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Genetic marking as an approach to studying in vivo hematopoiesis: progress in the non-human primate model

Oncogene volume 21, pages 3274–3283 (2002)Cite this article

Abstract

Retroviral insertion site analysis following transplantation of marked hematopoietic stem cells (HSCs) is a powerful method for studying hematopoiesis in vivo. High-level gene transfer efficiency was achieved in murine models in the late 1980s, but early human gene transfer protocols into hematopoietic stem and progenitor cells using the murine methodology showed consistently poor results. The utility of non-human primates as pre-clinical models has since become apparent. Modifications in retroviral transduction conditions have resulted in stable long-term gene transfer efficiency as high as 15–20% to primitive repopulating cells in non-human primate models. This has permitted, for the first time in a large animal model, tracking of individual stem and progenitor cell clones via insertion site analysis, an advantage over competitive transplantation studies, which cannot firmly evaluate the number or life span of individual clones contributing to hematopoiesis. Retroviral tracking studies in mice suggest that stable hematopoiesis may be dominated by a small number of clones, but these studies have been limited by insensitive detection methods, low numbers of transplanted stem cells, and limited life span of immunodeficient mice. Autologous transplantation studies in non-human primates have just begun and have the potential to shed light on controversial issues such as the number of clones contributing to stable hematopoiesis, clonal succession, and lineage commitment, as well as the effect of clinically relevant manipulations such as cytokines, chemotherapy, and radiation on hematopoiesis. These approaches will have significant impact in studying various aspects of stem cell biology including the phenomenon of stem cell plasticity.

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References

  • Abkowitz JL, Catlin SN, Guttorp P . 1996 Nat. Med. 2: 190–197

  • Abkowitz JL, Golinelli D, Harrison DE, Guttorp P . 2000 Blood 96: 3399–3405

  • Abkowitz JL, Lineberger ML, Newton MA, Shelton GH, Ott RL, Guttorp P . 1992 Proc. Natl. Acad. Sci. USA 87: 9062–9066

  • Abkowitz JL, Persik MT, Shelton GH, Ott RL, Kiklevich V, Catlin SN, Guttorp P . 1995 Proc. Natl. Acad. Sci. USA 92: 2031–2035

  • Abkowitz JL, Taboada M, Shelton GH, Catlin SN, Guttorp P, Kiklevich JV . 1998 Proc. Natl. Acad. Sci. USA 95: 3862–3866

  • An DS, Wersto RP, Agricola BA, Metzger M, Lu S, Amado RG, Chen ISY, Donahue RE . 2000 J. Virol. 74: 1286–1295

  • Anderson WF, Kantoff P, Eglitis M, McLachlin J, Karson E, Zwiebel J, Nienhuis A, Karlsson S, Blaese RM, Kohn D . 1986 Cold Spring Harb. Symp. Quant. Biol. 51: 2 1073–1081

  • Andrews RG, Briddell RA, Knitter GH, Rowley SD, Appelbaum FR, McNiece IK . 1995 Blood 85: 15–20

  • Berenson RJ, Andrews RG, Bensinger WI, Kalamasz D, Knitter G . 1988 J. Clin. Invest. 81: 951–955

  • Bock TA, Orlic D, Dunbar CE, Broxmeyer HE, Bodine DM . 1995 J. Exp. Med. 182: 2037–2043

  • Bodine DM, McDonagh KT, Seidel NE, Nienhuis AW . 1991 Exp. Hematol. 19: 206–212

  • Bodine DM, Seidel NE, Gale MS, Nienhuis AW, Orlic D . 1994 Blood 84: 1482–1491

  • Boggs DR, Boggs SS, Saxe DF, Gress LA, Canfield DR . 1982 J. Clin. Invest. 70: 242–253

  • Brenner M . 1996 Hum. Gene Ther. 7: 1927–1936

  • Brenner MK, Rill DR, Moen RC, Krance RA, Mirro J, Anderson WF, Ihle JN . 1993 Lancet 341: 85–86

  • Brown CJ, Robinson WP . 2000 Blood 95: 2449–2451

  • Bunting KD, Sangster MY, Ihle JN, Sorrentino BP . 1998 Nat. Med. 4: 58–64

  • Burger H, van Leen RW, Dorssers LCJ, Persoon NLM, Lemson PJ, Wagemaker G . 1990 Blood 76: 2229–2234

  • Busque L, Mio R, Mattioli J, Brais E, Blais N, Lalonde Y, Maragh M, Gilliland DG . 1996 Blood 88: 59–65

  • Capel B, Hawley R, Covarrubias L, Hawley T, Mintz B . 1989 Proc. Natl. Acad. Sci. USA 86: 4564–4568

  • Cashman JD, Lapidot T, Wang JCY, Doedens M, Shultz LD, Lansdorp P, Dick JE, Eaves CJ . 1997 Blood 89: 4307–4316

  • Cavazzana-Calvo M, Hacein-Bey S, de Saint Basile G, Gross F, Yvon E, Nusbaum P, Selz F, Hue C, Certain S, Casanova JL, Bousso P, Deist FL, Fischer A . 2000 Science 288: 669–672

  • Champion KM, Gilbert JG, Asimakopoulous FA, Hinshelwood S, Green AR . 1997 Br. J. Haematol. 97: 920–926

  • Christensen K, Kristiansen M, Hagen-Larsen H, Skytthe A, Bathum L, Jeune B, Anderson-Ranberg K, Vaupel JW, Orstavik KH . 2000 Blood 95: 2449–2451

  • Dick JE, Magli MC, Huszar D, Phillips RA, Berstein A . 1985 Cell 42: 71–79

  • Donahue RE, Dunbar CE . 2001 Hum. Gene Ther. 12: 607–617

  • Donahue RE, Kirby MR, Metzger ME, Agricola BA, Sellers SE, Cullis HM . 1996 Blood 87: 1644–1653

  • Dorrell C, Gan OI, Pereira DS, Hawlet RG, Dick JE . 2000 Blood 95: 102–110

  • Drize N, Olshanskaya YV, Gerasimova LP, Manakova TE, Samoylina NL, Todria TV, Chertkov JL . 2001 Exp. Hematol. 29: 786–794

  • Drize NJ, Keller JR, Chertkov JL . 1996 Blood 88: 2927–2938

  • Dunbar CE . 1996 Annu. Rev. Med. 47: 11–20

  • Dunbar CE, Cottler-Fox M, O'Shaughnessy J, Doren S, Carter CS, Berenson R, Brown S, Moen RC, Greenblatt J, Stewart FM, Leitman SF, Wilson W, Cowan KH, Young NS, Nienhuis AW . 1995 Blood 85: 3048–3057

  • Dunbar CE, Seidel NE, Doren S, Sellers S, Cline AP, Metzger ME, Agricola BA, Donahue RE, Bodine DM . 1996 Proc. Natl. Acad. Sci. USA 93: 11871–11876

  • Emerson SG . 1996 Blood 87: 3082–3088

  • Fialkow PJ, Jacobsen RJ, Papayannopolov T . 1977 Am. J. Med. 63: 125–

  • Gale RE, Fielding AK, Harrison CN, Linch DC . 1997 Br. J. Haematol. 98: 512–519

  • Gothot A, van der Loo JCM, Clapp DW, Srour EF . 1998 Blood 92: 2641–2649

  • Greiner DL, Hesselton RA, Shultz LD . 1998 Stem Cells 16: 166–177

  • Guenechea G, Gan OI, Dorrell C, Dick JE . 2001 Nat. Immunol. 2: 75–82

  • Habibian HK, Peters SO, Hsieh CC, Wuu J, Vergilis K, Grimaldi CI, Reilly J, Carlson JE, Frimberger AE, Stewart FM, Quesenberry PJ . 1998 J. Exp. Med. 188: 393–398

  • Hanania EG, Giles RE, Kavanagh J, Ellerson D, Zu Z, Wang T, Su Y, Kudelka A, Rahman Z, Holmes F, Hortobagyi G, Claxton D, Bachier C, Thall P, Cheng S, Hester J, Ostrove JM, Bird RE, Chang A, Korbling M, Seong D, Cote R, Holzmayer T, Mechetner E, Deisseroth AB . 1996 Proc. Natl. Acad. Sci. USA 93: 15346–15351

  • Hanenberg H, Xiao XL, Dilloo D, Hashino K, Kato I, Williams DA . 1996 Nat. Med. 2: 876–882

  • Harrison DE . 1980 Blood 55: 77–83

  • Harrison DE, Astle CM, Lerner C . 1988 Proc. Natl. Acad. Sci. USA 85: 822–826

  • Harrison DE, Lerner CP . 1991 Blood 78: 1237–1240

  • Jordan CT, Lemischka IR . 1990 Genes Dev. 4: 220–232

  • Jordan CT, McKearn JP, Lemischka IR . 1990 Cell 68: 953–963

  • Kantoff PW, Gillio AP, McLachlin JR, Bordignon C, Eglitis MA, Kernan NA, Moen RC, Kohn DB, Yu SF, Karson E, Karlsson S, Zweibel J, Gilboa E, Blaese RM, Neinhuis A, O'Reilly RJ, Anderson WF . 1987 J. Exp. Med. 166: 219–234

  • Karlsson S . 1991 Blood 78: 2481–2492

  • Kay HEM . 1965 Lancet 7409: 418–419

  • Keller G, Paige C, Gilboa E, Wagner EF . 1985 Nature 318: 149–154

  • Keller G, Snodgrass R . 1990 J. Exp. Med. 171: 1407–1418

  • Kelly PF, Carrington J, Nathwani A, Vanin EF . 2001 Ann. N. Y. Acad. Sci. 938: 262–276

  • Kiem HP, Andrews RG, Morris J, Peterson L, Heyward S, Allen JM, Rasko JEJ, Potter J, Miller AD . 1998 Blood 92: 1878–1886

  • Kiem HP, Heyward S, Winkler A, Potter J, Allen JM, Miller AD, Andrews RG . 1997 Blood 90: 4638–4645

  • Kim HJ, Tisdale JF, Wu T, Takatoku M, Sellers SE, Zickler P, Metzger ME, Agricola BA, Malley JD, Kato I, Donahue RE, Brown KE, Dunbar CE . 2000 Blood 96: 1–8

  • Lagasse E, Connors H, Al Dhalimy M, Reitsma M, Dohse M, Osborne L, Wang X, Finegold M, Weissman IL, Grompe M . 2000 Nat. Med. 6: 1229–1234

  • Larochelle A, Vormoor J, Hanenberg H, Wang JCY, Bhatia M, Lapidot T, Moritz T, Murdoch B, Xiao XL, Kato I, Williams DA, Dick JE . 1996 Nat. Med. 2: 1329–1337

  • Lemischka I . 1999 Proc. Natl. Acad. Sci. USA 96: 14193–14195

  • Lemischka IR, Raulet DH, Mulligan RC . 1986 Cell 45: 917–927

  • Luskey BD, Rosenblatt M, Zsebo K, Williams DA . 1992 Blood 80: 396–402

  • Miller AD . 1992 Curr. Top. Microbiol. Immunol. 158: 1–24

  • Miyoshi H, Smith KA, Mosier DE, Verma IM, Torbett BE . 1999 Science 283: 682–686

  • Naldini L . 1998 Curr. Opin. Biotechnol. 9: 457–463

  • Nash R, Storb R, Neiman P . 1988 Blood 2031: 2037

  • Nolta JA, Dao MA, Wells S, Smogorzewska EM, Kohn DB . 1996 Proc. Natl. Acad. Sci. USA 93: 2414–2419

  • Nolta JA, Handley MB, Kohn DB . 1994 Blood 83: 3041–3051

  • Ochman HA, Gerber S, Hart DL . 1988 Genetics 120: 621–626

  • Orlic D, Girard LJ, Jordan CT, Anderson SM, Cline AP, Bodine DM . 1996 Proc. Natl. Acad. Sci. USA 93: 11097–11102

  • Orlic D, Kajstura J, Chimenti S, Bodine DM, Leri A, Anversa P . 2001b Ann. N. Y. Acad. Sci. 938: 221–229

  • Orlic D, Kajstura J, Chimenti S, Limana F, Jakoniuk I, Quaini F, Nadal-Ginard B, Bodine DM, Leri A, Anversa P . 2001a Proc. Natl. Acad. Sci. USA 98: 10344–10349

  • Petzer AL, Zandstra PW, Piret JM, Eaves CJ . 1996 J. Exp. Med. 183: 2551–2558

  • Rebel VI, Tanaka M, Lee J, Hartnett S, Pulsipher M, Nathan DG, Mulligan RC, Sieff CA . 1999 Blood 93: 2217–2224

  • Rosenberg SA, Aebersold P, Cornetta K, Kasid A, Morgan R, Moen R, Karson E, Lotze MT, Yang JC, Topalian SL, Merino MJ, Culver K, Miller AD, Blaese RM, Anderson WF . 1990 N. Engl. J. Med. 323: 570–578

  • Schmidt M, Hoffmann G, Wissler M, Lemke N, Mussig A, Glimm H, Williams DA, Ragg S, Hesemann CU, von Kalle C . 2001 Hum. Gene Ther. 12: 743–749

  • Snodgrass R, Keller G . 1987 EMBO J. 6: 3955–3960

  • Srour EF, Abonour R, Cornetta K, Traycoff CM . 1999 J. Hematother. 8: 93–102

  • Takatoku M, Sellers S, Agricola BA, Metzger ME, Kato I, Donahue RE, Dunbar CE . 2001 J. Clin. Invest. 108: 447–455

  • Tisdale JF, Hanazono Y, Sellers SE, Agricola BA, Metzger ME, Donahue RE, Dunbar CE . 1998 Blood 92: 1131–1141

  • Tonon L, Bergamaschi G, Dellavecchia C, Rosti V, Lucotti C, Malabarba L, Novella A, Vercesi E, Frassoni F, Cazzola M . 1998 Br. J. Haematol. 102: 996–1003

  • van Bekkum D W . 1978 Transplant. Proc. 10: 105–111

  • Van Beusechem VW, Valerio D . 1996 Hum. Gene Ther. 7: 1649–1668

  • Wu T, Kim HJ, Sellers SE, Meade KE, Agricola BA, Metzger ME, Kato I, Donahue RE, Dunbar CE, Tisdale JF . 2000 Mol. Ther. 1: 285–293

  • Yokota T, Oritani K, Mitsui H, Aoyema K, Ishikawa J, Sugahara H, Matsumura I, Tsai S, Tomiyama Y, Kanakura Y, Matsuzawa Y . 1998 Blood 91: 3263–3272

  • Zanjani ED, Almeida-Porada G, Flake AW . 1996 Int. J. Hematol. 63: 179–192

  • Zhong RK, Astle CM, Harrison DE . 1996 J. Immunol. 157: 138–145

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Authors and Affiliations

  1. Molecular Hematopoiesis Section, Hematology Branch, NHLBI, NIH, 9000 Rockville Pike, Bethesda, 20892, Maryland, MD, USA

    Patricia A Shi, Peiman Hematti & Cynthia E Dunbar

  2. Department of Internal Medicine, University of Freiburg, Freiburg, Germany

    Christof von Kalle

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  1. Patricia A Shi
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  2. Peiman Hematti
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Correspondence to Cynthia E Dunbar.

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Shi, P., Hematti, P., von Kalle, C. et al. Genetic marking as an approach to studying in vivo hematopoiesis: progress in the non-human primate model. Oncogene 21, 3274–3283 (2002). https://doi.org/10.1038/sj.onc.1205320

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