Hematopoietic stem cell (HSC) divisional memory: The journey of mitochondrial metabolism through HSC division
2021; Elsevier BV; Volume: 96; Linguagem: Inglês
10.1016/j.exphem.2021.01.006
ISSN1873-2399
Autores Tópico(s)Epigenetics and DNA Methylation
Resumo•HSC functions are inversely correlated with their divisional history.•Mitochondria remodeling occurs in HSCs throughout the cell cycle.•Mitochondria-driven metabolic adaptation drives HSC functional decline.•Mitochondria-driven metabolic adaptation may keep HSC divisional memory. Hematopoietic stem cells (HSCs) are characterized by their ability to produce all cells of the blood and immune system and have been used for transplantation for decades. Although the regenerative potential of HSCs is high, their self-renewal potential is limited. HSC functions are inversely correlated with their divisional history. Recent advances in our understanding of the regulation of HSCs through cell division suggest that HSCs may never replicate into identical self, but rather replicate into progeny that gradually lose functionality at each round of division. HSC division is accompanied by major transcriptional and metabolic changes. In this perspective, the possibility that mitochondrial metabolism confers HSC division memory and programs HSCs for extinction is discussed. Hematopoietic stem cells (HSCs) are characterized by their ability to produce all cells of the blood and immune system and have been used for transplantation for decades. Although the regenerative potential of HSCs is high, their self-renewal potential is limited. HSC functions are inversely correlated with their divisional history. Recent advances in our understanding of the regulation of HSCs through cell division suggest that HSCs may never replicate into identical self, but rather replicate into progeny that gradually lose functionality at each round of division. HSC division is accompanied by major transcriptional and metabolic changes. In this perspective, the possibility that mitochondrial metabolism confers HSC division memory and programs HSCs for extinction is discussed. Adult hematopoietic stem cells (HSCs) are at the apex of all hematopoietic cells. Being multipotent, HSCs give rise to all blood and immune lineages. HSCs are long-lived cells and reside mostly in a quiescent state. They divide infrequently to give rise to progeny that will maintain stem cell characteristics, that is, self-renewal. They also differentiate into highly proliferative progenitors that commit to mature lineage differentiation. HSCs are endowed with high regenerative potential and can sustain the production of all mature blood and immune cells for extended periods and, for this reason, have been used for clinical transplantation for decades. Yet, HSC self-renewal is not unlimited [1Bernitz JM Kim HS MacArthur B Sieburg H Moore K. Hematopoietic stem cells count and remember self-renewal divisions.Cell. 2016; 167: 1296-1309.e10Abstract Full Text Full Text PDF PubMed Scopus (152) Google Scholar, 2Hinge A Xu J Javier J et al.p190-B RhoGAP and intracellular cytokine signals balance hematopoietic stem and progenitor cell self-renewal and differentiation.Nat Commun. 2017; 8: 14382Crossref PubMed Scopus (25) Google Scholar, 3Qiu J Papatsenko D Niu X Schaniel C Moore K. Divisional history and hematopoietic stem cell function during homeostasis.Stem Cell Rep. 2014; 2: 473-490Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar, 4Wilson A Oser G van der Wath RC et al.Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair.Cell. 2008; 135: 1118-1129Abstract Full Text Full Text PDF PubMed Scopus (1332) Google Scholar, 5Yamamoto R Morita Y Ooehara J et al.Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells.Cell. 2013; 154: 1112-1126Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar]. Conditions that induce excessive HSC proliferation eventually cause HSC attrition [2Hinge A Xu J Javier J et al.p190-B RhoGAP and intracellular cytokine signals balance hematopoietic stem and progenitor cell self-renewal and differentiation.Nat Commun. 2017; 8: 14382Crossref PubMed Scopus (25) Google Scholar,5Yamamoto R Morita Y Ooehara J et al.Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells.Cell. 2013; 154: 1112-1126Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar]. It is generally believed that HSCs self-renew for a few divisions—under high regenerative needs or at steady state. After several divisions, HSC functions decline. The decline in HSC functions may come from a natural degradation of physiological functions caused by sustained cumulative stresses over time. Such a process could be relatively stochastic. Yet, with the advances in our understanding of the heterogeneity of HSC biology, an alternative model is emerging that suggests that HSCs may in fact never replicate into identical self, but rather replicate into progeny that gradually lose functionality at each round of division [3Qiu J Papatsenko D Niu X Schaniel C Moore K. Divisional history and hematopoietic stem cell function during homeostasis.Stem Cell Rep. 2014; 2: 473-490Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar,4Wilson A Oser G van der Wath RC et al.Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair.Cell. 2008; 135: 1118-1129Abstract Full Text Full Text PDF PubMed Scopus (1332) Google Scholar]. In this model, HSC functional decline starts as soon as after the first division and is progressive. It raises the intriguing possibility that yet-to-be-defined pathways are activated during the first cell division, the purpose of which is to reduce the functions of the HSC progeny. In this model, HSC functional decline would be developmentally programmed rather than stochastic and would be activated once HSCs exit dormancy. We know that HSC division is accompanied by major transcriptional and metabolic changes [6Ho TT Warr MR Adelman ER et al.Autophagy maintains the metabolism and function of young and old stem cells.Nature. 2017; 543: 205-210Crossref PubMed Scopus (450) Google Scholar, 7Ito K Suda T. Metabolic requirements for the maintenance of self-renewing stem cells.Nat Rev Mol Cell Biol. 2014; 15: 243-256Crossref PubMed Scopus (653) Google Scholar, 8Maryanovich M Gross A. 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In this perspective, I review the evidence supporting the model of a gradual HSC decline with divisions and what we know about the metabolic changes occurring in HSCs during and after the division process. I also discuss the possibility that division-associated metabolic remodeling may cause permanent epigenetic and transcriptional changes that confer HSC division memory and program HSCs for extinction.Figure 2HSC metabolic activity through division history. Quiescent HSCs have very low metabolic activity, but their mitochondrial content is high [6Ho TT Warr MR Adelman ER et al.Autophagy maintains the metabolism and function of young and old stem cells.Nature. 2017; 543: 205-210Crossref PubMed Scopus (450) Google Scholar,13Umemoto T Hashimoto M Matsumura T Nakamura-Ishizu A Suda T. Ca2+-mitochondria axis drives cell division in hematopoietic stem cells.J Exp Med. 2018; 215: 2097-2113Crossref PubMed Scopus (66) Google Scholar,14Hinge A He J Bartram J et al.Asymmetrically segregated mitochondria provide cellular memory of hematopoietic stem cell replicative history and drive HSC attrition.Cell Stem Cell. 2020; 26: 420-430.e6Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,22Ito K Turcotte R Cui J et al.Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance.Science. 2016; 354: 1156-1160Crossref PubMed Scopus (171) Google Scholar, 23Karigane D Kobayashi H Morikawa T et al.p38alpha activates purine metabolism to initiate hematopoietic stem/progenitor cell cycling in response to stress.Cell Stem Cell. 2016; 19: 192-204Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 24Signer RAJ Magee JA Salic A Morrison SJ. Haematopoietic stem cells require a highly regulated protein synthesis rate.Nature. 2014; 509: 49-54Crossref PubMed Scopus (345) Google Scholar, 25Morganti C Bonora M Ito K Ito K. Electron transport chain complex II sustains high mitochondrial membrane potential in hematopoietic stem and progenitor cells.Stem Cell Res. 2019; 40101573Crossref PubMed Scopus (15) Google Scholar]. Mitochondria are very dynamic and are regulated through a fission/fusion mechanism that maintains HSC homeostasis through cell division. On activation, both glycolysis and mitochondrial activity increase, along with several anabolic processes necessary for cell division [6Ho TT Warr MR Adelman ER et al.Autophagy maintains the metabolism and function of young and old stem cells.Nature. 2017; 543: 205-210Crossref PubMed Scopus (450) Google Scholar,13Umemoto T Hashimoto M Matsumura T Nakamura-Ishizu A Suda T. Ca2+-mitochondria axis drives cell division in hematopoietic stem cells.J Exp Med. 2018; 215: 2097-2113Crossref PubMed Scopus (66) Google Scholar,14Hinge A He J Bartram J et al.Asymmetrically segregated mitochondria provide cellular memory of hematopoietic stem cell replicative history and drive HSC attrition.Cell Stem Cell. 2020; 26: 420-430.e6Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,22Ito K Turcotte R Cui J et al.Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance.Science. 2016; 354: 1156-1160Crossref PubMed Scopus (171) Google Scholar,27Liang R Arif T Kalmykova S et al.Restraining lysosomal activity preserves hematopoietic stem cell quiescence and potency.Cell Stem Cell. 2020; 26: 359-376.e7Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. Initially, mitochondria are homogenously distributed to daughter cells [14Hinge A He J Bartram J et al.Asymmetrically segregated mitochondria provide cellular memory of hematopoietic stem cell replicative history and drive HSC attrition.Cell Stem Cell. 2020; 26: 420-430.e6Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar]. On return to quiescence, mitochondria are not fully repaired or removed and sustain injury. HSCs with divisional history carry abnormal mitochondria that have low membrane potential and are organized in a compact and polarized network [14Hinge A He J Bartram J et al.Asymmetrically segregated mitochondria provide cellular memory of hematopoietic stem cell replicative history and drive HSC attrition.Cell Stem Cell. 2020; 26: 420-430.e6Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar]. One consequence of this is an asymmetric segregation of abnormal mitochondria, coupled with an inability to reactivate mitochondria and metabolic pathways during HSC reactivation into cycle [14Hinge A He J Bartram J et al.Asymmetrically segregated mitochondria provide cellular memory of hematopoietic stem cell replicative history and drive HSC attrition.Cell Stem Cell. 2020; 26: 420-430.e6Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar].View Large Image Figure ViewerDownload Hi-res image Download (PPT) HSCs reside in specialized microenvironments or "niches" that maintain HSCs in a quiescent state. From time to time, HSCs exit quiescence to generate progeny that will either maintain stemness characteristics or fully commit to differentiation. Although HSCs are often introduced as possessing extensive self-renewal capacity, evidence indicates that HSCs can transmit stemness properties to progeny only a few times. In the classic mouse model of competitive serial transplantation, the transplantation cell dose needed to reconstitute the blood of secondary recipients is higher than that for repopulating primary recipients [2Hinge A Xu J Javier J et al.p190-B RhoGAP and intracellular cytokine signals balance hematopoietic stem and progenitor cell self-renewal and differentiation.Nat Commun. 2017; 8: 14382Crossref PubMed Scopus (25) Google Scholar,5Yamamoto R Morita Y Ooehara J et al.Clonal analysis unveils self-renewing lineage-restricted progenitors generated directly from hematopoietic stem cells.Cell. 2013; 154: 1112-1126Abstract Full Text Full Text PDF PubMed Scopus (438) Google Scholar,15Xu H Eleswarapu S Geiger H et al.Loss of the Rho GTPase activating protein p190-B enhances hematopoietic stem cell engraftment potential.Blood. 2009; 114: 3557-3566Crossref PubMed Scopus (18) Google Scholar]. Likewise, after myeloablative chemotherapy, HSCs possess reduced capacity to reconstitute the hematopoietic system. Reduced repopulation potential is also observed after repeated inflammatory challenges in vivo (bioRxiv doi: https://doi.org/10.1101/2020.08.01.230433) [16Bogeska R, Kaschutnig P, Fawaz M, et al. Hematopoietic stem cells fail to regenerate following inflammatory challenge, BioRxiv, doi:org/10.1101/2020.08.01.230433.Google Scholar]. It is thus well documented that quiescence is a means to prevent HSC premature exhaustion associated with excessive replication [17Hsu P Qu CK. Metabolic plasticity and hematopoietic stem cell biology.Curr Opin Hematol. 2013; 20: 289-294Crossref PubMed Scopus (18) Google Scholar, 18Takubo K Suda T. Roles of the hypoxia response system in hematopoietic and leukemic stem cells.Int J Hematol. 2012; 95: 478-483Crossref PubMed Scopus (32) Google Scholar, 19Vannini N Girotra M Naveiras O et al.Specification of haematopoietic stem cell fate via modulation of mitochondrial activity.Nat Commun. 2016; 7: 13125Crossref PubMed Scopus (141) Google Scholar]. Interestingly, studies that used doxycycline-induced histone 2B (H2B) fusion protein labeling systems to track HSC division in vivo under homeostatic conditions have reported that HSC functional decline with divisions also occurs at steady state. In this model, after Histone-2B Green Fluorescent Protein (H2B-GFP) labeling, H2B-GFP is diluted with each round of division. Five divisions are required for a H2B-GFP+ cell to be rendered undetectable by fluorescence-activated cell sorting (FACS) [4Wilson A Oser G van der Wath RC et al.Hematopoietic stem cells reversibly switch from dormancy to self-renewal during homeostasis and repair.Cell. 2008; 135: 1118-1129Abstract Full Text Full Text PDF PubMed Scopus (1332) Google Scholar]. The highest repopulation potential is always found within GFP-positive cells. Studies by Moore's group further established that reconstitution potential progressively diminishes at each division [3Qiu J Papatsenko D Niu X Schaniel C Moore K. Divisional history and hematopoietic stem cell function during homeostasis.Stem Cell Rep. 2014; 2: 473-490Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar]. They reported that within a hematopoietic stem and progenitor population (hematopoietic stem/progenitor cells [HSPCs], Lin–cKit+Sca-1+ [LSK]), the cells retain different levels of H2B-GFP label over the course of several months, which presumably represent HSPC subsets with distinct division history. They identified four successive GFP levels within an LSK population. They found that the frequency of cells in the G0 phase of the cell cycle progressively diminishes with GFP dilution. Remarkably, reconstitution potential gradually decreased along with GFP dilution [3Qiu J Papatsenko D Niu X Schaniel C Moore K. Divisional history and hematopoietic stem cell function during homeostasis.Stem Cell Rep. 2014; 2: 473-490Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar]. In vitro, the long-term culture potential of GFP-labeled LSK subsets also correlated with the degree of GFP retention [3Qiu J Papatsenko D Niu X Schaniel C Moore K. Divisional history and hematopoietic stem cell function during homeostasis.Stem Cell Rep. 2014; 2: 473-490Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar]. Similar findings were obtained using a more HSC-enriched LSK–CD48–CD150+ population. Sawen et al. [20Sawen P Lang S Mandal P Rossi DJ Soneji S Bryder D. Mitotic history reveals distinct stem cell populations and their contributions to hematopoiesis.Cell Rep. 2016; 14: 2809-2918Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar] independently reported that HSCs [LSK–CD48–CD150+] with a more restricted proliferative history but the highest repopulation potential exhibited higher Sca1 expression and lower c-Kit expression when compared with HSCs that had proliferated more extensively [20Sawen P Lang S Mandal P Rossi DJ Soneji S Bryder D. Mitotic history reveals distinct stem cell populations and their contributions to hematopoiesis.Cell Rep. 2016; 14: 2809-2918Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. These findings have now been confirmed by our group (unpublished data, James Bartram and MFD). Molecularly, these HSC subsets also have distinct transcriptional signatures [3Qiu J Papatsenko D Niu X Schaniel C Moore K. Divisional history and hematopoietic stem cell function during homeostasis.Stem Cell Rep. 2014; 2: 473-490Abstract Full Text Full Text PDF PubMed Scopus (77) Google Scholar,20Sawen P Lang S Mandal P Rossi DJ Soneji S Bryder D. Mitotic history reveals distinct stem cell populations and their contributions to hematopoiesis.Cell Rep. 2016; 14: 2809-2918Abstract Full Text Full Text PDF PubMed Scopus (46) Google Scholar]. Hence, HSCs seem to acquire distinct characteristics, both phenotypic and functional, with each division. Therefore, in contrast to the conventional view that HSC activity can be maintained for few divisions before declining, HSC functional decline is rather gradual and starts at the first division in a still "young" environment. The model of a progressive HSC functional decline with subsequent cell divisions raises several intriguing questions: Does cellular division memory exist, and if so, what carries this memory from cell to cell to permanently change HSC functions and determine the life span of the HSC pool? Until two years ago, quiescent HSCs were believed to possess few mitochondria, have low oxidative phosphorylation and reactive oxygen species, and rely mostly on anaerobic glycolysis [17Hsu P Qu CK. Metabolic plasticity and hematopoietic stem cell biology.Curr Opin Hematol. 2013; 20: 289-294Crossref PubMed Scopus (18) Google Scholar, 18Takubo K Suda T. Roles of the hypoxia response system in hematopoietic and leukemic stem cells.Int J Hematol. 2012; 95: 478-483Crossref PubMed Scopus (32) Google Scholar, 19Vannini N Girotra M Naveiras O et al.Specification of haematopoietic stem cell fate via modulation of mitochondrial activity.Nat Commun. 2016; 7: 13125Crossref PubMed Scopus (141) Google Scholar,21Ito K Carracedo A Weiss D et al.A PML–PPAR-delta pathway for fatty acid oxidation regulates hematopoietic stem cell maintenance.Nat Med. 2012; 18: 1350-1358Crossref PubMed Scopus (471) Google Scholar]. Although some of these features remain true, recent studies suggest that the metabolism of HSCs is more complex than initially thought. Quiescent HSCs do have very low metabolic activity, including low levels of gene transcription, protein translation, and mitochondrial activity [6Ho TT Warr MR Adelman ER et al.Autophagy maintains the metabolism and function of young and old stem cells.Nature. 2017; 543: 205-210Crossref PubMed Scopus (450) Google Scholar,13Umemoto T Hashimoto M Matsumura T Nakamura-Ishizu A Suda T. Ca2+-mitochondria axis drives cell division in hematopoietic stem cells.J Exp Med. 2018; 215: 2097-2113Crossref PubMed Scopus (66) Google Scholar,14Hinge A He J Bartram J et al.Asymmetrically segregated mitochondria provide cellular memory of hematopoietic stem cell replicative history and drive HSC attrition.Cell Stem Cell. 2020; 26: 420-430.e6Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,22Ito K Turcotte R Cui J et al.Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance.Science. 2016; 354: 1156-1160Crossref PubMed Scopus (171) Google Scholar, 23Karigane D Kobayashi H Morikawa T et al.p38alpha activates purine metabolism to initiate hematopoietic stem/progenitor cell cycling in response to stress.Cell Stem Cell. 2016; 19: 192-204Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar, 24Signer RAJ Magee JA Salic A Morrison SJ. Haematopoietic stem cells require a highly regulated protein synthesis rate.Nature. 2014; 509: 49-54Crossref PubMed Scopus (345) Google Scholar, 25Morganti C Bonora M Ito K Ito K. Electron transport chain complex II sustains high mitochondrial membrane potential in hematopoietic stem and progenitor cells.Stem Cell Res. 2019; 40101573Crossref PubMed Scopus (15) Google Scholar]. However, several groups have now established that HSCs contain large numbers of mitochondria [14Hinge A He J Bartram J et al.Asymmetrically segregated mitochondria provide cellular memory of hematopoietic stem cell replicative history and drive HSC attrition.Cell Stem Cell. 2020; 26: 420-430.e6Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,26de Almeida MJ L.L. Corrigan DJ Williams LJ Snoeck HW Dye-independent methods reveal elevated mitochondrial mass in hematopoietic stem cells.Cell Stem Cell. 2017; 6: 725-729Abstract Full Text Full Text PDF Scopus (111) Google Scholar, 27Liang R Arif T Kalmykova S et al.Restraining lysosomal activity preserves hematopoietic stem cell quiescence and potency.Cell Stem Cell. 2020; 26: 359-376.e7Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar, 28Takihara Y Nakamura-Ishizu A Tan DQ et al.High mitochondrial mass is associated with reconstitution capacity and quiescence of hematopoietic stem cells.Blood Adv. 2019; 3: 2323-2327Crossref PubMed Scopus (16) Google Scholar]. Elegant studies from Suda's laboratory identified subsets of HSCs (LSK–CD48–CD150+) based on their mitochondrial content. They found that the highest repopulation activity is within the HSC pool possessing the largest number of mitochondria [28Takihara Y Nakamura-Ishizu A Tan DQ et al.High mitochondrial mass is associated with reconstitution capacity and quiescence of hematopoietic stem cells.Blood Adv. 2019; 3: 2323-2327Crossref PubMed Scopus (16) Google Scholar]. At the same time, HSCs exhibit low mitochondrial activity, with low mitochondrial membrane potential (mt-mp), low reactive oxygen species (ROS), and oxidative phosphorylation (OXPHOS). When separated based on their mt-mp, HSCs (LSK–CD48–CD150+] with low mt-mp are deeply quiescent and exhibit low rates of protein translation and mRNA transcription, confirming their low metabolic state [27Liang R Arif T Kalmykova S et al.Restraining lysosomal activity preserves hematopoietic stem cell quiescence and potency.Cell Stem Cell. 2020; 26: 359-376.e7Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar], but they possess the highest reconstitution potential and self-renewal ability in engraftment studies [18Takubo K Suda T. Roles of the hypoxia response system in hematopoietic and leukemic stem cells.Int J Hematol. 2012; 95: 478-483Crossref PubMed Scopus (32) Google Scholar,27Liang R Arif T Kalmykova S et al.Restraining lysosomal activity preserves hematopoietic stem cell quiescence and potency.Cell Stem Cell. 2020; 26: 359-376.e7Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar,29Simsek T Kocabas F Zheng J et al.The distinct metabolic profile of hematopoietic stem cells reflects their location in a hypoxic niche.Cell Stem Cell. 2010; 7: 380-390Abstract Full Text Full Text PDF PubMed Scopus (725) Google Scholar]. It was suggested that HSCs with high mt-mp may be in a primed—or ready-for-activation—cellular state [27Liang R Arif T Kalmykova S et al.Restraining lysosomal activity preserves hematopoietic stem cell quiescence and potency.Cell Stem Cell. 2020; 26: 359-376.e7Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. These findings suggest that mitochondria may not participate in energy supply in HSCs. HSCs may use anaerobic glycolysis as a source of energy. HSCs (LSK–CD48–CD41–CD150+) have high expression of HIF1a and a high degree of retention of pimonidazole, indicative of hypoxic status [30Takubo K Goda N Yamada W et al.Regulation of the HIF-1alpha level is essential for hematopoietic stem cells.Cell Stem Cell. 2010; 7: 391-402Abstract Full Text Full Text PDF PubMed Scopus (648) Google Scholar]. Initial metabolomic analyses revealed that phenotypically defined LSK–Flt3–CD34– HSCs accumulate fructose-1,6-biphosphate and have high pyruvate kinase activity, which is indicative of active glycolysis [18Takubo K Suda T. Roles of the hypoxia response system in hematopoietic and leukemic stem cells.Int J Hematol. 2012; 95: 478-483Crossref PubMed Scopus (32) Google Scholar,31Takubo K Nagamatsu G Kobayashi CI et al.Regulation of glycolysis by Pdk functions as a metabolic checkpoint for cell cycle quiescence in hematopoietic stem cells.Cell Stem Cell. 2013; 12: 49-61Abstract Full Text Full Text PDF PubMed Scopus (481) Google Scholar]. More recent studies report that low-mt-mp LSK–CD48–CD150+ HSCs exhibit low glucose uptake and glycolytic rate, implying that these cells rely on an alternate source of nutrients. A role for lysosomes instead of glucose was suggested to maintain low metabolic activity of quiescent HSCs [27Liang R Arif T Kalmykova S et al.Restraining lysosomal activity preserves hematopoietic stem cell quiescence and potency.Cell Stem Cell. 2020; 26: 359-376.e7Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. These findings are important and require further in-depth investigation to fully understand what nutrients HSCs utilize for fueling their energy demand. Information on the metabolic changes necessary for HSC transition into cell cycle have recently emerged. The transition into cell cycle requires the coordination between cell cycle control, anabolic/synthetic activities (to generate nucleotides, proteins, and lipids), and the production of energy to fuel these processes. Unsurprisingly, transition into cell cycle is accompanied by major increases in transcriptional activity mostly targeting expression of cell cycle genes and genes encoding metabolic enzymes [14Hinge A He J Bartram J et al.Asymmetrically segregated mitochondria provide cellular memory of hematopoietic stem cell replicative history and drive HSC attrition.Cell Stem Cell. 2020; 26: 420-430.e6Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar,23Karigane D Kobayashi H Morikawa T et al.p38alpha activates purine metabolism to initiate hematopoietic stem/progenitor cell cycling in response to stress.Cell Stem Cell. 2016; 19: 192-204Abstract Full Text Full Text PDF PubMed Scopus (60) Google Scholar]. Consistently, an increase in metabolites is observed in active HSPCs, as seen in metabolomic analyses of HSC-enriched populations (i.e., LSK cells) collected within hours of bone marrow transplantation [22Ito K Turcotte R Cui J et al.Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance.Science. 2016; 354: 1156-1160Crossref PubMed Scopus (171) Google Scholar]. Interestingly, both glycolysis and mitochondrial activity increase with HSPC cell cycle [6Ho TT Warr MR Adelman ER et al.Autophagy maintains the metabolism and function of young and old stem cells.Nature. 2017; 543: 205-210Crossref PubMed Scopus (450) Google Scholar,13Umemoto T Hashimoto M Matsumura T Nakamura-Ishizu A Suda T. Ca2+-mitochondria axis drives cell division in hematopoietic stem cells.J Exp Med. 2018; 215: 2097-2113Crossref PubMed Scopus (66) Google Scholar,14Hinge A He J Bartram J et al.Asymmetrically segregated mitochondria provide cellular memory of hematopoietic stem cell replicative history and drive HSC attrition.Cell Stem Cell. 2020; 26: 420-430.e6Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar, 22Ito K Turcotte R Cui J et al.Self-renewal of a purified Tie2+ hematopoietic stem cell population relies on mitochondrial clearance.Science. 2016; 354: 1156-1160Crossref PubMed Scopus (171) Google Scholar,27Liang R Arif T Kalmykova S et al.Restraining lysosomal activity preserves hematopoietic stem cell quiescence and potency.Cell Stem Cell. 2020; 26: 359-376.e7Abstract Full Text Full Text PDF PubMed Scopus (73) Google Scholar]. Each of these metabolic changes is fun
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