Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions

Guitart, Amélie V.; Panagopoulou, Theano I.; Villacreces, Arnaud; Vukovic, Milica; Sepúlveda, Catarina; Allen, Lewis; Carter, Roderick N.; Lagemaat, Louie N. van de; Morgan, Marcos; Giles, Peter; Sas, Zuzanna; González, Marta Vilà; Lawson, Hannah; Paris, J; Edwards-Hicks, Joy; Schaak, Katrin; Subramani, Chithra; Gezer, Deniz; Armesilla-Diaz, Alejandro; Wills, Jimi; Easterbrook, Aaron; Coman, David; So, Chi Wai Eric; O’Carroll, Dónal; Vernimmen, Douglas; Rodrigues, Neil P.; Pollard, Patrick J.; Morton, Nicholas M.; Finch, Andrew J.; Kranc, Kamil R.

doi:10.1084/jem.20161087

Cited by 70 publications

(68 citation statements)

References 69 publications

(118 reference statements)

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“…We showed previously that the mitochondrial fusion protein, Mitofusin 2 (Mfn2), is required for the maintenance of HSCs with extensive lymphoid potential, and that this effect was mediated through enhanced buffering of intracellular calcium by mitochondria (Luchsinger et al, 2016). Though recent publications do indicate an important role for respiration in HSC maintenance as well (Anso et al, 2017; Bejarano-Garcia et al, 2016; Guitart et al, 2017), these findings suggest that mitochondria perform specific and essential roles in HSCs, including but likely not limited to calcium buffering, that may not be directly dependent on ATP production. We therefore suggest that the role of mitochondria in the biology of HSCs may need to be revisited.…”

Section: Discussionmentioning

confidence: 69%

“…In contrast to most mature cells, HSCs rely predominantly on glycolytic ATP production (Ito and Suda, 2014; Shyh-Chang et al, 2013; Simsek et al, 2010; Takubo et al, 2013). While shown to be important for HSC maintenance (Anso et al, 2017; Bejarano-Garcia et al, 2016; Guitart et al, 2017), some experimental data suggest that mitochondrial respiration may indeed be more dispensable for HSCs than for progenitors (Norddahl et al, 2011; Yu et al, 2013). Consistent with their reduced mitochondrial respiration, HSCs have been reported to be endowed with low mitochondrial mass based on staining with mitochondrial dyes (Mantel et al, 2012; Mohrin et al, 2015; Romero-Moya et al, 2013; Simsek et al, 2010; Takubo et al, 2013; Vannini et al, 2016; Xiao et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

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Dye-Independent Methods Reveal Elevated Mitochondrial Mass in Hematopoietic Stem Cells

et al. 2017

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Hematopoietic stem cells (HSCs) produce most cellular energy through glycolysis rather than through mitochondrial respiration. Consistent with this notion, mitochondrial mass has been reported to be low in HSCs. However, we found that staining with mitotracker green, a commonly used dye to measure mitochondrial content, leads to artifactually low fluorescence specifically in HSCs because of dye efflux. Using mtDNA quantification, enumeration of mitochondrial nucleoids and fluorescence intensity of a genetically encoded mitochondrial reporter we unequivocally show here that HSCs and multipotential progenitors (MPPs) have higher mitochondrial mass than lineage-committed progenitors and mature cells. Despite similar mitochondrial mass, respiratory capacity of MPPs exceeds that of HSCs. Furthermore, although elevated mitophagy has been invoked to explain low mitochondrial mass in HSCs, we observed that mitochondrial turnover capacity is comparatively low in HSCs. We propose that the role of mitochondria in HSC biology may have to be revisited in light of these findings.

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Section: Discussionmentioning

confidence: 69%

Section: Introductionmentioning

confidence: 99%

Dye-Independent Methods Reveal Elevated Mitochondrial Mass in Hematopoietic Stem Cells

et al. 2017

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“…On the other hand, loss of fumarate hydratase (Fh1), a TCA cycle enzyme, in HSCs blocks that cycle. Fh1-deficient fetal HSCs fail to self-renew and differentiate into a lymphoid lineage, defects potentially due to increased histone trimethylation, including H3K9me3, H3K27me3, and H3K36me3 but not H3K4me3 [25]. Recently, mitochondrial dynamics as well as activity of mitochondrial enzymes was shown to contribute to HSC heterogeneity.…”

Section: Role Of the Tca Cycle And Oxphos In Hsc Differentiationmentioning

confidence: 99%

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Karigane

Takubo

2017

Int J Hematol

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organisms. HSPCs are composed of hematopoietic stem cells (HSCs) and several types of lineage-biased, but not fully committed, hematopoietic progenitor cells (HPCs). HSC capacities such as self-renewal and multilineage differentiation maintain the whole hematopoietic system over an organism's lifetime [1], and contribute to blood regeneration under stress condition, whereas HPCs reportedly function to maintain the supply of blood cells at steady state [2,3]. The surrounding BM microenvironment or "niche" determines HSC fate, namely its quiescence, symmetric/asymmetric division, differentiation, or migration potential, in both steady state and during stress. It is now evident that metabolic programs operating in HSCs play critical roles in maintaining hematopoietic homeostasis [4], often in response to BM niche signals [5]. Cellular pathways generate various metabolites through enzymatic activity that supplies material used as fuel, building blocks for other factors, or modulators of intra-or intercellular activities (Fig. 1). Despite the fact that numerous biochemical studies have addressed HSC metabolic regulation, numerous gaps in our knowledge of that regulation remain.Recently, novel means to fractionate metabolites using highly sensitive mass spectrometric technology [6] have dramatically facilitated metabolome analysis. These technologies reduce the need for high cell numbers and increase sensitivity of metabolite selection. As a result, metabolome analysis is feasible in rare cell populations such as HSCs. These analyses have revealed that metabolic programs play critical roles in maintaining stem cell "stemness" (Fig. 2). Here we review recent advances in the field of how metabolic changes regulate HSC dynamics under quiescence, proliferation, and differentiation from the viewpoint of each pathway. In addition to the normal HSC system, we also review activity of leukemia-related metabolic pathways, tumor-associated metabolites (oncometabolites), and Abstract Hematopoietic stem cells (HSCs) exhibit multilineage differentiation and self-renewal activities that maintain the entire hematopoietic system during an organism's lifetime. These abilities are sustained by intrinsic transcriptional programs and extrinsic cues from the microenvironment or niche. Recent studies using metabolomics technologies reveal that metabolic regulation plays an essential role in HSC maintenance. Metabolic pathways provide energy and building blocks for other factors functioning at steady state and in stress. Here we review recent advances in our understanding of metabolic regulation in HSCs relevant to cell cycle quiescence, symmetric/asymmetric division, and proliferation following stress and lineage commitment, and discuss the therapeutic potential of targeting metabolic factors or pathways to treat hematological malignancies.

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“…Results showed increased OCR, mitochondrial potential and ROS levels in FL derived HSCs indicating altered metabolic pathways. Deletion of a key component of TCA, Fumarate hydratase (Fh), in hematopoietic tissue‐specific manner resulted in decrease in OCR in the FL derived HSCs . While no viable Vav‐Fh –/– offspring were observed, E14.5 embryos showed severe impairment in FL hematopoiesis.…”

Section: Is the Metabolic Status Of Fetal Hscs Same As In Adults?mentioning

confidence: 99%

Energy Producing Metabolic Pathways in Functional Regulation of the Hematopoietic Stem Cells

et al. 2018

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The hematopoietic system has a very well-studied hierarchy with the long-term (LT) hematopoietic stem cells (HSCs) taking the top position. The pool of quiescent adult LT-HSCs generated during the fetal and early postnatal life acts as a reservoir to supply all the blood cells. Therefore, the maintenance of this stem cell pool is pivotal to maintaining homeostasis in hematopoietic system. It has long been known that external cues, along with the internal genetic factors influence the status of HSCs in the bone marrow (BM). Hypoxia is one such factor that regulates the vascular as well as hematopoietic ontogeny from a very early time point in development. The metabolic outcomes of a hypoxic microenvironment play important roles in functional regulation of HSCs, especially in case of adult BM HSCs. Anaerobic metabolic pathways therefore perform prominent role in meeting energy demands. Increased oxidative pathways on the other hand result in loss of stemness. Recent studies have attributed the functional differences in HSCs across different life stages to their metabolic phenotypes regulated by respective niches. Indicating thus, that various energy production pathways could play distinct role in regulating HSC function at different developmental/physiological states. Here, we review the current status of our understanding over the role that energy production pathways play in regulating HSC stemness. © 2018 IUBMB Life, 70(7):612-624, 2018.

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Fumarate hydratase is a critical metabolic regulator of hematopoietic stem cell functions

Abstract: Guitart et al. performed an in vivo genetic dissection of the Krebs cycle enzyme fumarate hydratase (Fh1) in the hematopoietic system. Their investigations revealed multifaceted functions of Fh1 in the regulation of hematopoietic stem cell biology and leukemic transformation.

Cited by 70 publications

References 69 publications

Dye-Independent Methods Reveal Elevated Mitochondrial Mass in Hematopoietic Stem Cells

Dye-Independent Methods Reveal Elevated Mitochondrial Mass in Hematopoietic Stem Cells

Metabolic regulation of hematopoietic and leukemic stem/progenitor cells under homeostatic and stress conditions

Energy Producing Metabolic Pathways in Functional Regulation of the Hematopoietic Stem Cells

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