repressive complex 2 (PRC2), occurs during successive divisions and could explain the loss of self-renewal in HSCs [28]. Although this hypothesis appears intriguing, as discussed in a later section, there is an argument against the H2B-GFP-based estimation of divisional history [29][30], and alternative methods to precisely monitor HSC divisional history in vivo would be necessary for further investigation. In sum, upon emergence, fetal HSCs actively expand their clones by self-renewing cell division to make up a diverse pool of adult HSCs and constitute a spectrum of differentiated progeny. However, by the time HSCs are expanded enough to establish hematopoietic homeostasis, they are likely instructed to limit their self-renewal ability and enter quiescence in order to maximize their longevity and minimize the risk of malignant transformation.

3. Hematopoietic Stem Cell Clonal Behavior during Aging

Aging in the hematopoietic system leads to disrupted hematopoietic homeostasis, such as anemia, a deregulated immune system and an increased propensity to hematological malignancies in aged individuals. Most, if not all, of these age-dependent changes in hematopoiesis are closely associated with, and often attributed to, age-related alterations in HSCs. Such alterations include an increase in the number of phenotypic HSCs, a reduction in their self-renewal and regeneration potential, an impaired homing to the bone marrow, a skewed differentiation to myeloid and megakaryocytic lineage cells and reduced production of lymphoid progenitor cells [31][32][33][34]. Of note, a preceding study on X-chromosomal inactivation has revealed an age-dependent progressive increase in the clonality of blood leukocytes [35]. The clonal analysis of HSCs with single fluorescent color demonstrated an age-related differentiation block between HSCs and MPPs [36]. Furthermore, Nakauchi and colleagues have analyzed the clonal behavior of transplanted single HSCs of aged mice, and revealed a marked alteration in their clonal composition [8]. Even though the majority of aged HSCs are either myeloid-biased clones with less or no self-renewing capacity, a small portion of them maintain long-term repopulating potential with balanced myeloid and lymphoid output. Moreover, there are some latent HSC clones only observed in aged mice that undergo limited differentiation upon first transplantation, but show multilineage output after secondary transplantation. These results point to the age-related expansion of HSC clones with relative resistance to differentiation-instructing stimuli, and although these latent HSCs are essentially defined by transplantation experiments, it is possible that they may also be childless in the native hematopoiesis of aged organisms. The heterogeneity of aged HSCs is also demonstrated in terms of transcriptome [31][37][38][39], autophagic activity [40], mitochondrial membrane potential [41] and cell size [42]. Such remarkable heterogeneity in the aged HSC pool indicates that individual HSCs are differentially affected in the course of aging, perhaps depending on their behavioral histories (Figure 2a). Below researchers describe age-dependent cell-intrinsic and -extrinsic changes and discuss how these alterations could affect the clonal behavior of individual HSCs.
Figure 2. Age-dependent induction of functionally defective HSC clones. (a) Factors that are involved in age-associated emergence of HSC clones with impaired function. Intrinsic changes that are inherited by daughter cells upon cell division (e.g., genomic, epigenomic and mitochondrial changes) can alter the property of HSCs and their progeny, thereby increasing the heterogeneity of the HSC pool. Environmental stress, such as exposure to inflammation, irradiation and cytotoxic drugs can cause such inheritable cellular scars in HSCs. (b) Inheritable molecular scars on DNA. Mutation and DNA methylation status are copied to synthesized strands and inherited by daughter cells. DNMT3A and TET2, which are frequently mutated in clonal hematopoiesis and hematological malignancies, are involved in DNA methylation and demethylation, respectively. (c) Inheritable histone modifications known to be altered in HSCs during aging. Aging alters the activity of EZH1 and EZH2 in HSCs, and changes the genomic regions that are repressed by H3K27me3. The heterochromatin-associated repressive histone mark H3K9me3 decreases with age, which could account for the derepression of transposable elements, such as LINEs, SINEs and LTRs. (d) Inheritance of damaged mitochondria. During aging, HSCs are shown to accumulate dysfunctional mitochondria that have low mitochondrial membrane potential (ΔΨ). The damaged mitochondria can be induced and accumulated by various mechanisms, including age-related membrane damage, the impairment of electron transport chain machinery, deregulation in fission and fusion and defective mitophagy.

3.1. Somatic Mutation

Most of the aged HSC phenotypes are largely maintained after transplantation into young recipient mice [33]. Thus, age-dependent functional decline could be attributed to intrinsic changes that are accumulated in HSCs during aging. Human HSCs are estimated to accrue approximately 10–14 base substitutions per year [43], raising the possibility for mutation accumulation to serve as age-dependent cellular memory (Figure 2b). Indeed, multiple groups have performed large-scale DNA sequencing studies with human blood samples and have independently revealed the existence of somatic mutations in peripheral leukocytes without hematological malignancies [44][45][46]. This outgrowth of mutant clones, termed “clonal hematopoiesis”, often accompanies mutations of genes involved in HSC competitive fitness and differentiation, such as DNMT3A [47][48], TET2 [49][50], ASXL1 [51], JAK2 [52][53], TP53 [54][55], PPM1D [56][57], and thus believed to be derived from the clonal expansion of mutant HSCs. Of note, the prevalence of clonal hematopoiesis increases with age, becoming apparent around 40 years of age and reaching 10–20% over age 70, indicating that clonal hematopoiesis emerges as a result of age-dependent mechanisms [45][46]. Thus, it is conceivable that human HSCs acquire specific mutations and expand clonally during aging, leading to clonal hematopoiesis where a portion of mutant HSC subsets give rise to mutant mature hematopoietic cells. Of note, clonal hematopoiesis is shown to be an independent risk factor for atherosclerotic cardiovascular diseases, and the risk of coronary heart disease is estimated to increase ~two-fold with DNMT3A, TET2 and ASXL1 mutations, and ~10-fold with the JAK2V617F mutation [58]. Whether and how clonal hematopoiesis should be managed is a topic of active discussion [59].
However, aged HSC phenotypes significantly overlap between mice and humans [60], even though mice have a much shorter lifetime (~2 years) compared to humans (~70 years) and seemingly accumulate fewer mutations until the end of life [9]. Moreover, the mutations that frequently occur in human clonal hematopoiesis do not seem to occur in mouse HSCs during aging [9]. Although more comprehensive work remains to be done on the mutational landscape of aged HSCs, including non-coding as well as coding regions of the genome, the considerable similarity of the aged HSC phenotype between mice and humans rather suggests the existence of non-genetic mechanisms underlying HSC aging.

3.2. Epigenetic Memory

Epigenetic modifications regulate gene expression without changes in the DNA sequence, and are important determinants of cell fate. Some of the epigenetic modifications, including DNA methylation and post-translational histone modifications, such as PRC2-mediated histone H3 lysine 27 trimethylation (H3K27me3) and heterochromatin-associated lysine 9 trimethylation (H3K9me3), are known to be mitotically inheritable, and can be retained in daughter cells upon cell division, and clonally propagated in the progeny [61]. HSC fate decision is also guided by the epigenetic status, and the deregulation of epigenetic regulators significantly alters HSC function [47][49][62][63].
Various age-dependent epigenetic changes have also been identified, and the genes involved in epigenetic regulations are frequently mutated in human clonal hematopoiesis. For example, DNMT3A and TET2 are involved in DNA methylation and demethylation, respectively (Figure 2b). Rossi and colleagues have demonstrated the proliferation-dependent DNA hypermethylation of PRC2 target genes in aged murine HSCs [25]. Such age-dependent changes in DNA methylation are refractory to exposure to the young bone marrow environment and seem to underlie many of the HSC functional changes, including reduced engraftment and lymphopoietic potential [64][65]. DNA methylation status is closely linked to histone marks, and Goodell and colleagues have indeed revealed a PRC2-mediated H3K27me3 increase in both the length of coverage, by 29%, and in average signal intensity at the transcription start sites, by ~50%, despite similar H3K27me3 peak counts in aged murine HSCs [66]. On the other hand, Figueroa and colleagues have demonstrated that the signal intensity of H3K27me3 peaks decreases with age in a human HSC-enriched population [67], highlighting the complexity of age-related changes in PRC2 activity. The expression of Ezh1 may increase with age [66][68], albeit this observation appears not always to be reproduced [69]. Although the function of EZH1 and EZH2 seems largely overlapping, EZH1 has non-redundant, ontogeny-specific, and dose-dependent roles, such as inhibition of HSC emergence before definitive hematopoiesis via repression of HSC signature genes, and the prevention of adult HSC depletion by Cdkn2a repression [68][70]. While EZH2 appears largely dispensable for HSC function [70][71], the pharmacological inhibition of EZH2 catalytic activity over EZH1 seems to prevent cell division-dependent loss of HSC self-renewal, perhaps by dominating EZH1 function over EZH2 [28]. Thus, the age-associated overexpression of EZH1 and cell division-coupled PRC2 switching from EZH1 to EZH2 may underlie the phenotypic expansion and functional decline of HSCs during aging (Figure 2c).
On the other hand, Goodhardt and colleagues have reported a global reduction of heterochromatin-associated repressive histone mark H3K9me3 and a reduced expression of the histone methyltransferase SUV39H1 in aged murine and human HSCs [72], which correlates with the derepression of the transposable elements (TEs), such as LINEs, SINEs and LTRs [72]. As recognition of the derepressed TE expression by MDA5, it has recently been suggested that an intracellular receptor for double-strand RNAs is critical for 5-FU-induced HSC cell cycle entry, as well as for the type I interferon response [73]. A similar mechanism could be involved in age-related HSC alternation (Figure 2c).
DNA methylation and histone modification can regulate the expression of not only protein-coding RNAs but also non-coding RNAs, such as long non-coding RNAs (lncRNAs) and microRNAs (miRNAs). These non-coding RNAs play critical roles in many features of adult HSCs [74], and emerging evidence suggests the roles of such non-coding RNAs in HSC aging. For example, Baltimore and colleagues have shown that miR-132 is overexpressed in aged murine HSCs and is involved in the protection of HSC survival and balanced lineage output by directly targeting FOXO3A and promoting autophagy [75]. In addition, Karsan and colleagues have indicated that the loss of miR-146a, which mainly targets TRAF6 and IRAK1 and thus can act as a rheostat of the Toll-like receptor (TLR) and the NF-κB pathway, may drive HSC aging by increasing immune cell-derived inflammatory signals and HSC sensitivity to inflammatory cytokines, such as IL-6 and TNF-α [76]. Moreover, Goodell and colleagues have identified 29 lncRNAs that are enriched in HSCs compared to mature hematopoietic cells and which are differentially expressed between young and aged HSCs, albeit their functions remain uninvestigated [77].
Taken together, epigenetic memory is likely a mechanism that can mediate the age-dependent conversion of HSCs to functionally altered clones. Obviously, further investigation is needed to clarify how these age-related epigenetic changes coordinate with each other to mediate age-related HSC functional decline. In addition, since recent studies using scATAC-seq revealed heterogeneity in chromatin accessibility of fetal HSCs that is closely linked to their lineage priming [78], it would be interesting to see how such epigenetic heterogeneity is affected during aging.

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