Skip to main content
SpringerLink
Log in

Redox Regulation of Stem Cell Function

  • Chapter
  • First Online:
Oxidative Stress and Redox Regulation

Abstract

Stem cells are critical for tissue regeneration and homeostasis, and their regenerative potential has to be carefully managed to prevent degenerative diseases and cancer. In recent years, it has emerged that stem cells are uniquely sensitive to changes in intracellular reactive oxygen species (ROS) (Hochmuth et al., Cell Stem Cell 8:1–12, 2011a; Ito et al., Nature 431:997–1002, 2004; Owusu-Ansah and Banerjee, Nature 461:537–541, 2009; Smith et al., Proc Natl Acad Sci USA 97:10032–10037, 2000; Tothova et al., Cell 128:325–339, 2007; Tsatmali et al., Brain Res 1040:137–150, 2005). Dynamic regulation of intracellular ROS seems to be critical to control the regenerative potential and to avoid loss of self-renewal capabilities and pluripotency of stem cells. Here, we review these findings, highlighting recent observations in genetic model organisms that clarify the role of ROS in stem cell regulation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 169.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 169.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Abou-Khalil R, Brack AS (2010) Muscle stem cells and reversible quiescence: the role of sprouty. Cell Cycle 9:2575–2580

    CAS  PubMed  Google Scholar 

  • Amcheslavsky A, Jiang J, Ip YT (2009) Tissue damage-induced intestinal stem cell division in Drosophila. Cell Stem Cell 4:49–61

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • An JH, Blackwell TK (2003) SKN-1 links C. elegans mesendodermal specification to a conserved oxidative stress response. Genes Dev 17:1882–1893

    Article  CAS  PubMed  Google Scholar 

  • Bashan N, Kovsan J, Kachko I, Ovadia H, Rudich A (2009) Positive and negative regulation of insulin signaling by reactive oxygen and nitrogen species. Physiol Rev 89:27–71

    Article  CAS  PubMed  Google Scholar 

  • Bhatti S, Kozlov S, Farooqi AA, Naqi A, Lavin M, Khanna KK (2011) ATM protein kinase: the linchpin of cellular defenses to stress. Cell Mol Life Sci 68:2977–3006

    Article  CAS  PubMed  Google Scholar 

  • Biteau B, Jasper H (2011) EGF signaling regulates the proliferation of intestinal stem cells in Drosophila. Development 138:1045–1055

    Article  CAS  PubMed  Google Scholar 

  • Biteau B, Hochmuth CE, Jasper H (2008) JNK activity in somatic stem cells causes loss of tissue homeostasis in the aging Drosophila gut. Cell Stem Cell 3:442–455

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Biteau B, Karpac J, Hwangbo D, Jasper H (2010) Regulation of Drosophila lifespan by JNK signaling. Exp Gerontol 46:349–354

    Article  PubMed Central  PubMed  Google Scholar 

  • Biteau B, Hochmuth CE, Jasper H (2011) Maintaining tissue homeostasis: dynamic control of somatic stem cell activity. Cell Stem Cell 9:402–411

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Borras C, Gomez-Cabrera MC, Vina J (2011) The dual role of p53: DNA protection and antioxidant. Free Radic Res 45:643–652

    Article  PubMed  Google Scholar 

  • Buchon N, Broderick NA, Chakrabarti S, Lemaitre B (2009) Invasive and indigenous microbiota impact intestinal stem cell activity through multiple pathways in Drosophila. Genes Dev 23:2333–2344

    Article  CAS  PubMed  Google Scholar 

  • Burt RK, Loh Y, Pearce W, Beohar N, Barr WG, Craig R, Wen Y, Rapp JA, Kessler J (2008) Clinical applications of blood-derived and marrow-derived stem cells for nonmalignant diseases. JAMA 299:925–936

    Article  CAS  PubMed  Google Scholar 

  • Cheng J, Turkel N, Hemati N, Fuller MT, Hunt AJ, Yamashita YM (2008) Centrosome misorientation reduces stem cell division during ageing. Nature 456:599–604

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Choi NH, Kim JG, Yang DJ, Kim YS, Yoo MA (2008) Age-related changes in Drosophila midgut are associated with PVF2, a PDGF/VEGF-like growth factor. Aging Cell 7:318–334

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Cuadrado A, Nebreda AR (2010) Mechanisms and functions of p38 MAPK signalling. Biochem J 429:403–417

    Article  CAS  PubMed  Google Scholar 

  • Curran SP, Wu X, Riedel CG, Ruvkun G (2009) A soma-to-germline transformation in long-lived Caenorhabditis elegans mutants. Nature 459:1079–1084

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • DeGennaro M, Hurd TR, Siekhaus DE, Biteau B, Jasper H, Lehmann R (2011) Peroxiredoxin stabilization of DE-Cadherin promotes primordial germ cell adhesion. Dev Cell 20(2):233–243

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Diehn M, Cho RW, Lobo NA, Kalisky T, Dorie MJ, Kulp AN, Qian D, Lam JS, Ailles LE, Wong M et al (2009) Association of reactive oxygen species levels and radioresistance in cancer stem cells. Nature 458:780–783

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Essers MA, Weijzen S, de Vries-Smits AM, Saarloos I, de Ruiter ND, Bos JL, Burgering BM (2004) FOXO transcription factor activation by oxidative stress mediated by the small GTPase Ral and JNK. EMBO J 23:4802–4812

    Article  CAS  PubMed  Google Scholar 

  • Evans CJ, Hartenstein V, Banerjee U (2003) Thicker than blood: conserved mechanisms in Drosophila and vertebrate hematopoiesis. Dev Cell 5:673–690

    Article  CAS  PubMed  Google Scholar 

  • Fuller MT, Spradling AC (2007) Male and female Drosophila germline stem cells: two versions of immortality. Science 316:402–404

    Article  CAS  PubMed  Google Scholar 

  • Glintborg B, Weimann A, Kensler TW, Poulsen HE (2006) Oltipraz chemoprevention trial in Qidong, People’s Republic of China: unaltered oxidative biomarkers. Free Radic Biol Med 41:1010–1014

    Article  CAS  PubMed  Google Scholar 

  • Gratwohl A, Baldomero H, Aljurf M, Pasquini MC, Bouzas LF, Yoshimi A, Szer J, Lipton J, Schwendener A, Gratwohl M et al (2010) Hematopoietic stem cell transplantation: a global perspective. JAMA 303:1617–1624

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Ha EM, Oh CT, Bae YS, Lee WJ (2005) A direct role for dual oxidase in Drosophila gut immunity. Science 310:847–850

    Article  CAS  PubMed  Google Scholar 

  • Ha EM, Lee KA, Park SH, Kim SH, Nam HJ, Lee HY, Kang D, Lee WJ (2009a) Regulation of DUOX by the Galphaq-phospholipase Cbeta-Ca2+ pathway in Drosophila gut immunity. Dev Cell 16:386–397

    Article  CAS  PubMed  Google Scholar 

  • Ha EM, Lee KA, Seo YY, Kim SH, Lim JH, Oh BH, Kim J, Lee WJ (2009b) Coordination of multiple dual oxidase-regulatory pathways in responses to commensal and infectious microbes in drosophila gut. Nat Immunol 10:949–957

    Article  CAS  PubMed  Google Scholar 

  • Hayes JD, McMahon M (2009) NRF2 and KEAP1 mutations: permanent activation of an adaptive response in cancer. Trends Biochem Sci 34:176–188

    Article  CAS  PubMed  Google Scholar 

  • Hochmuth CE, Biteau B, Bohmann D, Jasper H (2011a) Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila. Cell Stem Cell 8:1–12

    Article  Google Scholar 

  • Hochmuth CE, Biteau B, Bohmann D, Jasper H (2011b) Redox regulation by Keap1 and Nrf2 controls intestinal stem cell proliferation in Drosophila. Cell Stem Cell 8:188–199

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Inoue H, Hisamoto N, An JH, Oliveira RP, Nishida E, Blackwell TK, Matsumoto K (2005) The C. elegans p38 MAPK pathway regulates nuclear localization of the transcription factor SKN-1 in oxidative stress response. Genes Dev 19:2278–2283

    Article  CAS  PubMed  Google Scholar 

  • Ito K, Hirao A, Arai F, Matsuoka S, Takubo K, Hamaguchi I, Nomiyama K, Hosokawa K, Sakurada K, Nakagata N et al (2004) Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 431:997–1002

    Article  CAS  PubMed  Google Scholar 

  • Jang YY, Sharkis SJ (2007) A low level of reactive oxygen species selects for primitive hematopoietic stem cells that may reside in the low-oxygenic niche. Blood 110:3056–3063

    Article  CAS  PubMed  Google Scholar 

  • Jasper H, Jones DL (2010) Metabolic regulation of stem cell behavior and implications for aging. Cell Metab 12:561–565

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Jiang H, Edgar BA (2011) Intestinal stem cells in the adult Drosophila midgut. Exp Cell Res 317:2780–2788

    Article  CAS  PubMed  Google Scholar 

  • Jiang H, Patel PH, Kohlmaier A, Grenley MO, McEwen DG, Edgar BA (2009) Cytokine/Jak/Stat signaling mediates regeneration and homeostasis in the Drosophila midgut. Cell 137:1343–1355

    Article  PubMed Central  PubMed  Google Scholar 

  • Jones DL, Wagers AJ (2008) No place like home: anatomy and function of the stem cell niche. Nat Rev Mol Cell Biol 9:11–21

    Article  CAS  PubMed  Google Scholar 

  • Lambeth JD (2004) NOX enzymes and the biology of reactive oxygen. Nat Rev Immunol 4:181–189

    Article  CAS  PubMed  Google Scholar 

  • Lee JM, Li J, Johnson DA, Stein TD, Kraft AD, Calkins MJ, Jakel RJ, Johnson JA (2005) Nrf2, a multi-organ protector? FASEB J 19:1061–1066

    Article  PubMed  Google Scholar 

  • Lee WC, Beebe K, Sudmeier L, Micchelli CA (2009) Adenomatous polyposis coli regulates Drosophila intestinal stem cell proliferation. Development 136:2255–2264

    Article  CAS  PubMed  Google Scholar 

  • Lin G, Xu N, Xi R (2008) Paracrine Wingless signalling controls self-renewal of Drosophila intestinal stem cells. Nature 455:1119–1123

    Article  CAS  PubMed  Google Scholar 

  • Liu J, Lin A (2005) Role of JNK activation in apoptosis: a double-edged sword. Cell Res 15:36–42

    Article  PubMed  Google Scholar 

  • Liu J, Cao L, Finkel T (2011) Oxidants, metabolism, and stem cell biology. Free Radic Biol Med 51:2158–2162

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Maher J, Yamamoto M (2010) The rise of antioxidant signaling–the evolution and hormetic actions of Nrf2. Toxicol Appl Pharmacol 244:4–15

    Article  CAS  PubMed  Google Scholar 

  • McEwen DG, Peifer M (2005) Puckered, a Drosophila MAPK phosphatase, ensures cell viability by antagonizing JNK-induced apoptosis. Development 132:3935–3946

    Article  CAS  PubMed  Google Scholar 

  • McMahon M, Itoh K, Yamamoto M, Chanas SA, Henderson CJ, McLellan LI, Wolf CR, Cavin C, Hayes JD (2001) The Cap‘n’Collar basic leucine zipper transcription factor Nrf2 (NF-E2 p45-related factor 2) controls both constitutive and inducible expression of intestinal detoxification and glutathione biosynthetic enzymes. Cancer Res 61:3299–3307

    CAS  PubMed  Google Scholar 

  • Micchelli CA, Perrimon N (2006) Evidence that stem cells reside in the adult Drosophila midgut epithelium. Nature 439:475–479

    Article  CAS  PubMed  Google Scholar 

  • Miyamoto K, Araki KY, Naka K, Arai F, Takubo K, Yamazaki S, Matsuoka S, Miyamoto T, Ito K, Ohmura M et al (2007) Foxo3a is essential for maintenance of the hematopoietic stem cell pool. Cell Stem Cell 1:101–112

    Article  CAS  PubMed  Google Scholar 

  • Miyamoto K, Miyamoto T, Kato R, Yoshimura A, Motoyama N, Suda T (2008) FoxO3a regulates hematopoietic homeostasis through a negative feedback pathway in conditions of stress or aging. Blood 112:4485–4493

    Article  CAS  PubMed  Google Scholar 

  • Motohashi H, O’Connor T, Katsuoka F, Engel JD, Yamamoto M (2002) Integration and diversity of the regulatory network composed of Maf and CNC families of transcription factors. Gene 294:1–12

    Article  CAS  PubMed  Google Scholar 

  • Nguyen T, Nioi P, Pickett CB (2009) The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem 284:13291–13295

    Article  CAS  PubMed  Google Scholar 

  • Noble M, Smith J, Power J, Mayer-Proschel M (2003) Redox state as a central modulator of precursor cell function. Ann N Y Acad Sci 991:251–271

    Article  CAS  PubMed  Google Scholar 

  • Ohlstein B, Spradling A (2006) The adult Drosophila posterior midgut is maintained by pluripotent stem cells. Nature 439:470–474

    Article  CAS  PubMed  Google Scholar 

  • Ohlstein B, Kai T, Decotto E, Spradling A (2004) The stem cell niche: theme and variations. Curr Opin Cell Biol 16:693–699

    Article  CAS  PubMed  Google Scholar 

  • Orkin SH, Zon LI (2008) Hematopoiesis: an evolving paradigm for stem cell biology. Cell 132:631–644

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Owusu-Ansah E, Banerjee U (2009) Reactive oxygen species prime Drosophila haematopoietic progenitors for differentiation. Nature 461:537–541

    Article  CAS  PubMed  Google Scholar 

  • Owusu-Ansah E, Yavari A, Mandal S, Banerjee U (2008) Distinct mitochondrial retrograde signals control the G1-S cell cycle checkpoint. Nat Genet 40:356–361

    Article  CAS  PubMed  Google Scholar 

  • Pan L, Chen S, Weng C, Call G, Zhu D, Tang H, Zhang N, Xie T (2007) Stem cell aging is controlled both intrinsically and extrinsically in the Drosophila ovary. Cell Stem Cell 1:458–469

    Article  CAS  PubMed  Google Scholar 

  • Parmar K, Mauch P, Vergilio JA, Sackstein R, Down JD (2007) Distribution of hematopoietic stem cells in the bone marrow according to regional hypoxia. Proc Natl Acad Sci USA 104:5431–5436

    Article  CAS  PubMed  Google Scholar 

  • Radtke F, Clevers H (2005) Self-renewal and cancer of the gut: two sides of a coin. Science 307:1904–1909

    Article  CAS  PubMed  Google Scholar 

  • Radtke F, Clevers H, Riccio O (2006) From gut homeostasis to cancer. Curr Mol Med 6:275–289

    Article  CAS  PubMed  Google Scholar 

  • Rando TA (2006) Stem cells, ageing and the quest for immortality. Nature 441:1080–1086

    Article  CAS  PubMed  Google Scholar 

  • Ray PD, Huang BW, Tsuji Y (2012) Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal 24(5):981–990

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Salih DA, Brunet A (2008) FoxO transcription factors in the maintenance of cellular homeostasis during aging. Curr Opin Cell Biol 20:126–136

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Simons BD, Clevers H (2011) Stem cell self-renewal in intestinal crypt. Exp Cell Res 317:2719–2724

    Article  CAS  PubMed  Google Scholar 

  • Smith J, Ladi E, Mayer-Proschel M, Noble M (2000) Redox state is a central modulator of the balance between self-renewal and differentiation in a dividing glial precursor cell. Proc Natl Acad Sci USA 97:10032–10037

    Article  CAS  PubMed  Google Scholar 

  • Snippert HJ, van der Flier LG, Sato T, van Es JH, van den Born M, Kroon-Veenboer C, Barker N, Klein AM, van Rheenen J, Simons BD et al (2010) Intestinal crypt homeostasis results from neutral competition between symmetrically dividing Lgr5 stem cells. Cell 143:134–144

    Article  CAS  PubMed  Google Scholar 

  • Spradling AC, de Cuevas M, Drummond-Barbosa D, Keyes L, Lilly M, Pepling M, Xie T (1997) The Drosophila germarium: stem cells, germ line cysts, and oocytes. Cold Spring Harb Symp Quant Biol 62:25–34

    Article  CAS  PubMed  Google Scholar 

  • Spradling A, Drummond-Barbosa D, Kai T (2001) Stem cells find their niche. Nature 414:98–104

    Article  CAS  PubMed  Google Scholar 

  • Sykes SM, Lane SW, Bullinger L, Kalaitzidis D, Yusuf R, Saez B, Ferraro F, Mercier F, Singh H, Brumme KM et al (2011) AKT/FOXO signaling enforces reversible differentiation blockade in myeloid leukemias. Cell 146:697–708

    Article  CAS  PubMed  Google Scholar 

  • Sykiotis GP, Bohmann D (2008) Keap1/Nrf2 signaling regulates oxidative stress tolerance and lifespan in Drosophila. Dev Cell 14:76–85

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Sykiotis GP, Bohmann D (2010) Stress-activated Cap‘n’collar transcription factors in aging and human disease. Sci Signal 3:re3

    PubMed Central  PubMed  Google Scholar 

  • Tian H, Biehs B, Warming S, Leong KG, Rangell L, Klein OD, de Sauvage FJ (2011) A reserve stem cell population in small intestine renders Lgr5-positive cells dispensable. Nature 478:255–259

    Article  CAS  PubMed  Google Scholar 

  • Toledano MB (2009) The guardian recruits cops: the p53-p21 axis delegates prosurvival duties to the Keap1-Nrf2 stress pathway. Mol Cell 34:637–639

    Article  CAS  PubMed  Google Scholar 

  • Toledano MB, Planson AG, Delaunay-Moisan A (2010) Reining in H(2)O(2) for safe signaling. Cell 140:454–456

    Article  CAS  PubMed  Google Scholar 

  • Tonks NK (2006) Protein tyrosine phosphatases: from genes, to function, to disease. Nat Rev Mol Cell Biol 7:833–846

    Article  CAS  PubMed  Google Scholar 

  • Tothova Z, Gilliland DG (2007) FoxO transcription factors and stem cell homeostasis: insights from the hematopoietic system. Cell Stem Cell 1:140–152

    Article  CAS  PubMed  Google Scholar 

  • Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE, McDowell EP, Lazo-Kallanian S, Williams IR, Sears C et al (2007) FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 128:325–339

    Article  CAS  PubMed  Google Scholar 

  • Tsatmali M, Walcott EC, Crossin KL (2005) Newborn neurons acquire high levels of reactive oxygen species and increased mitochondrial proteins upon differentiation from progenitors. Brain Res 1040:137–150

    Article  CAS  PubMed  Google Scholar 

  • Tullet JMA, Hertweck M, An JH, Baker J, Oliviera RP, Baumeister R, Blackwell TK (2008) Direct inhibition of the longevity promoting factor SKN-1 by Insulin like signaling in C. elegans. Cell 132:1025–1038

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Voog J, Jones DL (2010) Stem cells and the niche: a dynamic duo. Cell Stem Cell 6:103–115

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  • Wakabayashi N, Itoh K, Wakabayashi J, Motohashi H, Noda S, Takahashi S, Imakado S, Kotsuji T, Otsuka F, Roop DR et al (2003) Keap1-null mutation leads to postnatal lethality due to constitutive Nrf2 activation. Nat Genet 35:238–245

    Article  CAS  PubMed  Google Scholar 

  • Walker MR, Patel KK, Stappenbeck TS (2009) The stem cell niche. J Pathol 217:169–180

    Article  CAS  PubMed  Google Scholar 

  • Wang L, Jones DL (2010) The effects of aging on stem cell behavior in Drosophila. Exp Gerontol 46:340–344

    Article  PubMed Central  PubMed  Google Scholar 

  • Wang MC, Bohmann D, Jasper H (2005) JNK extends life span and limits growth by antagonizing cellular and organism-wide responses to insulin signaling. Cell 121:115–125

    Article  CAS  PubMed  Google Scholar 

  • Weston CR, Davis RJ (2007) The JNK signal transduction pathway. Curr Opin Cell Biol 19:142–149

    Article  CAS  PubMed  Google Scholar 

  • Woo HA, Yim SH, Shin DH, Kang D, Yu DY, Rhee SG (2010) Inactivation of peroxiredoxin I by phosphorylation allows localized H(2)O(2) accumulation for cell signaling. Cell 140:517–528

    Article  CAS  PubMed  Google Scholar 

  • Yu X, Kensler T (2005) Nrf2 as a target for cancer chemoprevention. Mutat Res 591:93–102

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

This work was supported by grants two joint grants to DB and HJ: N08G-048 from New York State stem cell science and R01 GM100196 from NIH/NIGMS.

Author information

Authors and Affiliations

  1. Biology Department, University of Rochester, Rochester, NY, 14627, USA

    Heinrich Jasper

  2. The Buck Institute for Research on Aging, Novato, CA, 94945, USA

    Heinrich Jasper

  3. Department of Biomedical Genetics, University of Rochester Medical Center, Rochester, NY, 14642, USA

    Dirk Bohmann

Authors
  1. Heinrich Jasper
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Dirk Bohmann
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Heinrich Jasper or Dirk Bohmann .

Editor information

Editors and Affiliations

  1. Mol.,Cel. and Developmental Biology, University of Michigan, Ann Arbor, Michigan, USA

    Ursula Jakob

  2. The Alexander Silberman Institute of Life Science, Department of Biological Chemistry, The Hebrew University of Jerusalem, Jerusalem, Israel

    Dana Reichmann

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Springer Science+Business Media Dordrecht

About this chapter

Cite this chapter

Jasper, H., Bohmann, D. (2013). Redox Regulation of Stem Cell Function. In: Jakob, U., Reichmann, D. (eds) Oxidative Stress and Redox Regulation. Springer, Dordrecht. https://doi.org/10.1007/978-94-007-5787-5_12

Download citation

Publish with us

Policies and ethics

Search

Navigation