Wikipedia

Metabolic regulation of hematopoiesis

Hematopoietic stem cells (HSCs) have high regenerative potentials and are capable of differentiating into all blood and immune system cells. Despite this impressive potential, HSCs have limited potential to produce more multipotent stem cells.[1] This limited self-renewal potential is protected through maintenance of a quiescent state in HSCs. Stem cells maintained in this quiescent state are known as long term HSCs (LT-HSCs). During quiescence, HSCs maintain a low level of metabolic activity and do not divide.[2][3][4] LT-HSCs can be signaled to proliferate, producing either myeloid or lymphoid progenitors. Production of these progenitors does not come without a cost: When grown under laboratory conditions that induce proliferation, HSCs lose their ability to divide and produce new progenitors.[5] Therefore, understanding the pathways that maintain proliferative or quiescent states in HSCs could reveal novel pathways to improve existing therapeutics involving HSCs.[6]

Background edit

All adult stem cells can undergo two types of division: symmetric and asymmetric. When a cell undergoes symmetric division, it can either produce two differentiated cells or two new stem cells. When a cell undergoes asymmetric division, it produces one stem and one differentiated cell. Production of new stem cells is necessary to maintain this population within the body.[7] Like all cells, hematopoietic stem cells undergo metabolic shifts to meet their bioenergetic needs throughout development.[1] These metabolic shifts play an important role in signaling, generating biomass, and protecting the cell from damage. Metabolic shifts also guide development in HSCs and are one key factor in determining if an HSC will remain quiescent, symmetrically divide, or asymmetrically divide.[1][8][9][10] As mentioned above, quiescent cells maintain a low level of oxidative phosphorylation and primarily rely on glycolysis to generate energy. Fatty acid beta-oxidation has been shown to influence fate decisions in HSCs.[11] In contrast, proliferative HSCs primarily depend on oxidative phosphorylation. This switch is accompanied by an increase in intracellular reactive oxygen species (ROS) levels and increased anabolic activity in cells[3][12][13][14]

Maintenance of quiescence edit

Glycolysis and Hif signaling edit

It is well understood that quiescent HSCs have very low levels of metabolic activity. LT-HSCs primarily rely on anaerobic glycolysis to generate energy. Unlike other types of HSCs, little energy is produced from mitochondrial oxidative respiration. The reason from this is likely two-fold: LT-HSCs reside within the hypoxic niche of the bone marrow, and low levels of mitochondrial respiration protect quiescent cells from damage induced ROS.[15][16] When excessive levels of ROS are present, LT-HSCs undergo differentiation or apoptosis, losing their ability to self-renew.[17] This suggests that dependence on glycolysis is not only an environmental adaptation, but also a necessity for LT-HSCs to preserve their stemness.

LT-HSC preference for glycolysis is encoded by the transcription factor MEIS1 and, to a lesser extent, the protein CBP/p300-interacting transactivator 2 (CITED2).[18][19][20] Both enzymes up regulate hypoxia-inducible factor 1α (HIF1α). Under hypoxic conditions, HIF1α dimerizes with HIF1ß to increase expression of several glycolytic enzymes to lead to an enhanced rate of glycolysis.[19] HIF1α also activates pyruvate dehydrogenase kinases (PDK) 2 and 4.[15] These enzymes inhibit pyruvate dehydrogenase (PDH). PDH converts pyruvate into acetyl-CoA, a crucial first step for metabolite entry into the TCA cycle and oxidative phosphorylation. Because this system inhibits mitochondrial metabolism and activates glycolysis, it is thought that the metabolic reprogramming by HIF1α is a main driver of LT-HSC quiescence.

Metabolic reprogramming by HIF1α does not always happen through action on PDKs. HIF1α can also promote expression of the cytosolic protein CRIPTO. CRIPTO then interacts with its cell surface receptor GRP78 to activate glycolytic enzymes.[21][22] Extracellular cytokines and chemokines may also contribute to HIF1α activity, but further work is required to elucidate the exact contribution of these signaling molecules.

In addition to HIF1α, MEIS1 induces transcription of HIF2α. Though this enzyme is structurally similar to HIF1α, HIF2α has distinct functions. HIF2α is thought to protect HSCs from mitochondrial ROS production. An accumulation of ROS in HSCs causes stress at the endoplasmic reticulum, eventually inducing the unfolded protein response and apoptosis.[23] HIF2α protects the cell from ROS accumulation by up regulating several genes involved in ROS quenching, including catalase, glutathione peroxidase type I, and superoxide dismutases.[8] Activation of HIF2α is therefore necessary to maintain cellular health during quiescence.

Mitochondrial metabolism edit

 
Figure 1. Summary of the effects of mitochondrial mass on hematopoietic stem cell quiescence and proliferation.[24] Created with BioRender.com

Despite low levels of mitochondrial respiration, emerging evidence shows that LT-HSCs with the highest regenerative potential also have a high number of mitochondria.[25] Despite this, quiescent HSC mitochondria have a low membrane potential and low rates of oxidative phosphorylation. This again highlights the dependence of LT-HSCs on glycolysis to generate energy. Despite their inactivity, possessing many mitochondria may indicate that the quiescent HSCs are prepared for proliferation once an appropriate signal is received[24]

Cell fate decisions edit

Recently, it has been discovered that fatty acid oxidation (FAO) is a major determinant in whether a stem cell will symmetrically or asymmetrically divide.[26] Transport of fatty acids into the mitochondria and their subsequent metabolism must be efficient in order for cells to maintain the ability to self-renew. In HSCs, transcriptional activation of nuclear genes involved in fatty acid transport and ß-oxidation through a promyelocytic leukemia protein (PML)/peroxisome proliferation-activated receptor-gamma coactivator 1α (PGC-1α)/peroxisome proliferator-activating receptor type δ (PPARδ) mediates efficiency of these processes. This pathway is also essential for HSC self-renewal because it promotes maintenance of the stem cell population.[26] FAO promotes asymmetric HSC division to produce one progenitor and one stem cell. Inhibition of FAO has been shown to expand the population of progenitor cells, thus decreasing the stem cell population.[27] Despite correlations between FAO and asymmetrical HSC divisions, the exact mechanism by which FAO governs stem cell fate decisions is still unclear.

Metabolism during proliferation edit

Hif1 and the switch to mitochondrial metabolism edit

 
Figure 2. Summary of HIF1α regulation in hematopoietic stem cells. Stabilization of HIF1α causes a shift towards glycolysis, while degradation promotes the TCA cycle and oxidative phosphorylation.[28]

Though maintenance of quiescence is important to HSCs to preserve their self-renewal capacity, proliferation is necessary to regenerate blood cells and immune cells for the body. During divisions, HSCs leave the hypoxic niche and begin circulating. Under these normoxic conditions, HIF1α is hydroxylated by prolyl hydroxylases PHD1, 2 and 3.[29][30][31] This hydroxylation triggers the cell to degrade HIF1α through the von Hippel-Lindau (VHL) ubiquitin ligases. Degradation of HIF1α prevents dimerization with HIF1ß, impeding the transcription of glycolytic genes. Degrading HIF1α also prevents activation of PDK2 and 4, thus resuming function of PDH in the mitochondria. Because the cell is now able to catalyze the production of acetyl-CoA, mitochondrial metabolism is able to resume. Restoration of this mitochondrial metabolism is coordinated by reentry into the cell cycle. Concurrent with reinitiation of mitochondrial metabolism is an upregulation in transcription of cell cycle genes and genes involved in anabolic activities.[32][33] As expected, HSCs with a high mitochondrial membrane potential have higher rates of expression for genes related to the cell cycle and metabolism.[33] The accompanying increase in ROS levels in these proliferating HSCs may in part drive differentiation of HSCs, but more work is needed to fully elucidate the role of ROS in this process[27]

Accompanying the processes driven by HIF1α is an activation of mitochondrial oxidative phosphorylation through inactivation of the protein tyrosine phosphatase mitochondrial 1 (PTPMT1) enzyme.[27] PTPMT-1 is essential for differentiation of HSCs into progenitors, and loss of this enzyme results in failure to produce blood cells in mice.[34] Targets of PTPMT-1 include phosphatidylinositol phosphates (PIPs). When PIPs are acted upon by PTPMT-1, the mitochondrial membrane potential decreases. This decrease inhibits glucose entry into the TCA cycle and subsequent ATP generation through the electron transport chain.[34] Thus, PTPMT-1 activity is crucial for HSCs to differentiate.

MTCH2 signaling edit

Another important suppressor of mitochondrial metabolism during quiescence is mitochondrial carrier homolog 2 (MTCH2).[16] Loss of MTCH2 increases oxidative phosphorylation and triggers HSC differentiation. As expected, this increase in oxidative phosphorylation increases ROS levels, ATP levels, and mitochondrial size. These phenotypes highlight the importance of MTCH2 in directing HSC fate.

The pentose phosphate pathway edit

Upregulation of glycolysis in proliferative HSCs may drive the pentose phosphate pathway (PPP) to maintain redox balance upon mitochondrial activation.[35][36] The PPP generates nicotinamide adenine dinucleotide phosphate (NADPH), which is a powerful cellular reducing agent. Production of NADPH may protect cells against accumulation of ROS because it is a key component in the glutathione-reductase system.[36] Additionally, NADPH is required for synthesis of nucleic acids and lipids. Thus, high intracellular NADPH may be essential to generate biomass for HSCs as they reenter the cell cycle.[35] Work in ex-vivo HSC expansion systems supports this idea, but further work is needed to characterize the role of the PPP in vivo[35]

Other signaling pathways edit

Several signaling pathways also have roles in mediating the metabolic shift from quiescent to proliferative HSCs. For example, purine metabolism is upregulated and thus promotes entry into the cell cycle through signaling in the p38MAPK pathway. ERK and mTOR, other major signaling pathways, are also activated during cell cycle entry. Among other functions, these pathways promote protein, nucleotide, and lipid synthesis. Active ERK and mTOR pathways also lead to increased nutrient uptake in HSCs. In addition to this biosynthetic role, mTOR can also increase the rate of ATP production in cells.[28]

See also edit

References edit

  1. ^ a b c Filippi, Marie-Dominique (2021-04-01). "Hematopoietic stem cell (HSC) divisional memory: The journey of mitochondrial metabolism through HSC division". Experimental Hematology. 96: 27–34. doi:10.1016/j.exphem.2021.01.006. ISSN 0301-472X. PMID 33515636. S2CID 231768217.
  2. ^ Hsu, Peter; Qu, Cheng-Kui (July 2013). "Metabolic plasticity and hematopoietic stem cell biology". Current Opinion in Hematology. 20 (4): 289–294. doi:10.1097/MOH.0b013e328360ab4d. ISSN 1065-6251. PMC 3736335. PMID 23615055.
  3. ^ a b Takubo, Keiyo; Suda, Toshio (2012-05-01). "Roles of the hypoxia response system in hematopoietic and leukemic stem cells". International Journal of Hematology. 95 (5): 478–483. doi:10.1007/s12185-012-1071-4. ISSN 1865-3774. PMID 22539363. S2CID 11018633.
  4. ^ Vannini, Nicola; Girotra, Mukul; Naveiras, Olaia; Nikitin, Gennady; Campos, Vasco; Giger, Sonja; Roch, Aline; Auwerx, Johan; Lutolf, Matthias P. (2016-10-12). "Specification of haematopoietic stem cell fate via modulation of mitochondrial activity". Nature Communications. 7 (1): 13125. Bibcode:2016NatCo...713125V. doi:10.1038/ncomms13125. ISSN 2041-1723. PMC 5064016. PMID 27731316.
  5. ^ Fares, Iman; Calvanese, Vincenzo; Mikkola, Hanna K. A. (2022-06-01). "Decoding Human Hematopoietic Stem Cell Self-Renewal". Current Stem Cell Reports. 8 (2): 93–106. doi:10.1007/s40778-022-00209-w. ISSN 2198-7866. S2CID 248254399.
  6. ^ Yamamoto, Ryo; Morita, Yohei; Ooehara, Jun; Hamanaka, Sanae; Onodera, Masafumi; Rudolph, Karl Lenhard; Ema, Hideo; Nakauchi, Hiromitsu (2013-08-29). "Clonal Analysis Unveils Self-Renewing Lineage-Restricted Progenitors Generated Directly from Hematopoietic Stem Cells". Cell. 154 (5): 1112–1126. doi:10.1016/j.cell.2013.08.007. ISSN 0092-8674. PMID 23993099. S2CID 3360028.
  7. ^ Shahriyari, Leili; Komarova, Natalia L. (2013-10-29). "Symmetric vs. Asymmetric Stem Cell Divisions: An Adaptation against Cancer?". PLOS ONE. 8 (10): e76195. arXiv:1305.0100. Bibcode:2013PLoSO...876195S. doi:10.1371/journal.pone.0076195. ISSN 1932-6203. PMC 3812169. PMID 24204602.
  8. ^ a b Mohammad, Karamat; Dakik, Paméla; Medkour, Younes; Mitrofanova, Darya; Titorenko, Vladimir I. (2019). "Quiescence Entry, Maintenance, and Exit in Adult Stem Cells". International Journal of Molecular Sciences. 20 (9): 2158. doi:10.3390/ijms20092158. ISSN 1422-0067. PMC 6539837. PMID 31052375.
  9. ^ Papa, Luena; Djedaini, Mansour; Hoffman, Ronald (2019-02-06). "Mitochondrial Role in Stemness and Differentiation of Hematopoietic Stem Cells". Stem Cells International. 2019: e4067162. doi:10.1155/2019/4067162. ISSN 1687-966X. PMC 6381553. PMID 30881461.
  10. ^ Zhang, Cheng Cheng; Sadek, Hesham A. (2014-04-20). "Hypoxia and Metabolic Properties of Hematopoietic Stem Cells". Antioxidants & Redox Signaling. 20 (12): 1891–1901. doi:10.1089/ars.2012.5019. ISSN 1523-0864. PMC 3967354. PMID 23621582.
  11. ^ Lee, Man K. S.; Al-sharea, Annas; Dragoljevic, Dragana; Murphy, Andrew J. (June 2018). "Hand of FATe: lipid metabolism in hematopoietic stem cells". Current Opinion in Lipidology. 29 (3): 240–245. doi:10.1097/MOL.0000000000000500. ISSN 0957-9672. PMID 29528857. S2CID 3858164.
  12. ^ Vannini, Nicola; Girotra, Mukul; Naveiras, Olaia; Nikitin, Gennady; Campos, Vasco; Giger, Sonja; Roch, Aline; Auwerx, Johan; Lutolf, Matthias P. (2016-10-12). "Specification of haematopoietic stem cell fate via modulation of mitochondrial activity". Nature Communications. 7 (1): 13125. Bibcode:2016NatCo...713125V. doi:10.1038/ncomms13125. ISSN 2041-1723. PMC 5064016. PMID 27731316.
  13. ^ Simsek, Tugba; Kocabas, Fatih; Zheng, Junke; DeBerardinis, Ralph J.; Mahmoud, Ahmed I.; Olson, Eric N.; Schneider, Jay W.; Zhang, Cheng Cheng; Sadek, Hesham A. (2010-09-03). "The Distinct Metabolic Profile of Hematopoietic Stem Cells Reflects Their Location in a Hypoxic Niche". Cell Stem Cell. 7 (3): 380–390. doi:10.1016/j.stem.2010.07.011. ISSN 1934-5909. PMC 4159713. PMID 20804973.
  14. ^ Inoue, Shin-Ichi; Noda, Shinichi; Kashima, Koutarou; Nakada, Kazuto; Hayashi, Jun-Ichi; Miyoshi, Hiroyuki (2010-08-04). "Mitochondrial respiration defects modulate differentiation but not proliferation of hematopoietic stem and progenitor cells". FEBS Letters. 584 (15): 3402–3409. doi:10.1016/j.febslet.2010.06.036. PMID 20600007. S2CID 2160267.
  15. ^ a b Takubo, Keiyo; Nagamatsu, Go; Kobayashi, Chiharu I.; Nakamura-Ishizu, Ayako; Kobayashi, Hiroshi; Ikeda, Eiji; Goda, Nobuhito; Rahimi, Yasmeen; Johnson, Randall S.; Soga, Tomoyoshi; Hirao, Atsushi; Suematsu, Makoto; Suda, Toshio (2013-01-03). "Regulation of Glycolysis by Pdk Functions as a Metabolic Checkpoint for Cell Cycle Quiescence in Hematopoietic Stem Cells". Cell Stem Cell. 12 (1): 49–61. doi:10.1016/j.stem.2012.10.011. ISSN 1934-5909. PMC 6592822. PMID 23290136.
  16. ^ a b Maryanovich, Maria; Zaltsman, Yehudit; Ruggiero, Antonella; Goldman, Andres; Shachnai, Liat; Zaidman, Smadar Levin; Porat, Ziv; Golan, Karin; Lapidot, Tsvee; Gross, Atan (2015-07-29). "An MTCH2 pathway repressing mitochondria metabolism regulates haematopoietic stem cell fate". Nature Communications. 6 (1): 7901. Bibcode:2015NatCo...6.7901M. doi:10.1038/ncomms8901. ISSN 2041-1723. PMID 26219591. S2CID 5170503.
  17. ^ Tothova, Zuzana; Gilliland, D. Gary (2007-08-16). "FoxO Transcription Factors and Stem Cell Homeostasis: Insights from the Hematopoietic System". Cell Stem Cell. 1 (2): 140–152. doi:10.1016/j.stem.2007.07.017. ISSN 1934-5909. PMID 18371346.
  18. ^ Kranc, Kamil R.; Schepers, Hein; Rodrigues, Neil P.; Bamforth, Simon; Villadsen, Ellen; Ferry, Helen; Bouriez-Jones, Tiphaine; Sigvardsson, Mikael; Bhattacharya, Shoumo; Jacobsen, Sten Eirik; Enver, Tariq (2009-12-04). "Cited2 Is an Essential Regulator of Adult Hematopoietic Stem Cells". Cell Stem Cell. 5 (6): 659–665. doi:10.1016/j.stem.2009.11.001. ISSN 1934-5909. PMC 2828538. PMID 19951693.
  19. ^ a b Du, Jinwei; Chen, Ju; Li, Qiang; Han, Xiangzi; Cheng, Cindy; Wang, Zhengqi; Danielpour, David; Dunwoodie, Sally; Bunting, Kevin; Yang, Yu-Chung (March 22, 2012). "HIF-1α deletion partially rescues defects of hematopoietic stem cell quiescence caused by Cited2 deficiency". Blood. 119 (12): 2789–2798. doi:10.1182/blood-2011-10-387902. PMC 3327457. PMID 22308296.
  20. ^ Du, Jinwei; Li, Qiang; Tang, Fangqiang; Puchowitz, Michelle A.; Fujioka, Hisashi; Dunwoodie, Sally L.; Danielpour, David; Yang, Yu-Chung (2014-01-15). "Cited2 Is Required for the Maintenance of Glycolytic Metabolism in Adult Hematopoietic Stem Cells". Stem Cells and Development. 23 (2): 83–94. doi:10.1089/scd.2013.0370. ISSN 1547-3287. PMC 3887429. PMID 24083546.
  21. ^ Lum, Julian J.; Bui, Thi; Gruber, Michaela; Gordan, John D.; DeBerardinis, Ralph J.; Covello, Kelly L.; Simon, M. Celeste; Thompson, Craig B. (2007-05-01). "The transcription factor HIF-1α plays a critical role in the growth factor-dependent regulation of both aerobic and anaerobic glycolysis". Genes & Development. 21 (9): 1037–1049. doi:10.1101/gad.1529107. ISSN 0890-9369. PMC 1855230. PMID 17437992.
  22. ^ Miharada, Kenichi; Karlsson, Göran; Rehn, Matilda; Rörby, Emma; Siva, Kavitha; Cammenga, Jörg; Karlsson, Stefan (2011-10-04). "Cripto Regulates Hematopoietic Stem Cells as a Hypoxic-Niche-Related Factor through Cell Surface Receptor GRP78". Cell Stem Cell. 9 (4): 330–344. doi:10.1016/j.stem.2011.07.016. ISSN 1934-5909. PMID 21982233.
  23. ^ Miharada, Kenichi; Karlsson, Göran; Rehn, Matilda; Rörby, Emma; Siva, Kavitha; Cammenga, Jörg; Karlsson, Stefan (August 2012). "Hematopoietic stem cells are regulated by Cripto, as an intermediary of HIF-1α in the hypoxic bone marrow niche: The role for Cripto-GRP78 in the hypoxic niche". Annals of the New York Academy of Sciences. 1266 (1): 55–62. doi:10.1111/j.1749-6632.2012.06564.x. PMID 22901256. S2CID 22814989.
  24. ^ a b Takihara, Y.; Nakamura-Ishizu, A.; Tan, D. Q.; Fukuda, M.; Matsumura, T.; Endoh, M.; Arima, Y.; Chin, D. W. L.; Umemoto, T.; Hashimoto, M.; Mizuno, H.; Suda, T. (August 13, 2019). "High mitochondrial mass is associated with reconstitution capacity and quiescence of hematopoietic stem cells". Blood Advances. 3 (15): 2323–2327. doi:10.1182/bloodadvances.2019032169. PMC 6692999. PMID 31387881. Retrieved 2022-12-13.
  25. ^ Rouault-Pierre, Kevin; Lopez-Onieva, Lourdes; Foster, Katie; Anjos-Afonso, Fernando; Lamrissi-Garcia, Isabelle; Serrano-Sanchez, Martin; Mitter, Richard; Ivanovic, Zoran; de Verneuil, Hubert; Gribben, John; Taussig, David; Rezvani, Hamid Reza; Mazurier, Frédéric; Bonnet, Dominique (2013-11-07). "HIF-2α Protects Human Hematopoietic Stem/Progenitors and Acute Myeloid Leukemic Cells from Apoptosis Induced by Endoplasmic Reticulum Stress". Cell Stem Cell. 13 (5): 549–563. doi:10.1016/j.stem.2013.08.011. ISSN 1934-5909. PMID 24095676.
  26. ^ a b Liang, Raymond; Arif, Tasleem; Kalmykova, Svetlana; Kasianov, Artem; Lin, Miao; Menon, Vijay; Qiu, Jiajing; Bernitz, Jeffrey M.; Moore, Kateri; Lin, Fangming; Benson, Deanna L.; Tzavaras, Nikolaos; Mahajan, Milind; Papatsenko, Dmitri; Ghaffari, Saghi (2020-03-05). "Restraining Lysosomal Activity Preserves Hematopoietic Stem Cell Quiescence and Potency". Cell Stem Cell. 26 (3): 359–376.e7. doi:10.1016/j.stem.2020.01.013. ISSN 1934-5909. PMC 8075247. PMID 32109377.
  27. ^ a b c Ito, K.; Carracedo, A.; Arai, F.; Ala, U.; Avigan, D.; Schafer, Z.; Evans, R. M.; Suda, T.; Lee, C.-H.; Pandolfi, P. P. (2012). "A PML–PPAR-δ Pathway for Fatty Acid Oxidation Regulates Hematopoietic Stem Cell Maintenance Through the Control of Asymmetric Division". Blood. 120 (21): 2327. doi:10.1182/blood.v120.21.2327.2327.
  28. ^ a b Ito, Keisuke; Suda, Toshio (April 2014). "Metabolic requirements for the maintenance of self-renewing stem cells". Nature Reviews Molecular Cell Biology. 15 (4): 243–256. doi:10.1038/nrm3772. ISSN 1471-0080. PMC 4095859. PMID 24651542.
  29. ^ Kohli, Latika; Passegué, Emmanuelle (2014-08-01). "Surviving change: the metabolic journey of hematopoietic stem cells". Trends in Cell Biology. 24 (8): 479–487. doi:10.1016/j.tcb.2014.04.001. ISSN 0962-8924. PMC 4112160. PMID 24768033.
  30. ^ Bruick, Richard K.; McKnight, Steven L. (2001-11-09). "A Conserved Family of Prolyl-4-Hydroxylases That Modify HIF". Science. 294 (5545): 1337–1340. Bibcode:2001Sci...294.1337B. doi:10.1126/science.1066373. ISSN 0036-8075. PMID 11598268. S2CID 9695199.
  31. ^ Epstein, Andrew C. R.; Gleadle, Jonathan M.; McNeill, Luke A.; Hewitson, Kirsty S.; O'Rourke, John; Mole, David R.; Mukherji, Mridul; Metzen, Eric; Wilson, Michael I.; Dhanda, Anu; Tian, Ya-Min; Masson, Norma; Hamilton, Donald L.; Jaakkola, Panu; Barstead, Robert (2001-10-05). "C. elegans EGL-9 and Mammalian Homologs Define a Family of Dioxygenases that Regulate HIF by Prolyl Hydroxylation". Cell. 107 (1): 43–54. doi:10.1016/S0092-8674(01)00507-4. ISSN 0092-8674. PMID 11595184. S2CID 18372306.
  32. ^ Ivan, Mircea; Haberberger, Thomas; Gervasi, David C.; Michelson, Kristen S.; Günzler, Volkmar; Kondo, Keiichi; Yang, Haifeng; Sorokina, Irina; Conaway, Ronald C.; Conaway, Joan W.; Kaelin, William G. (2002-10-15). "Biochemical purification and pharmacological inhibition of a mammalian prolyl hydroxylase acting on hypoxia-inducible factor". Proceedings of the National Academy of Sciences. 99 (21): 13459–13464. Bibcode:2002PNAS...9913459I. doi:10.1073/pnas.192342099. ISSN 0027-8424. PMC 129695. PMID 12351678.
  33. ^ a b Vander Heiden, Matthew G.; Cantley, Lewis C.; Thompson, Craig B. (2009-05-22). "Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation". Science. 324 (5930): 1029–1033. Bibcode:2009Sci...324.1029V. doi:10.1126/science.1160809. ISSN 0036-8075. PMC 2849637. PMID 19460998.
  34. ^ a b Suda, Toshio; Takubo, Keiyo; Semenza, Gregg L. (2011-10-04). "Metabolic Regulation of Hematopoietic Stem Cells in the Hypoxic Niche". Cell Stem Cell. 9 (4): 298–310. doi:10.1016/j.stem.2011.09.010. ISSN 1934-5909. PMID 21982230.
  35. ^ a b c Yu, Wen-Mei; Liu, Xia; Shen, Jinhua; Jovanovic, Olga; Pohl, Elena E.; Gerson, Stanton L.; Finkel, Toren; Broxmeyer, Hal E.; Qu, Cheng-Kui (2013-01-03). "Metabolic Regulation by the Mitochondrial Phosphatase PTPMT1 Is Required for Hematopoietic Stem Cell Differentiation". Cell Stem Cell. 12 (1): 62–74. doi:10.1016/j.stem.2012.11.022. ISSN 1934-5909. PMC 3632072. PMID 23290137.
  36. ^ a b Jin, Yuting; Wang, Qin; Ding, Qingwei; Yao, Chunxu; Jiang, Rongzhen; Guo, Bin; Meng, Qingyou (2022-06-01). "H6PD overexpression promotes ex vivo expansion of human cord blood hematopoietic stem cells". Stem Cell Reviews and Reports. 18 (5): 1878–1880. doi:10.1007/s12015-022-10352-w. ISSN 2629-3277. PMC 9209374. PMID 35122629.
Retrieved from "https://en.wikipedia.org/w/index.php?title=Metabolic_regulation_of_hematopoiesis&oldid=1185208255"