Oxidative Stress as a Critical Determinant of Adult Cardiac Progenitor Cell-Fate Decisions

  • Diego Herrero
  • Susana Cañón
  • Guillermo Albericio
  • Susana Aguilar
  • Rosa María Carmona
  • Adrián Holguín
  • Antonio BernadEmail author


Tissue homeostasis and the response to injury require a tight regulation of the balance between self-renewal and differentiation of adult stem/progenitor cells. Recent evidence obtained in several tissues suggests that this balance is regulated, at least in part, by the cellular redox status via the control of reactive oxygen species (ROS) levels and cellular metabolism. In this chapter, we consider the main sources and the relevance of oxidative stress in adult stem turnover and the key signaling pathways involved, with a particular focus on cardiac progenitor cell turnover. While it is generally accepted that the mammalian heart has high physiological levels of ROS and an oxidative metabolism, few studies have explored the importance of redox signaling in cardiac progenitor cells. We propose that low-ROS areas in the heart are permissive niches for adult cardiac progenitor cells. Accordingly, manipulation of ROS-related signaling pathways in the adult heart might open new horizons for stem cell therapy by enhancing their heretofore limited cardiac regenerative potential.


Cardiac progenitor cell CPC ROS Bmi1 Turnover Cardiomyocyte Low-ROS niche 


Financial Acknowledgment

MINECO/FEDER; SAF2015–70882-R and ISCIII; RETICS-RD12/001.


  1. 1.
    Dröge W (2002) Free radicals in the physiological control of cell function. Physiol Rev 82:47–95PubMedCrossRefGoogle Scholar
  2. 2.
    Chandel NS, Maltepe E, Goldwasser E et al (1998) Mitochondrial reactive oxygen species trigger hypoxia-induced transcription. Proc Natl Acad Sci U S A 95:11715–11720PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Nemoto S, Takeda K, Yu ZX et al (2000) Role for mitochondrial oxidants as regulators of cellular metabolism. Mol Cell Biol 20:7311–7318PubMedPubMedCentralCrossRefGoogle Scholar
  4. 4.
    Kitamoto K, Miura Y, Karnan S et al (2018) Inhibition of NADPH oxidase 2 induces apoptosis in osteosarcoma: the role of reactive oxygen species in cell proliferation. Oncol Lett 15:7955–7962PubMedPubMedCentralGoogle Scholar
  5. 5.
    Lee SH, Kim JK, Jang HD (2014) Genistein inhibits osteoclastic differentiation of RAW 264.7 cells via regulation of ROS production and scavenging. Int J Mol Sci 15:10605–10621PubMedPubMedCentralCrossRefGoogle Scholar
  6. 6.
    Hou G, Zhao H, Teng H et al (2018) N-cadherin attenuates high glucose-induced nucleus pulposus cell senescence through regulation of the ROS/NF-κB pathway. Cell Physiol Biochem 47:257–265PubMedCrossRefGoogle Scholar
  7. 7.
    Sulciner DJ, Irani K, Yu ZX et al (1996) Rac1 regulates a cytokine-stimulated, redox-dependent pathway necessary for NF-kappaB activation. Mol Cell Biol 16:7115–7121PubMedPubMedCentralCrossRefGoogle Scholar
  8. 8.
    Mathew R, Karp CM, Beaudoin B et al (2009) Autophagy suppresses tumorigenesis through elimination of p62. Cell 137:1062–1075PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Herrero D, Tomé M, Cañón S et al (2018) Redox-dependent BMI1 activity drives in vivo adult cardiac progenitor cell differentiation. Cell Death Differ 25:807–820PubMedCentralCrossRefPubMedGoogle Scholar
  10. 10.
    Kim JH, Song SY, Park SG et al (2012) Primary involvement of NADPH oxidase 4 in hypoxia-induced generation of reactive oxygen species in adipose-derived stem cells. Stem Cells Dev 21:2212–2221PubMedCrossRefGoogle Scholar
  11. 11.
    Borodkina A, Shatrova A, Abushik P et al (2014) Interaction between ROS dependent DNA damage, mitochondria and p38 MAPK underlies senescence of human adult stem cells. Aging 6:481–495PubMedPubMedCentralCrossRefGoogle Scholar
  12. 12.
    Shi B, Wang Y, Zhao R et al (2018) Bone marrow mesenchymal stem cell-derived exoso-mal miR-21 protects C-kit+ cardiac stem cells from oxidative injury through the PTEN/PI3K/Akt axis. PLoS One 13:e0191616PubMedPubMedCentralCrossRefGoogle Scholar
  13. 13.
    Varum S, Rodrigues AS, Moura MB et al (2011) Energy metabolism in human pluripotent stem cells and their differentiated counterparts. PLoS One 6:e20914PubMedPubMedCentralCrossRefGoogle Scholar
  14. 14.
    Saretzki G, Armstrong L, Leake A et al (2004) Stress defense in murine embryonic stem cells is superior to that of various differentiated murine cells. Stem Cells 22:962–971PubMedCrossRefGoogle Scholar
  15. 15.
    Schmelter M, Ateghang B, Helmig S et al (2006) Embryonic stem cells utilize reactive oxygen species as transducers of mechanical strain-induced cardiovascular differentiation. FASEB J 20:1182–1184PubMedCrossRefGoogle Scholar
  16. 16.
    Ji AR, Ku SY, Cho MS et al (2010) Reactive oxygen species enhance differentiation of human embryonic stem cells into mesendodermal lineage. Exp Mol Med 42:175–186PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Brand MD (2010) The sites and topology of mitochondrial superoxide production. Exp Gerontol 45:466–472PubMedPubMedCentralCrossRefGoogle Scholar
  18. 18.
    Aon MA, Stanley BA, Sivakumaran V et al (2012) Glutathione/thioredoxin systems modu-late mitochondrial H2O2 emission: an experimental-computational study. J Gen Physiol 139:479–491PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Tahara EB, Navarete FD, Kowaltowski AJ (2009) Tissue-, substrate-, and site-specific characteristics of mitochondrial reactive oxygen species generation. Free Radic Biol Med 46:1283–1297PubMedCrossRefPubMedCentralGoogle Scholar
  20. 20.
    Lapuente-Brun E, Moreno-Loshuertos R, Acín-Pérez R et al (2013) Supercomplex assem-bly determines electron flux in the mitochondrial electron transport chain. Science 340:1567–1570PubMedCrossRefGoogle Scholar
  21. 21.
    Drahota Z, Chowdhury SK, Floryk D et al (2002) Glycerophosphate-dependent hydrogen peroxide production by brown adipose tissue mitochondria and its activation by ferricyanide. J Bioenerg Biomembr 34:105–113PubMedCrossRefGoogle Scholar
  22. 22.
    Frerman FE (1987) Reaction of electron-transfer flavoprotein ubiquinone oxidoreductase with the mitochondrial respiratory chain. Biochim Biophys Acta 893:161–169PubMedCrossRefGoogle Scholar
  23. 23.
    Vasquez-Vivar J, Kalyanaraman B, Kennedy MC (2000) Mitochondrial aconitase is a source of hydroxyl radical. An electron spin resonance investigation. J Biol Chem 275:14064–14069PubMedCrossRefGoogle Scholar
  24. 24.
    Hauptmann N, Grimsby J, Shih JC et al (1996) The metabolism of tyramine by monoamine oxidase A/B causes oxidative damage to mitochondrial DNA. Arch Biochem Biophys 335:295–304PubMedCrossRefGoogle Scholar
  25. 25.
    Giorgio M, Migliaccio E, Orsini F et al (2005) Electron transfer between cytochrome c and p66Shc generates reactive oxygen species that trigger mitochondrial apoptosis. Cell 122:221–233PubMedCrossRefGoogle Scholar
  26. 26.
    Tothova Z, Kollipara R, Huntly BJ et al (2007) FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128:325–339PubMedCrossRefGoogle Scholar
  27. 27.
    Sansone P, Storci G, Giovannini C et al (2007) p66Shc/Notch-3 interplay controls self-renewal and hypoxia survival in human stem/progenitor cells of the mammary gland expanded in vitro as mammospheres. Stem Cells 25:807–815PubMedCrossRefGoogle Scholar
  28. 28.
    Starkov AA, Fiskum G, Chinopoulos C et al (2004) Mitochondrial alpha-ketoglutarate dehydrogenase complex generates reactive oxygen species. J Neurosci 24:7779–7788PubMedPubMedCentralCrossRefGoogle Scholar
  29. 29.
    Prigione A, Fauler B, Lurz R et al (2010) The senescence-related mitochondrial/oxidative stress pathway is repressed in human induced pluripotent stem cells. Stem Cells 28:721–733PubMedCrossRefGoogle Scholar
  30. 30.
    Chung S, Dzeja PP, Faustino RS et al (2007) Mitochondrial oxidative metabolism is required for the cardiac differentiation of stem cells. Nat Clin Pract Cardiovasc Med 4(Suppl 1):S60–S67PubMedPubMedCentralCrossRefGoogle Scholar
  31. 31.
    St John JC, Ramalho-Santos J, Gray HL et al (2005) The expression of mitochondrial DNA transcription factors during early cardiomyocyte in vitro differentiation from human embryonic stem cells. Cloning Stem Cells 7:141–153PubMedCrossRefPubMedCentralGoogle Scholar
  32. 32.
    Chung S, Arrell DK, Faustino RS et al (2010) Glycolytic network restructuring integral to the energetics of embryonic stem cell cardiac differentiation. J Mol Cell Cardiol 48:725–734PubMedPubMedCentralCrossRefGoogle Scholar
  33. 33.
    Skonieczna M, Hejmo T, Poterala-Hejmo A et al (2017) NADPH oxidases: insights into selected functions and mechanisms of action in cancer and stem cells. Oxidative Med Cell Longev 2017:9420539CrossRefGoogle Scholar
  34. 34.
    Li J, Stouffs M, Serrander L et al (2006) The NADPH oxidase NOX4 drives cardiac differentiation: role in regulating cardiac transcription factors and MAP kinase activation. Mol Biol Cell 17:3978–3988PubMedPubMedCentralCrossRefGoogle Scholar
  35. 35.
    Nadworny AS, Guruju MR, Poor D et al (2013) Nox2 and Nox4 influence neonatal c-kit(+) cardiac precursor cell status and differentiation. Am J Physiol Heart Circ Physiol 305:H829–H842PubMedPubMedCentralCrossRefGoogle Scholar
  36. 36.
    Topchiy E, Panzhinskiy E, Griffin WS (2013) Nox4-generated superoxide drives angiotensin II-induced neural stem cell proliferation. Dev Neurosci 35:293–305PubMedPubMedCentralCrossRefGoogle Scholar
  37. 37.
    Moruno-Manchon JF, Uzor NE, Kesler SR et al (2018) Peroxisomes contribute to oxidative stress in neurons during doxorubicin-based chemotherapy. Mol Cell Neurosci 86:65–71PubMedCrossRefPubMedCentralGoogle Scholar
  38. 38.
    Jiang S, He R, Zhu L et al (2018) Endoplasmic reticulum stress-dependent ROS production mediates synovial myofibroblastic differentiation in the immobilization-induced rat knee joint contracture model. Exp Cell Res S0014-4827(18):30316–30311Google Scholar
  39. 39.
    Zangar RC, Davydov DR, Verma S (2004) Mechanisms that regulate production of reactive oxygen species by cytochrome P450. Toxicol Appl Pharmacol 199:316–331PubMedCrossRefPubMedCentralGoogle Scholar
  40. 40.
    Chuang DY, Simonyi A, Kotzbauer PT et al (2015) Cytosolic phospholipase A2 plays a crucial role in ROS/NO signaling during microglial activation through the lipoxygenase pathway. J Neuroinflammation 12:199PubMedPubMedCentralCrossRefGoogle Scholar
  41. 41.
    Huang CC, Chen KL, Cheung CH et al (2013) Autophagy induced by cathepsin S inhibition induces early ROS production, oxidative DNA damage, and cell death via xanthine oxidase. Free Radic Biol Med 65:1473–1486PubMedCrossRefPubMedCentralGoogle Scholar
  42. 42.
    He L, He T, Farrar S et al (2017) Antioxidants maintain cellular redox homeostasis by elimination of reactive oxygen species. Cell Physiol Biochem 44:532–553PubMedCrossRefGoogle Scholar
  43. 43.
    Dernbach E, Urbich C, Brandes RP et al (2004) Antioxidative stress-associated genes in circulating progenitor cells: evidence for enhanced resistance against oxidative stress. Blood 104:3591–3597PubMedCrossRefPubMedCentralGoogle Scholar
  44. 44.
    Bognar Z, Kalai T, Palfi A et al (2006) A novel SOD-mimetic permeability transition inhibitor agent protects ischemic heart by inhibiting both apoptotic and necrotic cell death. Free Radic Biol Med 41:835–848PubMedCrossRefPubMedCentralGoogle Scholar
  45. 45.
    Saretzki G, Walter T, Atkinson S et al (2008) Downregulation of multiple stress defense mechanisms during differentiation of human embryonic stem cells. Stem Cells 26:455–464PubMedCrossRefPubMedCentralGoogle Scholar
  46. 46.
    Solari C, Vázquez Echegaray C, Cosentino MS et al (2015) Manganese superoxide dismutase gene expression is induced by nanog and Oct4, essential pluripotent stem cells’ transcription factors. PLoS One 10:e0144336PubMedPubMedCentralCrossRefGoogle Scholar
  47. 47.
    Miao W, Xufeng R, Park MR et al (2013) Hematopoietic stem cell regeneration enhanced by ectopic expression of ROS-detoxifying enzymes in transplant mice. Mol Ther 21:423–432PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Kwon T, Bak Y, Park YH et al (2016) Peroxiredoxin II is essential for maintaining stemness by redox regulation in liver cancer cells. Stem Cells 34:1188–1197PubMedCrossRefPubMedCentralGoogle Scholar
  49. 49.
    Spradling A, Drummond-Barbosa D, Kai T (2001) STem cells find their niche. Nature 414:98–104PubMedCrossRefPubMedCentralGoogle Scholar
  50. 50.
    Simon MC, Keith B (2008) The role of oxygen availability in embryonic development and stem cell function. Nat Rev Mol Cell Biol 9:285–296PubMedPubMedCentralCrossRefGoogle Scholar
  51. 51.
    Panchision DM (2009) The role of oxygen in regulating neural stem cells in development and disease. J Cell Physiol 220:562–568PubMedCrossRefGoogle Scholar
  52. 52.
    Eliasson P, Jönsson JI (2010) The hematopoietic stem cell niche: low in oxygen but a nice place to be. J Cell Physiol 222:17–22PubMedCrossRefGoogle Scholar
  53. 53.
    Silván U, Díez-Torre A, Arluzea J et al (2009) Hypoxia and pluripotency in embryonic and embryonal carcinoma stem cell biology. Differentiation 78:159–168PubMedCrossRefPubMedCentralGoogle Scholar
  54. 54.
    Cho YM, Kwon S, Pak YK et al (2006) LeeDynamic changes in mitochondrial biogenesis and antioxidant enzymes during the spontaneous differentiation of human embryonic stem cells. Biochem Biophys Res Commun 348:1472–1478PubMedCrossRefPubMedCentralGoogle Scholar
  55. 55.
    Wang K, Zhang T, Dong Q et al (2013) Redox homeostasis: the linchpin in stem cell self-renewal and differentiation. Cell Death Dis 4:e537PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Gardner LB, Li Q, Park MS et al (2001) Hypoxia inhibits G1/S transition through regulation of p27 expression. J Biol Chem 276:7919–7926PubMedCrossRefPubMedCentralGoogle Scholar
  57. 57.
    Iida T, Mine S, Fujimoto H et al (2002) Hypoxia-inducible factor-1alpha induces cell cycle arrest of endothelial cells. Genes Cells 7:143–149PubMedCrossRefPubMedCentralGoogle Scholar
  58. 58.
    Koshiji M, Kageyama Y, Pete EA et al (2004) HIF-1alpha induces cell cycle arrest by functionally counteracting Myc. EMBO J 23:1949–1956PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Adelman DM, Gertsenstein M, Nagy A et al (2000) Placental cell fates are regulated in vivo by HIF-mediated hypoxia responses. Genes Dev 14:3191–3203PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Lee SW, Jeong HK, Lee JY et al (2012) Hypoxic priming of mESCs accelerates vascular-lineage differentiation through HIF1-mediated inverse regulation of Oct4 and VEGF. EMBO Mol Med 4:924–938PubMedPubMedCentralCrossRefGoogle Scholar
  61. 61.
    Francis KR, Wei L (2010) Human embryonic stem cell neural differentiation and enhanced cell survival promoted by hypoxic preconditioning. Cell Death Dis 1:e22PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Ng KM, Lee YK, Chan YC et al (2010) Exogenous expression of HIF-1 alpha promotes cardiac differentiation of embryonic stem cells. J Mol Cell Cardiol 48:1129–1137PubMedCrossRefGoogle Scholar
  63. 63.
    De Miguel MP, Alcaina Y, de la Maza DS et al (2015) Cell metabolism under microenvironmental low oxygen tension levels in stemness, proliferation and pluripotency. Curr Mol Med 15:343–359PubMedCrossRefGoogle Scholar
  64. 64.
    Gustafsson MV, Zheng X, Pereira T et al (2005) Hypoxia requires notch signaling to maintain the undifferentiated cell state. Dev Cell 9:617–628PubMedCrossRefGoogle Scholar
  65. 65.
    Mutoh TS (2012) Oxygen levels epigenetically regulate fate switching of neural precursor cells via hypoxia-inducible factor 1α-notch signal interaction in the developing brain. Stem Cells 30:561–569PubMedCrossRefGoogle Scholar
  66. 66.
    Covello KL, Kehler J, Yu H et al (2006) HIF-2alpha regulates Oct-4: effects of hypoxia on stem cell function, embryonic development, and tumor growth. Genes Dev 20:557–570PubMedPubMedCentralCrossRefGoogle Scholar
  67. 67.
    Kaidi A, Williams AC, Paraskeva C (2007) Interaction between beta-catenin and HIF-1 promotes cellular adaptation to hypoxia. Nat Cell Biol 9:210–217PubMedCrossRefGoogle Scholar
  68. 68.
    Takubo K, Goda N, Yamada W et al (2010) Regulation of the HIF-1alpha level is essential for hematopoietic stem cells. Cell Stem Cell 7:391–402PubMedCrossRefGoogle Scholar
  69. 69.
    Zhang K, Zhou Y, Zhao T et al (2015) Reduced cerebral oxygen content in the DG and SVZ in situ promotes neurogenesis in the adult rat brain in vivo. PLoS One 10:e0140035PubMedPubMedCentralCrossRefGoogle Scholar
  70. 70.
    Lange C, Turrero-Garcia M, Decimo I et al (2016) Relief of hypoxia by angiogenesis promotes neural stem cell differentiation by targeting glycolysis. EMBO J 35:924–941PubMedPubMedCentralCrossRefGoogle Scholar
  71. 71.
    Li L, Candelario KM, Thomas K et al (2014) Hypoxia inducible factor-1α (HIF-1α) is required for neural stem cell maintenance and vascular stability in the adult mouse SVZ. J Neurosci 34:16713–16719PubMedPubMedCentralCrossRefGoogle Scholar
  72. 72.
    Estrada JC, Albo C, Benguría A et al (2012) Culture of human mesenchymal stem cells at low oxygen tension improves growth and genetic stability by activating glycolysis. Cell Death Differ 19:743–755PubMedCrossRefGoogle Scholar
  73. 73.
    Valorani MG, Montelatici E, Germani A et al (2012) Pre-culturing human adipose tissue mesenchymal stem cells under hypoxia increases their adipogenic and osteogenic differentiation potentials. Cell Prolif 45:225–238PubMedCrossRefGoogle Scholar
  74. 74.
    Ateghang B, Wartenberg M, Gassmann M et al (2006) Regulation of cardiotrophin-1 expression in mouse embryonic stem cells by HIF-1α and intracellular reactive oxygen species. J Cell Sci 119:1043–1052PubMedCrossRefGoogle Scholar
  75. 75.
    Salih DA, Brunet A (2008) FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 20:126–136PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    van der Horst A, Burgering BM (2007) Stressing the role of FoxO proteins in lifespan and disease. Nat Rev Mol Cell Biol 8:440–450PubMedCrossRefGoogle Scholar
  77. 77.
    Essers MA, de Vries-Smits LM, Barker N et al (2005) Functional interaction between beta-catenin and FOXO in oxidative stress signaling. Science 308:1181–1184PubMedCrossRefGoogle Scholar
  78. 78.
    Kops GJ, Dansen TB, Polderman PE et al (2002) Forkhead transcription factor FOXO3a protects quiescent cells from oxidative stress. Nature 419:316–321PubMedCrossRefGoogle Scholar
  79. 79.
    Paik JH, Ding Z, Narurkar R et al (2009) FoxOs cooperatively regulate diverse pathways governing neural stem cell homeostasis. Cell Stem Cell 5:540–553PubMedPubMedCentralCrossRefGoogle Scholar
  80. 80.
    Miyamoto K, Araki KY, Naka K et al (2007) Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1:101–112PubMedCrossRefGoogle Scholar
  81. 81.
    Miyamoto K, Miyamoto T, Kato R et al (2008) FoxO3a regulates hematopoietic homeostasis through a negative feedback pathway in conditions of stress or aging. Blood 112:4485–4493PubMedPubMedCentralCrossRefGoogle Scholar
  82. 82.
    Iyer S, Ambrogini E, Bartell SM et al (2013) FOXOs attenuate bone formation by suppressing Wnt signaling. J Clin Invest 123:3409–3419PubMedPubMedCentralCrossRefGoogle Scholar
  83. 83.
    Higuchi M, Dusting GJ, Peshavariya H et al (2013) Differentiation of human adipose -derived stem cells into fat involves reactive oxygen species and Forkhead box O1 mediated upregulation of antioxidant enzymes. Stem Cells Dev 22:878–888PubMedCrossRefGoogle Scholar
  84. 84.
    Zhang X, Yalcin S, Lee DF et al (2011) FOXO1 is an essential regulator of pluripotency in human embryonic stem cells. Nat Cell Biol 13:1092–1099PubMedPubMedCentralCrossRefGoogle Scholar
  85. 85.
    Nguyen T, Nioi P, Pickett CB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284:13291–13295PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Itoh K, Wakabayashi N, Katoh Y et al (1999) Keap1 represses nuclear activation of antioxidant responsive elements by Nrf2 through binding to the amino-terminal Neh2 domain. Genes Dev 13:76–86PubMedPubMedCentralCrossRefGoogle Scholar
  87. 87.
    Kobayashi A, Kang MI, Okawa H et al (2004) Oxidative stress sensor Keap1 functions as an adaptor for Cul3-based E3 ligase to regulate proteasomal degradation of Nrf2. Mol Cell Biol 24:7130–7139PubMedPubMedCentralCrossRefGoogle Scholar
  88. 88.
    Li J, Johnson D, Calkins M et al (2005) Stabilization of Nrf2 by tBHQ confers protection against oxidative stress-induced cell death in human neural stem cells. Toxicol Sci 83:313–328PubMedCrossRefGoogle Scholar
  89. 89.
    Tsai JJ, Dudakov JA, Takahashi K et al (2013) Nrf2 regulates haematopoietic stem cell function. Nat Cell Biol 15:309–316PubMedPubMedCentralCrossRefGoogle Scholar
  90. 90.
    Murakami S, Suzuki T, Harigae H et al (2017) NRF2 activation impairs quiescence and bone marrow reconstitution capacity of hematopoietic stem cells. Mol Cell Biol 37:e00086–e00017PubMedPubMedCentralCrossRefGoogle Scholar
  91. 91.
    Jang J, Wang Y, Kim HS et al (2014) Nrf2, a regulator of the proteasome, controls self-renewal and pluripotency in human embryonic stem cells. Stem Cells 32:2616–2625PubMedPubMedCentralCrossRefGoogle Scholar
  92. 92.
    Mohammadzadeh M, Halabian R, Gharehbaghian A et al (2012) Nrf-2 overexpression in mesenchymal stem cells reduces oxidative stress-induced apoptosis and cytotoxicity. Cell Stress Chaperones 17:553–565PubMedPubMedCentralCrossRefGoogle Scholar
  93. 93.
    Yoon DS, Choi Y, Lee JW (2016) Cellular localization of NRF2 determines the self-renewal and osteogenic differentiation potential of human MSCs via the P53–SIRT1 axis. Cell Death Dis 7:e2093PubMedPubMedCentralCrossRefGoogle Scholar
  94. 94.
    Bhattacharya R, Mustafi SB, Street M et al (2015) Bmi-1: at the crossroads of physiological and pathological biology. Genes Dis 2:225–239PubMedPubMedCentralCrossRefGoogle Scholar
  95. 95.
    Pietersen AM, van Lohuizen M (2008) Stem cell regulation by polycomb repressors: postponing commitment. Curr Opin Cell Biol 20:201–217PubMedCrossRefGoogle Scholar
  96. 96.
    Molofsky AV, Pardal R, Iwashita T et al (2003) Bmi-1 dependence distinguishes neural stem cell self-renewal from progenitor proliferation. Nature 425:962–967PubMedPubMedCentralCrossRefGoogle Scholar
  97. 97.
    Park IK, Qian D, Kiel M et al (2003) Bmi-1 is required for maintenance of adult self-renewing haematopoietic stem cells. Nature 423:302–325PubMedCrossRefGoogle Scholar
  98. 98.
    López-Arribillaga E, Rodilla V, Pellegrinet L et al (2015) Bmi1 regulates murine intestinal stem cell proliferation and self-renewal downstream of notch. Development 142:41–50PubMedCrossRefGoogle Scholar
  99. 99.
    Valiente-Alandi I, Albo-Castellanos C, Herrero D et al (2015) Cardiac Bmi1+ cells contribute to myocardial renewal in the murine adult heart. Stem Cell Res Ther 6:205PubMedPubMedCentralCrossRefGoogle Scholar
  100. 100.
    Liu L, Cao L, Chen J et al (2009) Bmi1 regulates mitochondrial function and the DNA damage response pathway. Nature 459:387–392PubMedPubMedCentralCrossRefGoogle Scholar
  101. 101.
    Valiente-Alandi I, Albo-Castellanos C, Herrero D et al (2016) Bmi1 (+) cardiac progenitor cells contribute to myocardial repair following acute injury. Stem Cell Res Ther 7:100PubMedPubMedCentralCrossRefGoogle Scholar
  102. 102.
    Herrero D, Cañón S, Pelacho B et al (2018) Bmi1-progenitor cell ablation impairs the angiogenic response to myocardial infarction. Arterioscler Thromb Vasc Biol 38:2160–2173. Scholar
  103. 103.
    Brodkina A, Shatrova A, Abushik P, Nikolsky N, Burova E (2014) Interaction between ROS dependent DNA damage, mitochondria and p38 MAPK underlies senescence of human adult stem cells. Aging (Albany NY) 6:481–495CrossRefGoogle Scholar
  104. 104.
    Kong Y, Song Y, Hu Y et al (2016) Increased reactive oxygen species and exhaustion of quiescent CD34-positive bone marrow cells may contribute to poor graft function after allotransplants. Oncotarget 7:30892–30906PubMedPubMedCentralGoogle Scholar
  105. 105.
    Brien GL, Healy E, Jerman E et al (2015) A chromatin-independent role of Polycomb-like 1 to stabilize p53 and promote cellular quiescence. Genes Dev 29:2231–2243PubMedPubMedCentralCrossRefGoogle Scholar
  106. 106.
    Mohrin M, Bourke E, Alexander D et al (2010) Hematopoietic stem cell quiescence promo-tes error-prone DNA repair and mutagenesis. Cell Stem Cell 7:174–185PubMedPubMedCentralCrossRefGoogle Scholar
  107. 107.
    Boregowda SV, Krishnappa V, Strivelli J (2018) Basal p53 expression is indispensable for mesenchymal stem cell integrity. Cell Death Differ 25:677–690PubMedCentralCrossRefPubMedGoogle Scholar
  108. 108.
    Cesselli D, Aleksova A, Sponga S et al (2017) Cardiac cell senescence and redox signaling. Front Cardiovasc Med 4:38PubMedPubMedCentralCrossRefGoogle Scholar
  109. 109.
    Khaper N, Bailey CDC, Ghugre NR et al (2018) Implications of disturbances in circadian rhythms for cardiovascular health: a new frontier in free radical biology. Free Radic Biol Med 119:85–92PubMedCrossRefGoogle Scholar
  110. 110.
    Kanaan GN, Harper ME (2017) Cellular redox dysfunction in the development of cardiovascular diseases. Biochim Biophys Acta 1861:2822–2829CrossRefGoogle Scholar
  111. 111.
    He F, Zuo L (2015) Redox roles of reactive oxygen species in cardiovascular diseases. Int J Mol Sci 16:27770–27780PubMedPubMedCentralCrossRefGoogle Scholar
  112. 112.
    Barančík M, Grešová L, Barteková M et al (2016) Nrf2 as a key player of redox regulation in cardiovascular diseases. Physiol Res 65(Suppl 1):S1–S10PubMedGoogle Scholar
  113. 113.
    Erkens R, Kramer CM, Lückstädt W et al (2015) Left ventricular diastolic dysfunction in Nrf2 knock out mice is associated with cardiac hypertrophy, decreased expression of SERCA2a, and preserved endothelial function. Free Radic Biol Med 89:906–917PubMedCrossRefGoogle Scholar
  114. 114.
    Xu B, Zhang J, Strom J et al (2014) Myocardial ischemic reperfusion induces de novo Nrf2 protein translation. Biochim Biophys Acta 1842:1638–1647PubMedPubMedCentralCrossRefGoogle Scholar
  115. 115.
    Taunk NK, Haffty BG, Kostis JB et al (2015) Radiation-induced heart disease: pathologic abnormalities and putative mechanisms. Front Oncol 5:39PubMedPubMedCentralCrossRefGoogle Scholar
  116. 116.
    Ahamed J, Laurence J (2017) Role of platelet-derived transforming growth factor-β1 and reactive oxygen species in radiation-induced organ fibrosis. Antioxid Redox Signal 27:977–988PubMedPubMedCentralCrossRefGoogle Scholar
  117. 117.
    Weigel C, Schmezer P, Plass C et al (2015) Epigenetics in radiation-induced fibrosis. Oncogene 34:2145–2155PubMedCrossRefGoogle Scholar
  118. 118.
    Bergmann O, Zdunek S, Felker A et al (2015) Dynamics of cell generation and turnover in the human heart. Cell 161:1566–1575PubMedCrossRefGoogle Scholar
  119. 119.
    Uygur A, Lee RT (2016) Mechanisms of cardiac regeneration. Dev Cell 36:362–374PubMedPubMedCentralCrossRefGoogle Scholar
  120. 120.
    Poss KD, Wilson LG, Keating MT (2002) Heart regeneration in Zebrafish. Science 298:2188–2190PubMedCrossRefPubMedCentralGoogle Scholar
  121. 121.
    Jopling C, Sleep E, Raya M et al (2010) Zebrafish heart regeneration occurs by cardiomyocyte dedifferentiation and proliferation. Nature 464:606–609PubMedPubMedCentralCrossRefGoogle Scholar
  122. 122.
    Wang J, Panáková D, Kikuchi K et al (2011) The regenerative capacity of zebrafish reverses cardiac failure caused by genetic cardiomyocyte depletion. Development 138:3421–3430PubMedPubMedCentralCrossRefGoogle Scholar
  123. 123.
    Kikuchi K, Holdway JE, Werdich AA et al (2010) Primary contribution to zebrafish heart regeneration by Gata4+ cardiomyocytes. Nature 464:601–605PubMedPubMedCentralCrossRefGoogle Scholar
  124. 124.
    González-Rosa JM, Sharpe M, Field D et al (2018) Myocardial polyploidization creates a barrier to heart regeneration in zebrafish. Dev Cell 44:433–446PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Roesner A, Hankeln T, Burmester T (2006) Hypoxia induces a complex response of globin expression in zebrafish (Danio rerio). J Exp Biol 209:2129–2137PubMedCrossRefGoogle Scholar
  126. 126.
    Rees BB, Sudradjat FA, Love JW (2001) Acclimation to hypoxia increases survival time of zebrafish, Danio rerio, during lethal hypoxia. J Exp Zool 289:266–272PubMedCrossRefGoogle Scholar
  127. 127.
    Flink IL (2002) Cell cycle reentry of ventricular and atrial cardiomyocytes and cells within the epicardium following amputation of the ventricular apex in the axolotl, Amblystoma mexicanum: confocal microscopic immunofluorescent image analysis of bromodeoxyuridine-label. Anat Embryol 205:235–244PubMedCrossRefGoogle Scholar
  128. 128.
    Oberpriller JO, Oberpriller JC (1974) Response of the adult newt ventricle to injury. J Exp Zool 187:249–253PubMedCrossRefPubMedCentralGoogle Scholar
  129. 129.
    Dawes GS, Mott JC, Widdicombe JG (1954) The foetal circulation in the lamb. J Physiol 126:563–587PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Suturzu AC, Rajarajan K, Passer D et al (2014) The fetal mammalian heart generates a robust compensatory response to cell loss. Circulation 132:109–121CrossRefGoogle Scholar
  131. 131.
    Porrello ER, Mahmoud AI, Simpson E et al (2011) Transient regenerative potential of the neonatal mouse heart. Science 331:1078–1080PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Sampaio-Pinto V, Rodrigues SC, Laundos TL et al (2018) Neonatal apex resection triggers cardiomyocyte proliferation, neovascularization and functional recovery despite local fibrosis. Stem Cell Rep 10:860–874CrossRefGoogle Scholar
  133. 133.
    Webster WS, Abela D (2007) The effect of hypoxia in development. Birth Defects Res C Embryo Today 81:215–228PubMedCrossRefGoogle Scholar
  134. 134.
    Puente BN, Kimura W, Muralidhar SA et al (2014) The oxygen rich postnatal environment induces cardiomyocyte cell cycle arrest through DNA damage response. Cell 157:565–579PubMedPubMedCentralCrossRefGoogle Scholar
  135. 135.
    Millis RJ, Titmarsh DM, Koenig X et al (2017) Functional screening in human cardiac organoids reveals a metabolic mechanism for cardiomyocyte cell cycle arrest. Proc Natl Acad Sci U S A 114:E8372–E8381CrossRefGoogle Scholar
  136. 136.
    Yang F, Liu YH, Yang XP et al (2002) Myocardial infarction and cardiac remodelling in mice. Exp Physiol 87:547–555PubMedCrossRefGoogle Scholar
  137. 137.
    Beltrami AP, Barlucchi L, Torella D et al (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114:763–776PubMedCrossRefPubMedCentralGoogle Scholar
  138. 138.
    Kramann R, Schneider RK, DiRocco DP et al (2015) Perivascular Gli1+ progenitors are key contributors to injury-induced organ fibrosis. Cell Stem Cell 16:51–66PubMedCrossRefPubMedCentralGoogle Scholar
  139. 139.
    Uchida S, De Gaspari P, Kostin S et al (2013) Sca1-derived cells are a source of myocardial renewal in the murine adult heart. Stem Cell Rep 1:397–410CrossRefGoogle Scholar
  140. 140.
    Noseda M, Harada M, McSweeney S et al (2015) PDGFRα demarcates the cardiogenic clonogenic Sca1+ stem/progenitor cell in adult murine myocardium. Nat Commun 6:6930PubMedPubMedCentralCrossRefGoogle Scholar
  141. 141.
    Vicinanza C, Aquila I, Scalise M et al (2017) Adult cardiac stem cells are multipotent and robustly myogenic: c-kit expression is necessary but not sufficient for their identification. Cell Death Differ 24:2101–2116PubMedPubMedCentralCrossRefGoogle Scholar
  142. 142.
    van Berlo JH, Molkentin JD (2016) Most of the dust has settled: cKit+ progenitor cells are an irrelevant source of cardiac myocytes in vivo. Circ Res 118:17–19PubMedPubMedCentralCrossRefGoogle Scholar
  143. 143.
    He L, Li Y, Li Y et al (2017) Enhancing the precision of genetic lineage tracing using dual recombinases. Nat Med 23:1488–1498PubMedCrossRefGoogle Scholar
  144. 144.
    Castaldi A, Dodia RM, Orogo AM et al (2017) Decline in cellular function of aged mouse c-kit+ cardiac progenitor cells. J Physiol 595:6249–6262PubMedPubMedCentralCrossRefGoogle Scholar
  145. 145.
    Saheera S, Nair RR (2017) Accelerated decline in cardiac stem cell efficiency in spontaneously hypertensive rat compared to normotensive wistar rat. PLoS One 12:e0189129PubMedPubMedCentralCrossRefGoogle Scholar
  146. 146.
    Kimura W, Xiao F, Canseco DC et al (2015) Hypoxia fate mapping identifies cycling cardiomyocytes in the adult heart. Nature 523:226–230PubMedCrossRefGoogle Scholar
  147. 147.
    Shao D, Zhai P, Del Re P et al (2014) A functional interaction between hippo-YAP signalling and FoxO1 mediates the oxidative stress response. Nat Commun 5:3315PubMedPubMedCentralCrossRefGoogle Scholar
  148. 148.
    Diez-Cuñado M, Wei K, Bushway PJ et al (2018) miRNAs that induce human cardiomyocyte proliferation converge on the hippo pathway. Cell Rep 23:2168–2174PubMedPubMedCentralCrossRefGoogle Scholar
  149. 149.
    Crespo FL, Sobrado VR, Gomez L et al (2010) Mitochondrial reactive oxygen species mediate cardiomyocyte formation from embryonic stem cells in high glucose. Stem Cells 28:1132–1142PubMedGoogle Scholar
  150. 150.
    Sauer H, Rahimi G, Hescheler J et al (2000) Role of reactive oxygen species and phosphatidylinositol 3-kinase in cardiomyocyte differentiation of embryonic stem cells. FEBS Lett 476:218–223PubMedCrossRefGoogle Scholar
  151. 151.
    Li X, He P, Wang XL et al (2018) Sulfiredoxin-1 enhances cardiac progenitor cell survival against oxidative stress via the upregulation of the ERK/NRF2 signal pathway. Free Radic Biol Med 123:8–19PubMedPubMedCentralCrossRefGoogle Scholar
  152. 152.
    Khatiwala RV, Zhang S, Li X et al (2018) Inhibition of p16INK4A to rejuvenate aging human cardiac progenitor cells via the upregulation of anti-oxidant and NFκB signal pathways. Stem Cell Rev 14:612–625. Scholar
  153. 153.
    Carresi C, Musolino V, Gliozzi M et al (2018) Anti-oxidant effect of bergamot polyphenolic fraction counteracts doxorubicin-induced cardiomyopathy: role of autophagy and c-kitposCD45negCD31neg cardiac stem cell activation. J Mol Cell Cardiol 119:10–18PubMedCrossRefPubMedCentralGoogle Scholar
  154. 154.
    Seo SK, Kim N, Lee JH et al (2018) β-arrestin2 affects cardiac progenitor cell survival through cell mobility and tube formation in severe hypoxia. Korean Circ J 48:296–309PubMedPubMedCentralCrossRefGoogle Scholar
  155. 155.
    Hernandez I, Baio JM, Tsay E et al (2018) Short-term hypoxia improves early cardiac progenitor cell function in vitro. Am J Stem Cells 7:1–17PubMedPubMedCentralGoogle Scholar
  156. 156.
    Amirrasouli MM, Shamsara M (2017) Comparing the in vivo and in vitro effects of hypoxia (3% O2) on directly derived cells from murine cardiac explants versus murine cardiosphere derived cells. J Stem Cells Regen Med 13:35–44PubMedPubMedCentralGoogle Scholar
  157. 157.
    Nakada Y, Canseco DC, Thet SW et al (2017) Hypoxia induces heart regeneration in adult mice. Nature 541:222–227PubMedCrossRefPubMedCentralGoogle Scholar
  158. 158.
    Bigarella CL, Li J, Rimmelé P et al (2014) Stem cells and the impact of ROS signaling. Development 141:4206–4218PubMedPubMedCentralCrossRefGoogle Scholar
  159. 159.
    Sanada F, Kim J, Czarna A et al (2014) c-Kit-positive cardiac stem cells nested in hypoxic niches are activated by stem cell factor reversing the aging myopathy. Circ Res 114:41–55PubMedCrossRefPubMedCentralGoogle Scholar
  160. 160.
    Seshadri G, Che PL, Boopathy AV et al (2012) Characterization of superoxide dismutases in cardiac progenitor cells demonstrates a critical role for manganese superoxide dismutase. Stem Cells Dev 21:3136–3146PubMedPubMedCentralCrossRefGoogle Scholar
  161. 161.
    Krishnamurthy P, Ross DD, Nakanishi T et al (2004) The stem cell marker Bcrp/ABCG2 enhances hypoxic cell survival through interactions with heme. J Biol Chem 279:24218–22425PubMedCrossRefPubMedCentralGoogle Scholar
  162. 162.
    Li TS, Cheng K, Malliaras K (2011) Expansion of human cardiac stem cells in physiological oxygen improves cell production efficiency and potency for myocardial repair. Cardiovasc Res 89:157–165PubMedCrossRefPubMedCentralGoogle Scholar
  163. 163.
    Moscoso I, Tejados N, Barreiro O et al (2016) Podocalyxin-like protein 1 is a relevant marker for human c-kit(pos) cardiac stem cells. J Tissue Eng Regen Med 10:580–590PubMedCrossRefGoogle Scholar
  164. 164.
    Sanz-Ruiz R, Casado-Plasencia A, Borlado LR et al (2017) Rationale and design of a clinical trial to evaluate the safety and efficacy of intracoronary infusion of allogeneic human cardiac stem cells in patients with acute myocardial infarction and left ventricular dysfunction: the randomized multicenter double-blind controlled CAREMI trial (cardiac stem cells in patients with acute myocardial infarction). Circ Res 121:71–80PubMedCrossRefPubMedCentralGoogle Scholar
  165. 165.
    Morrison SJ, Spradling C (2008) Stem cells and niches: mechanisms that promote stem cell maintenance throughout life. Cell 132:598–611PubMedPubMedCentralCrossRefGoogle Scholar
  166. 166.
    Itkin T, Gur-Cohen S, Spencer JA et al (2016) Distinct bone marrow blood vessels differentially regulate haematopoiesis. Nature 532:323–328PubMedPubMedCentralCrossRefGoogle Scholar
  167. 167.
    Spencer J, Ferraro F, Roussakis E et al (2014) Direct measurement of local oxygen concentration in the bone marrow of live animals. Nature 508:269–273PubMedPubMedCentralCrossRefGoogle Scholar
  168. 168.
    Kocabas F, Mahmoud AI, Sosic D et al (2012) The hypoxic epicardial and subepicardial microenvironment. J Cardiovasc Transl Res 5:654–665PubMedCrossRefPubMedCentralGoogle Scholar
  169. 169.
    Kimura W, Muralidhar S, Canseco DC et al (2014) Redox signaling in cardiac renewal. Antioxid Redox Signal 21:1660–1673PubMedPubMedCentralCrossRefGoogle Scholar
  170. 170.
    Fioret BA, Heimfeld JD, Paik DT et al (2014) Endothelial cells contribute to generation of adult ventricular myocytes during cardiac homeostasis. Cell Rep 8:229–241PubMedPubMedCentralCrossRefGoogle Scholar
  171. 171.
    Gómez-Gaviro MV, Lovell-Badge R, Fernández-Avilés F et al (2012) The vascular stem cell niche. J Cardiovasc Transl Res 5:618–630PubMedCrossRefPubMedCentralGoogle Scholar
  172. 172.
    Malliaras K, Ibrahim A, Tseliou E et al (2014) Stimulation of endogenous cardioblasts by exogenous cell therapy after myocardial infarction. EMBO Mol Med 6:760–777PubMedPubMedCentralCrossRefGoogle Scholar
  173. 173.
    Herrero D, Cañón S, Albericio G, Carmona RM, Aguilar S, Mañes S, Bernad A, (2019) Age-related oxidative stress confines damage-responsive Bmi1+ cells to perivascular regions in the murine adult heart. Redox Biology 22:101156PubMedPubMedCentralCrossRefGoogle Scholar

Copyright information

© Springer Nature Singapore Pte Ltd. 2019

Authors and Affiliations

  • Diego Herrero
    • 1
  • Susana Cañón
    • 1
  • Guillermo Albericio
    • 1
  • Susana Aguilar
    • 1
  • Rosa María Carmona
    • 1
  • Adrián Holguín
    • 1
  • Antonio Bernad
    • 1
    Email author
  1. 1.Department of Immunology and Oncology, Spanish National Center for Biotechnology (CNB-CSIC)Universidad Autónoma de MadridMadridSpain

Personalised recommendations