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Gene therapy approaches for stem cell protection

Abstract

Cytotoxic exposure of bone marrow and other non-hematopoietic organs containing self-renewing stem cell populations is associated with damage to the supportive microenvironment. Recent evidence indicates that radical oxygen species resulting from the initial oxidative stress persist for months after ionizing irradiation exposure of tissues including oral cavity, esophagus, lung and bone marrow. Antioxidant gene therapy using manganese superoxide dismutase plasmid liposomes has provided organ-specific radiation protection associated with delay or prevention of acute and late toxicity. Recent evidence has suggested that manganese superoxide dismutase transgene expression in cells of the organ microenvironment contributes significantly to the mechanism of protection. Incorporating this knowledge into designs of novel approaches for stem cell protection is addressed in the present review.

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References

  1. Siminovitch L, Till JE, McCulloch EA . Decline in colony-forming ability of marrow cells subjected to serial transplantation into irradiated mice. J Cell Physiol 1964; 64: 23–31.

    Article  CAS  Google Scholar 

  2. Mauch P, Rosenblatt M, Hellman S . Permanent loss in stem cell self renewal capacity following stress to the marrow. Blood 1988; 72: 1193–1196.

    CAS  PubMed  Google Scholar 

  3. Keisuke I, Atsushi H, Fumio A, Keiyo T, Sahoko M, Kana M et al. Reactive oxygen species act through p38 MAPK to limit the lifespan of hematopoietic stem cells. Nat Med 2006; 12: 446–451.

    Article  Google Scholar 

  4. Keisuke I, Atsushi H, Fumio A, Sahoko M, Keiyo T, Isai H et al. Regulation of oxidative stress by ATM is required for self-renewal of haematopoietic stem cells. Nature 2004; 431: 997–1000.

    Article  Google Scholar 

  5. Harrison DE, Astle CM, Delaittre JA . Loss of proliferative capacity in immunohematopoietic stem cells caused by serial transplantation rather than aging. J Exp Med 1978; 147: 1526–1531.

    Article  CAS  Google Scholar 

  6. Harrison DE . Proliferative capacity of erythropoietic stem cell lines and aging: an overview. Mech Ageing Dev 1979; 9: 409–426.

    Article  CAS  Google Scholar 

  7. Iscove NN, Nawa K . Hematopoietic stem cells expand during serial transplantation in vivo without apparent exhaustion. Curr Biol 1997; 7: 805–808.

    Article  CAS  Google Scholar 

  8. Yuan Y, Yu H, Boyer MJ, Song X, Cao S, Shen H et al. Hematopoietic stem cells are not the direct target of spontaneous leukemic transformation in p18INK4C-null reconstituted mice. Cancer Res 2006; 66: 343–351.

    Article  CAS  Google Scholar 

  9. Yu H, Yuan Y, Shen H, Cheng T . Hematopoietic stem cell exhaustion impacted by p18INK4C and p21Cipl/Wafl in opposite manners. Blood 2006; 107: 1200–1207.

    Article  CAS  Google Scholar 

  10. Maze R, Carney JP, Kelley MR, Glassner BJ, Williams DA, Samson L . Increasing DNA repair methyltransferase levels via bone marrow stem cell transduction rescues mice from the toxic effects of 1, 3-bis(2-chloroethyl)-1-nitrosourea, a chemotherapeutic alkylating agent. Proc Natl Acad Sci USA 1996; 93: 206–210.

    Article  CAS  Google Scholar 

  11. Greenberger JS, Epperly MW . Radioprotective antioxidant gene therapy: potential mechanisms of action. Gene Ther Mol Biol 2004; 8: 31–44.

    Google Scholar 

  12. Epperly MW, Goff JP, Sikora CA, Shields DS, Greenberger JS . Bone marrow origin of cells with capacity for homing and differentiation to esophageal squamous epithelium. Radiat Res 2004; 162: 233–240.

    Article  CAS  Google Scholar 

  13. Epperly MW, Shen H, Zhang X, Nie S, Cao S, Greenberger JS . Protection of esophageal stem cells from ionizing irradiation by MnSOD-plasmid liposome gene therapy. In Vivo 2005; 19: 965–974.

    PubMed  Google Scholar 

  14. Williams DA, Orkin SH . Somatic gene therapy. Current status and future prospects. J Clin Invest 1986; 77: 1053–1056.

    Article  CAS  Google Scholar 

  15. Greenberger JS, Epperly MW, Gretton J, Jefferson M, Nie S, Bernarding M et al. Radioprotective gene therapy. Curr Gene Ther 2003; 3: 183–195.

    Article  CAS  Google Scholar 

  16. Anklesaria P, FitzGerald TJ, Kase K, Ohara A, Bentley S, Greenberger JS . Improved hematopoiesis in anemic S1/S1d mice by therapeutic transplantation of a hematopoietic microenvironment. Blood 1989; 74: 1144–1152.

    CAS  PubMed  Google Scholar 

  17. Adams GB, Martin RP, Alley IR, Chabner KT, Cohen KS, Calvi LM et al. Therapeutic targeting of a stem cell niche. Nat Biotechnol 2007; 25: 238–245.

    Article  CAS  Google Scholar 

  18. Harrison DE, Astle CM . Loss of stem cell repopulating ability upon transplantation: effects of donor age, cell number, and transplantation procedure. J Exp Med 1982; 156: 1767–1779.

    Article  CAS  Google Scholar 

  19. Hellman S, Botnick LE, Hannon EC, Vigneulle RM . Proliferative capacity of murine hematopoietic stem cells. Proc Natl Acad Sci USA 1978; 75: 490–494.

    Article  CAS  Google Scholar 

  20. Greenberger JS . Long-term hematopoietic cultures. In: Golde D (ed). Methods in Hematology. Churchill Livingston: New York, 1984, pp 203–243.

    Google Scholar 

  21. Gorbunov NV, Pogue-Geile KL, Epperly MW, Bigbee WL, Draviam R, Day BW et al. Activation of the nitric oxide synthase 2 pathway in the response of bone marrow stromal cells to high doses of ionizing radiation. Radiat Res 2000; 154: 73–86.

    Article  CAS  Google Scholar 

  22. Christopherson II KW, Hangoc G, Mantel CR, Broxmeyer HE . Modulation of hematopoietic stem cell homing and engraftment by CD26. Science 2004; 305: 1000–1003.

    Article  CAS  Google Scholar 

  23. Lapidot T . Mechanism of human stem cell migration and repopulation of NOD/SCID and B2mnull NOD/SCID mice: the role of SDF-1/CXCR4 interactions. Ann NY Acad Sci 2001; 938: 83–95.

    Article  CAS  Google Scholar 

  24. Aliotta J, Keaney P, Passero M, Dooner M, Pimentel J, Greer D et al. Bone marrow production of lung cells: the impact of G-CSF, cardiotoxin, graded doses of irradiation, and subpopulation phenotype. Exp Hematol 2006; 34: 230–241.

    Article  CAS  Google Scholar 

  25. Reynolds SD, Giangreco A, Hong KU, McGrath KE, Ortiz LA, Stripp BR . Airway injury in lung disease pathophysiology: selective depletion of airway stem and progenitor cell pools potentiates lung inflammation and alveolar dysfunction. Am J Physiol Lung Cell Mol Physiol 2004; 287: L1256–L1265.

    Article  CAS  Google Scholar 

  26. Guo HL, Seixas-Silva JA, Epperly MW, Gretton JE, Shin DM, Greenberger JS . Prevention of irradiation-induced oral cavity mucositis by plasmid/liposome delivery of the human manganese superoxide dismutase (MnSOD) transgene. Radiat Res 2003; 159: 361–370.

    Article  CAS  Google Scholar 

  27. Petersen BE, Bowen WC, Patrene KD, Mars WM, Sullivan AK, Boggs SS et al. Bone marrow as a potential source of hepatic oval cells. Science 1999; 284: 1168–1170.

    Article  CAS  Google Scholar 

  28. Kraus DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R et al. Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 2001; 105: 369–377.

    Article  Google Scholar 

  29. Nakayama N, Lee J, Chiu L . Vascular endothelial growth factor synergistically enhances bone morphogenetic protein-4-dependent lymphohematopoietic cell generation from embryonic stem cells in vitro. Blood 2000; 95: 2275–2280.

    CAS  PubMed  Google Scholar 

  30. Bell DR, Van Zant G . Stem cells, aging, and cancer; inevitabilities and outcomes. Oncogene 2004; 23: 7290–7296.

    Article  CAS  Google Scholar 

  31. Weiss DJ, Berberich MA, Borok Z, Gail DB, Kolls IK, Penland C et al. Adult stem cells, lung biology, and lung disease. Proc Am Thorac Soc 2006; 3: 193–207.

    Article  Google Scholar 

  32. Gupta R, Karpatkin S, Basch RS . Hematopiesis and stem cell renewal in long-term bone marrow cultures containing catalase. Blood 2006; 107: 11837–11846.

    Article  Google Scholar 

  33. Epperly MW, Cao S, Zhang X, Franicola D, Kanai AJ, Greenberger EE et al. Increased longevity of hematopoiesis in continuous bone marrow cultures derived from mtNOS−/− homozygous recombinant negative mice correlates with increased radioresistance of hematopoietic and bone marrow stromal cells. Exp Hematol 2007; 35: 137–145.

    Article  CAS  Google Scholar 

  34. Epperly MW, Cao S, Goff J, Shields D, Zhou S, Glowacki J et al. Increased longevity of hematopoiesis in continuous bone marrow cultures and adipocytogenesis in marrow stromal cells derived from SMAD3−/− mice. Exp Hematol 2005; 33: 353–362.

    Article  CAS  Google Scholar 

  35. Pearce DJ, Ridler CM, Simpson C, Bonnet D . Multiparameter analysis of murine bone marrow side population cells. Blood 2004; 103: 2541–2546.

    Article  CAS  Google Scholar 

  36. Lim B, William DA, Orkin SH . Retrovirus-mediated gene transfer of human adenosine deaminase: expression of functional enzyme in murine hematopoietic stem cells in vivo. Mol Cell Biol 1987; 7: 3459–3465.

    Article  CAS  Google Scholar 

  37. Kalberer CP, Pawliuk R, Imren S, Bachelot T, Takekoshi KJ, Fabry M et al. Preselection of retrovirally transduced bone marrow avoids subsequent stem cell gene silencing and age-dependent extinction of expression of human β-globin in engrafted mice. Proc Natl Acad Sci USA 2000; 97: 5411–5415.

    Article  CAS  Google Scholar 

  38. Cohen-Haguenauer O, Peault B, Bauche C, Daniel MT, Casal I, Levy V et al. In vivo repopulation ability of genetically corrected bone marrow cells from Fanconi anemia patients. Proc Natl Acad Sci USA 2006; 103: 2340–2345.

    Article  CAS  Google Scholar 

  39. Biffi A, DePalma M, Quattrini A, DelCarro U, Amadio S, Visigalli I et al. Correction of metachromatic leukodystrophy in the mouse model by transplantation of genetically modified hematopoietic stem cells. J Clin Invest 2004; 113: 1118–1129.

    Article  CAS  Google Scholar 

  40. Malech HL, Maples PB, Whiting-Theobald N, Linton GF, Sekhsaria S, Vowells SJ et al. Prolonged production of NADPH oxidase-corrected granulocytes after gene therapy of chronic granulomatous disease. Proc Natl Acad Sci USA 1997; 94: 12133–12138.

    Article  CAS  Google Scholar 

  41. Davis BM, Encell LP, Zielske SP, Christians FC, Liu L, Friebert SE et al. Applied molecular evolution of O6-benzylguanine-resistant DNA alkyltransferases in human hematopoietic cells. Proc Natl Acad Sci USA 2001; 98: 4950–4954.

    Article  CAS  Google Scholar 

  42. Zhang J, Scadden DT, Crumpacker CS . Primitive hematopoietic cells resist HIV-1 infection via p21Waf1/Cip1/Sdi1. J Clin Invest 2007; 117: 473–481.

    Article  CAS  Google Scholar 

  43. Bonyhadi ML, Moss K, Voytovich A, Auten J, Kalfoglou C, Plavec I et al. RevM10-expressing T cells derived in vivo from transduced human hematopoietic stem-progenitor cells inhibit human immunodeficiency virus replication. J Virol 1997; 71: 4707–4716.

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Bunting KD, Flynn KJ, Riberdy JM, Doherty PC, Sorrentino BP . Virus-specific immunity after gene therapy in a murine model of severe combined immunodeficiency. Proc Natl Acad Sci USA 1999; 96: 232–237.

    Article  CAS  Google Scholar 

  45. Creusol RJ, Fathman CG . Gene therapy for type I diabetes: a novel approach for targeted treatment of autoimmunity. J Clin Invest 2004; 114: 892–894.

    Article  Google Scholar 

  46. Shi Q, Wilcox DA, Fahs SA, Weiler H, Wells CW, Cooley BC et al. Factor VIII ectopically targeted to platelets is therapeutic in hemophilia A with high-titer inhibitory antibodies. J Clin Invest 2006; 116: 1974–1982.

    Article  CAS  Google Scholar 

  47. Smith LE . Bone marrow-derived stem cells preserve cone vision in retinitis pigmentosa. J Clin Invest 2004; 114: 755–757.

    Article  CAS  Google Scholar 

  48. Otani A, Dorrell MI, Kinder K, Moreno SK, Nusinowitz S, Banin E et al. Rescue of retinal degeneration by intravitreally injected adult bone marrow-derived lineage-negative hematopoietic stem cells. J Clin Invest 2004; 114: 765–774.

    Article  CAS  Google Scholar 

  49. Hurtado-Lorenzo A, Millan E, Gonzalez-Nicolini V, Suwelack D, Castro MG, Lowenstein PR . Differentiation and transcription factor gene therapy in experimental Parkinson's disease: sonic hedgehog and Gli-1, but not Nurr-1, protect nigrostriatal cell bodies from 6-OHDA-induced neurodegeneration. Mol Ther 2004; 10: 507–524.

    Article  CAS  Google Scholar 

  50. Jacobs A, Breakefield XO, Fraefel C . HSV-1-based vectors for gene therapy of neurological diseases and brain tumors: part II. Vector systems and applications. Neoplasia 1999; 1: 402–416.

    Article  CAS  Google Scholar 

  51. Biffi A, Capotondo A, Fasano S, del Carro U, Marchesini S, Azuma H et al. Gene therapy of metachromatic leukodystrophy reverses neurological damage and deficits in mice. J Clin Invest 2006; 116: 3070–3082.

    Article  CAS  Google Scholar 

  52. Lee T, Matthews D, Blair G . Novel molecular approaches to cystic fibrosis gene therapy. Biochem J 2005; 387 (Part 1): 1–15.

    Article  CAS  Google Scholar 

  53. Dumon KR, Ishii H, Fong LY, Zanesi N, Fidanza V, Mancini R et al. FHIT gene therapy prevents tumor development in Fhit-deficient mice. Proc Natl Acad Sci USA 2001; 98: 3346–3351.

    Article  CAS  Google Scholar 

  54. Bernerd F, Asselineau D, Vioux C, Chevallier-Lagente O, Bouadjar B, Sarasin A et al. Clues to epidermal cancer proneness revealed by reconstruction of DNA repair-deficient xeroderma pigmentosum skin in vitro. Proc Natl Acad Sci USA 2001; 98: 7817–7822.

    Article  CAS  Google Scholar 

  55. Garver Jr RI, Chytil A, Karlsson S, Fells GA, Brantly ML, Courtney M et al. Production of glycosylated physiologically ‘normal’ human alpha 1-antitrypsin by mouse fibroblasts modified by insertion of a human alpha 1-antitrypsin cDNA using a retroviral vector. Proc Natl Acad Sci USA 1987; 84: 1050–1054.

    Article  CAS  Google Scholar 

  56. Yang J, Shultz RW, Mars WM, Wegner RE, Li Y, Dai C et al. Disruption of tissue-type plasminogen activator gene in mice reduced renal interstitial fibrosis in obstructive nephropathy. J Clin Invest 2002; 110: 1525–1538.

    Article  CAS  Google Scholar 

  57. Edwards PC, Mason JM . Gene-enhanced tissue engineering for dental hard tissue regeneration: (1) overview and practical considerations. Head Face Med 2006; 2: 12.

    Article  Google Scholar 

  58. Palmer G, Burger D, Mezin F, Magne D, Gabay C, Dayer JM et al. The active metabolite of leflunomide, A77 1726, increases the production of IL-1 receptor antagonist in human synovial fibroblasts and articular chondrocytes. Arthritis Res Ther 2004; 6: R181–R189.

    Article  CAS  Google Scholar 

  59. Xiao X, Li J, Tsao YP, Dressman D, Hoffman EP, Watchko JF . Full functional rescue of a complete muscle (TA) in dystrophic hamsters by adeno-associated virus vector-directed gene therapy. J Virol 2000; 74: 1436–1442.

    Article  CAS  Google Scholar 

  60. Bradshaw G, Gutierrez A, Miyake JH, Davis KR, Li AC, Glass CK et al. Facilitated replacement of Kupffer cells expressing a paraoxonase-1 transgene is essential for ameliorating atherosclerosis in mice. Proc Natl Acad Sci USA 2005; 102: 11029–11034.

    Article  CAS  Google Scholar 

  61. Mingozzi F, Liu YL, Dobrzynski E, Kaufhold A, Liu JH, Wang Y et al. Induction of immune tolerance to coagulation factor IX antigen by in vivo hepatic gene transfer. J Clin Invest 2003; 111: 1347–1356.

    Article  CAS  Google Scholar 

  62. Wang X, Zinkel S, Polonsky K, Fuchs E . Transgenic studies with a keratin promoter-driven growth hormone transgene: prospects for gene therapy. Proc Natl Acad Sci USA 1997; 94: 219–226.

    Article  CAS  Google Scholar 

  63. Di Natale P, Di Domenico C, Gargiulo N, Castaldo S, Reyero E, Mithbaokar P et al. Treatment of the mouse model of mucopolysaccharidosis type IIIB with lentiviral-NAGLU vector. Biochem J 2005; 388 (Part 2): 639–646.

    Article  CAS  Google Scholar 

  64. Pfutzner W, Terunuma A, Tock CL, Snead EK, Kolodka TM, Gottesman MM et al. Topical colchicine selection of keratinocytes transduced with the multidrug resistance gene (MDR1) can sustain and enhance transgene expression in vivo. Proc Natl Acad Sci USA 2002; 99: 13096–13104.

    Article  CAS  Google Scholar 

  65. Dimmeler S, Aicher A, Vasa M, Mildner-Rihm C, Adler K, Tiemann M et al. HMG-CoA reductase inhibitors (statins) increase endothelial progenitor cells via the PL 3-kinase/Akt pathway. J Clin Invest 2001; 108: 391–397.

    Article  CAS  Google Scholar 

  66. Paris F, Fuks Z, Kang A, Capodieci P, Juan G, Ehleiter D et al. Endothelial apoptosis as the primary lesion initiating intestinal radiation damage in mice. Science 2001; 293: 293–297.

    Article  CAS  Google Scholar 

  67. Wilson A, Trumpp A . Bone-marrow haematopoietic-stem-cell niches. Nat Rev Immunol 2006; 6: 93–109.

    Article  CAS  Google Scholar 

  68. Szilvassy SJ, Humphries RK, Lansdorp PM, Eaves AC, Eaves CJ . Quantitative assay for totipotent reconstituting hematopoietic stem cells by a competitive repopulation strategy. Proc Natl Acad Sci USA 1990; 87: 8736–8740.

    Article  CAS  Google Scholar 

  69. Tothova Z, Kollipara R, Huntly BJ, Lee BH, Castrillon DH, Cullen DE et al. FoxOs are critical mediators of hematopoietic stem cell resistance to physiologic oxidative stress. Cell 2007; 128: 325–339.

    Article  CAS  Google Scholar 

  70. Insoo B, Saijun F, Qinhui M, Keun RJ, Jong KH, Jin KH et al. BRCA1 induces antioxidant gene expression and resistance to oxidative stress. Cancer Res 2004; 64: 7893–7909.

    Article  Google Scholar 

  71. Carriere A, Carmona M-C, Fernandez Y, Rigoulet M, Wenger RH, Penicaud L et al. Mitochondrial reactive oxygen species control the transcription factor CHOP-10/GADD153 and adipocyte differentiation. J Biol Chem 2004; 279: 40462–40469.

    Article  CAS  Google Scholar 

  72. Cheng T, Rodrigues N, Shen H, Yang Y, Dombkowski D, Sykes M et al. Hematopoietic stem cell quiescence maintained by p21(cip1/waf1). Science 2000; 287: 1804–1808.

    Article  CAS  Google Scholar 

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Acknowledgements

This study was supported by NIH Grants nos. CA 083876 and U19-AI068021.

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Greenberger, J. Gene therapy approaches for stem cell protection. Gene Ther 15, 100–108 (2008). https://doi.org/10.1038/sj.gt.3303004

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