Blood and immune cells derive from multipotent hematopoietic stem cells (HSCs). Classically, stem and progenitor populations have been considered discrete homogeneous populations. However, recent ...technological advances have revealed significant HSC heterogeneity, with evidence for early HSC lineage segregation and the presence of lineage-biased HSCs and lineage-restricted progenitors within the HSC compartment. These and other findings challenge many aspects of the classical view of HSC biology. We review the most recent findings regarding the causes and consequences of HSC heterogeneity, discuss their far-reaching implications, and suggest that so-called continuum-based models may help consolidate apparently divergent experimental observations in this field.
Haas et al. review the most recent findings regarding the causes and consequences of HSC heterogeneity, discuss their far-reaching implications, and suggest that so-called continuum-based models may help consolidate apparently divergent experimental observations in this field.
In this study, we present integrated quantitative proteome, transcriptome, and methylome analyses of hematopoietic stem cells (HSCs) and four multipotent progenitor (MPP) populations. From the ...characterization of more than 6,000 proteins, 27,000 transcripts, and 15,000 differentially methylated regions (DMRs), we identified coordinated changes associated with early differentiation steps. DMRs show continuous gain or loss of methylation during differentiation, and the overall change in DNA methylation correlates inversely with gene expression at key loci. Our data reveal the differential expression landscape of 493 transcription factors and 682 lncRNAs and highlight specific expression clusters operating in HSCs. We also found an unexpectedly dynamic pattern of transcript isoform regulation, suggesting a critical regulatory role during HSC differentiation, and a cell cycle/DNA repair signature associated with multipotency in MPP2 cells. This study provides a comprehensive genome-wide resource for the functional exploration of molecular, cellular, and epigenetic regulation at the top of the hematopoietic hierarchy.
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•Analysis identifies 6,000 proteins, 27,000 transcripts, and 15,000 DMRs in HSCs/MPPs•Core signaling, regulatory networks, and lncRNAs are central nodes in HSCs•Differentiation-associated changes include shifts in alternative transcript isoforms•DNA methylation correlates inversely with gene expression in HSCs and their progeny
This study identifies regulatory networks of primary mouse HSCs and four downstream MPPs by combining proteome, transcriptome, and DNA methylome analyses with in vitro and in vivo functional assays.
Infections are associated with extensive platelet consumption, representing a high risk for health. However, the mechanism coordinating the rapid regeneration of the platelet pool during such ...stress conditions remains unclear. Here, we report that the phenotypic hematopoietic stem cell (HSC) compartment contains stem-like megakaryocyte-committed progenitors (SL-MkPs), a cell population that shares many features with multipotent HSCs and serves as a lineage-restricted emergency pool for inflammatory insults. During homeostasis, SL-MkPs are maintained in a primed but quiescent state, thus contributing little to steady-state megakaryopoiesis. Even though lineage-specific megakaryocyte transcripts are expressed, protein synthesis is suppressed. In response to acute inflammation, SL-MkPs become activated, resulting in megakaryocyte protein production from pre-existing transcripts and a maturation of SL-MkPs and other megakaryocyte progenitors. This results in an efficient replenishment of platelets that are lost during inflammatory insult. Thus, our study reveals an emergency machinery that counteracts life-threatening platelet depletions during acute inflammation.
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•Unipotent SL-MkPs are maintained in a quiescent, but primed, state during homeostasis•Inflammation instructs post-transcriptional Mk protein synthesis in SL-MkPs•Inflammation drives efficient cell cycle activation and maturation of SL-MkPs•Activation of SL-MkPs rapidly replenishes the platelet pool during acute inflammation
Haas et al. show that inflammatory signaling activates post-transcriptional protein synthesis, maturation, and cell cycle induction in quiescent, but primed, stem-like megakaryocyte progenitors. This emergency program efficiently prevents otherwise life-threatening platelet depletion during acute inflammation.
Adult stem cells are ultimately responsible for the lifelong maintenance of regenerating of tissues during both homeostasis and following injury. Hence, the functional attrition of adult stem cells ...is thought to be an important driving factor behind the progressive functional decline of tissues and organs that is observed during aging. The mechanistic cause underlying this age-associated exhaustion of functional stem cells is likely to be complex and multifactorial. However, it is clear that progressive remodeling of the epigenome and the resulting deregulation of gene expression programs can be considered a hallmark of aging, and is likely a key factor in mediating altered biological function of aged stem cells. In this review, we outline cell intrinsic and extrinsic mediators of epigenome remodeling during aging; discuss how such changes can impact on stem cell function; and describe how resetting the aged epigenome may rejuvenate some of the biological characteristics of stem cells.
The rates and patterns of somatic mutation in normal tissues are largely unknown outside of humans
. Comparative analyses can shed light on the diversity of mutagenesis across species, and on ...long-standing hypotheses about the evolution of somatic mutation rates and their role in cancer and ageing. Here we performed whole-genome sequencing of 208 intestinal crypts from 56 individuals to study the landscape of somatic mutation across 16 mammalian species. We found that somatic mutagenesis was dominated by seemingly endogenous mutational processes in all species, including 5-methylcytosine deamination and oxidative damage. With some differences, mutational signatures in other species resembled those described in humans
, although the relative contribution of each signature varied across species. Notably, the somatic mutation rate per year varied greatly across species and exhibited a strong inverse relationship with species lifespan, with no other life-history trait studied showing a comparable association. Despite widely different life histories among the species we examined-including variation of around 30-fold in lifespan and around 40,000-fold in body mass-the somatic mutation burden at the end of lifespan varied only by a factor of around 3. These data unveil common mutational processes across mammals, and suggest that somatic mutation rates are evolutionarily constrained and may be a contributing factor in ageing.
Haematopoietic stem cells (HSCs) are responsible for the lifelong production of blood cells. The accumulation of DNA damage in HSCs is a hallmark of ageing and is probably a major contributing factor ...in age-related tissue degeneration and malignant transformation. A number of accelerated ageing syndromes are associated with defective DNA repair and genomic instability, including the most common inherited bone marrow failure syndrome, Fanconi anaemia. However, the physiological source of DNA damage in HSCs from both normal and diseased individuals remains unclear. Here we show in mice that DNA damage is a direct consequence of inducing HSCs to exit their homeostatic quiescent state in response to conditions that model physiological stress, such as infection or chronic blood loss. Repeated activation of HSCs out of their dormant state provoked the attrition of normal HSCs and, in the case of mice with a non-functional Fanconi anaemia DNA repair pathway, led to a complete collapse of the haematopoietic system, which phenocopied the highly penetrant bone marrow failure seen in Fanconi anaemia patients. Our findings establish a novel link between physiological stress and DNA damage in normal HSCs and provide a mechanistic explanation for the universal accumulation of DNA damage in HSCs during ageing and the accelerated failure of the haematopoietic system in Fanconi anaemia patients.
Chromosomal rearrangements involving the H3K4 methyltransferase mixed-lineage leukemia (MLL) trigger aberrant gene expression in hematopoietic progenitors and give rise to an aggressive subtype of ...acute myeloid leukemia (AML). Insights into MLL fusion-mediated leukemogenesis have not yet translated into better therapies because MLL is difficult to target directly, and the identity of the genes downstream of MLL whose altered transcription mediates leukemic transformation are poorly annotated. We used a functional genetic approach to uncover that AML cells driven by MLL-AF9 are exceptionally reliant on the cell-cycle regulator CDK6, but not its functional homolog CDK4, and that the preferential growth inhibition induced by CDK6 depletion is mediated through enhanced myeloid differentiation. CDK6 essentiality is also evident in AML cells harboring alternate MLL fusions and a mouse model of MLL-AF9–driven leukemia and can be ascribed to transcriptional activation of CDK6 by mutant MLL. Importantly, the context-dependent effects of lowering CDK6 expression are closely phenocopied by a small-molecule CDK6 inhibitor currently in clinical development. These data identify CDK6 as critical effector of MLL fusions in leukemogenesis that might be targeted to overcome the differentiation block associated with MLL-rearranged AML, and underscore that cell-cycle regulators may have distinct, noncanonical, and nonredundant functions in different contexts.
•CDK6 is a critical effector of MLL fusions in myeloid leukemogenesis.•Genetic and pharmacologic inhibition of CDK6 overcome the differentiation block associated with MLL-rearranged AML.
With ageing, intrinsic haematopoietic stem cell (HSC) activity decreases, resulting in impaired tissue homeostasis, reduced engraftment following transplantation and increased susceptibility to ...diseases. However, whether ageing also affects the HSC niche, and thereby impairs its capacity to support HSC function, is still widely debated. Here, by using in-vivo long-term label-retention assays we demonstrate that aged label-retaining HSCs, which are, in old mice, the most quiescent HSC subpopulation with the highest regenerative capacity and cellular polarity, reside predominantly in perisinusoidal niches. Furthermore, we demonstrate that sinusoidal niches are uniquely preserved in shape, morphology and number on ageing. Finally, we show that myeloablative chemotherapy can selectively disrupt aged sinusoidal niches in the long term, which is linked to the lack of recovery of endothelial Jag2 at sinusoids. Overall, our data characterize the functional alterations of the aged HSC niche and unveil that perisinusoidal niches are uniquely preserved and thereby protect HSCs from ageing.
Ecotropic viral integration site 1 (EVI1), encoded at the MECOM locus, is an oncogenic zinc finger transcription factor with diverse roles in normal and malignant cells, most extensively studied in ...the context of hematopoiesis. EVI1 interacts with other transcription factors in a context‐dependent manner and regulates transcription and chromatin remodeling, thereby influencing the proliferation, differentiation, and survival of cells. Interestingly, it can act both as a transcriptional activator as well as a transcriptional repressor. EVI1 is expressed, and fulfills important functions, during the development of different tissues, including the nervous system and hematopoiesis, demonstrating a rigid spatial and temporal expression pattern. However, EVI1 is regularly overexpressed in a variety of cancer entities, including epithelial cancers such as ovarian and pancreatic cancer, as well as in hematologic malignancies like myeloid leukemias. Importantly, EVI1 overexpression is generally associated with a very poor clinical outcome and therapy‐resistance. Thus, EVI1 is an interesting candidate to study to improve the prognosis and treatment of high‐risk patients with “EVI1high” hematopoietic malignancies.
Hematopoietic stem cells (HSCs) mediate regeneration of the hematopoietic system following injury, such as following infection or inflammation. These challenges impair HSC function, but whether this ...functional impairment extends beyond the duration of inflammatory exposure is unknown. Unexpectedly, we observed an irreversible depletion of functional HSCs following challenge with inflammation or bacterial infection, with no evidence of any recovery up to 1 year afterward. HSCs from challenged mice demonstrated multiple cellular and molecular features of accelerated aging and developed clinically relevant blood and bone marrow phenotypes not normally observed in aged laboratory mice but commonly seen in elderly humans. In vivo HSC self-renewal divisions were absent or extremely rare during both challenge and recovery periods. The progressive, irreversible attrition of HSC function demonstrates that temporally discrete inflammatory events elicit a cumulative inhibitory effect on HSCs. This work positions early/mid-life inflammation as a mediator of lifelong defects in tissue maintenance and regeneration.
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•HSCs fail to recover functional potency after inflammatory/infection challenge•Discrete challenges have a cumulative effect, even if separated by weeks or months•Inflammation in early life accelerates the cellular and molecular aging of HSCs•Mice exposed to inflammation develop features of aged human hematopoiesis
Inflammation and infection acutely suppress HSC function. However, the long-term ramifications of such challenges are unclear. This study demonstrates that murine HSCs fail to recover functional potency up to 1 year post-inflammatory/infection challenge, meaning that such events can have accumulative effects over a lifetime; this promotes acquisition of the aged state.
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