Abstract
Stem and progenitor cells are present in cord blood at a high frequency making these cells a major target population for experimental and clinical studies. Over the past decade there has been considerable developments in cord blood research and transplantation but despite the rapid progress many problems remain. The initial hope that cord blood would be an alternative source of haemopoietic cells for transplantation has been tempered by the fact that there are insufficient cells in most cord blood collections to engraft an adult of average weight. In attempts to increase the cell number, a plethora of techniques for ex-vivo expansion have been developed.These techniques have also proved useful for gene therapy. As cord blood cells possess unique properties this allows them to be utilised as suitable vehicles for gene therapy and long-term engraftment of transduced cells has been achieved. Current work examining the nature of the stem cells present in this haematological source indicates that cord blood contains not only haemopoietic stem cells but also primitive non-haemopoietic cells with high proliferative and developmental potential. As attention focuses on stem cell biology and the controversies surrounding the potential use of embryonic stem cells in treatment of disease, the properties of stem cells from other sources including cord blood are being re-appraised. The purpose of this article is to review some of the current areas of work and highlight biological problems associated with the use of cord blood cells.
Keywords: cord blood, gene therapy, stem cells, transplantation
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References
- Abonour R, Williams DA, Einhorn L, Hall KM, Chen J, Coffman J, Traycoff CM, Bank A, Kato I, Ward M, Williams SD, Hromas R, Robertson MJ, Smith FO, Woo D, Mills B, Srour EF, Cornetta K. Efficient retrovirus-mediated transfer of the multidrug resistance 1 gene into autologous human long-term repopulating hematopoietic stem cells. Nat Med. 2000;6:652–658. doi: 10.1038/76225. [DOI] [PubMed] [Google Scholar]
- Barquinero J, Segovia JC, Ramírez M, Limón A, Güenechea G, Puig T, Briones J, García J, Bueren JA. Efficient transduction of human hematopoietic repopulating cells generating stable engraftment of transgene-expressing cells in NOD/SCID mice. Blood. 2000;95:3085–3093. [PubMed] [Google Scholar]
- Bertolini F, Battaglia M, Pedrazzoli P, Da Prada GA, Lanza A, Soligo D, Caneva L, Sarina B, Murphy S, Thomas T, della Cuna GR. Megakaryocytic progenitors can be generated ex vivo and safely administered to autologous peripheral blood progenitor cell transplant recipients. Blood. 1997;89:2679–2688. [PubMed] [Google Scholar]
- Borras FE, Matthews NC, Patel R, Navarette C. Dendritic cells can be successfully generated from CD34+ cord blood cells in the presence of autologous cord blood plasma. Bone Marrow Transplant. 2000;26:371–376. doi: 10.1038/sj.bmt.1702525. [DOI] [PubMed] [Google Scholar]
- Briddell RA, Kern BP, Zilm KL, Stoney GB, McNiece IK. Purification of CD34+ cells is essential for optimal ex vivo expansion of umbilical cord blood cells. J Hematother. 1997;6:145–150. doi: 10.1089/scd.1.1997.6.145. [DOI] [PubMed] [Google Scholar]
- Condiotti R, Zakai YB, Barak V, Nagler A. Ex vivo expansion of CD56+ cytotoxic cells from human umbilical cord blood. Exp Hematol. 2001;29:104–113. doi: 10.1016/S0301-472X(00)00617-2. [DOI] [PubMed] [Google Scholar]
- Conneally E, Eaves CJ, Humphries RK. Efficient retroviralmediated gene transfer to human cord blood stem cells with in vivo repopulating potential. Blood. 1998;91:3487–3493. [PubMed] [Google Scholar]
- Denning-Kendall PA, Evely R, Singha S, Chapman M, Bradley BA, Hows JM. In vitro expansion of cord blood does not prevent engraftment of severe combined immunodeficient repopulating cells. Br J Haematol. 2002;116:218–228. doi: 10.1046/j.1365-2141.2002.03254.x. [DOI] [PubMed] [Google Scholar]
- DiGiusto DL, Lee R, Moon J, Moss K, O'Toole T, Voytovich A, Webster D, Mule JJ. Hematopoietic potential of cryopreserved and ex vivo manipulated umbilical cord blood progenitor cells evaluated in vitro and in vivo. Blood. 1996;87:1261–1271. [PubMed] [Google Scholar]
- Donaldson C, Denning-Kendall P, Bradley B, Hows J. The CD34(+)CD38(neg) population is significantly increased in haemopoietic cell expansion cultures in serum-free compared to serum-replete conditions: Dissociation of phenotype and function. Bone Marrow Transplant. 2001;27:365–371. doi: 10.1038/sj.bmt.1702810. [DOI] [PubMed] [Google Scholar]
- Dorrell C, Gan OI, Pereira DS, Hawley RG, Dick JE. Expansion of human cord blood CD34+CD38 cells in ex vivo culture during retroviral transduction without a corresponding increase in SCID repopulating cell (SRC) frequency: Dissociation of SRC phenotype and function. Blood. 1999;95:102–110. [PubMed] [Google Scholar]
- Dravid G, Rao SG. Ex vivo expansion of stem cells from umbilical cord blood: Expression of cell adhesion molecules. Stem Cells. 2002;20:183–189. doi: 10.1634/stemcells.20-2-183. [DOI] [PubMed] [Google Scholar]
- Erices A, Conget P, Minguell JJ. Mesenchymal progenitor cells in human umbilical cord blood. Br J Haematol. 2000;109:235–242. doi: 10.1046/j.1365-2141.2000.01986.x. [DOI] [PubMed] [Google Scholar]
- Ferrari G, Cusella-De Angelis G, Coletta M, Paolucci E, Stornaiuolo A, Cossu G, Mavilio F. Muscle regeneration by bone marrow-derived myogenic progenitors. Science. 1998;279:1528–1530. doi: 10.1126/science.279.5356.1528. [DOI] [PubMed] [Google Scholar]
- Friedenstein AJ, Chailakhyan RK, Latsinik NV, Panasyuk AF, Keiliss-Borok IV. Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation. 1974;17:331–340. doi: 10.1097/00007890-197404000-00001. [DOI] [PubMed] [Google Scholar]
- Gluckman E, Rocha V, Boyer-Chammard A, Locatelli F, Arcese W, Pasquini R, Ortega J, Souillet G, Ferreira E, Laporte JP, Fernandez M, Chastang C. Outcome of cord-blood transplantation from related and unrelated donors. Eurocord Transplant Group and the European Blood and Marrow Transplantation Group. N Engl J Med. 1997;337:373–381. doi: 10.1056/NEJM199708073370602. [DOI] [PubMed] [Google Scholar]
- Gluckman E. Current status of umbilical cord blood hematopoietic stem cell transplantation. Exp Hematol. 2000;28:1197–1205. doi: 10.1016/S0301-472X(00)00540-3. [DOI] [PubMed] [Google Scholar]
- Goodwin HS, Bicknese AR, Chien S-N, Bogucki BD, Oliver DA, Quinn CO, Wall DA. Multilineage differentiation activity by cells isolated from umbilical cord blood: Expression of bone, fat and neural markers. Biol Blood Marrow Transplant. 2001;7:581–588. doi: 10.1053/bbmt.2001.v7.pm11760145. [DOI] [PubMed] [Google Scholar]
- Güenechea G, Segovia JC, Albella B, Lamana M, Ramírez M, Regidor C, Fernández MN, Bueren JA. Delayed engraftment of Non Obese Diabetic/Severe Combined Immunodeficient mice transplanted with ex vivo-expanded human CD34+ cord blood cells. Blood. 1999;93:1097–1105. [PubMed] [Google Scholar]
- Guenechea G, Gan OI, Inamitsu T, Dorrell C, Pereira DS, Kelly M, Naldini L, Dick JE. Transduction of human CD34+CD38– bone marrow and cord blood derived SCIDrepopulating cells with third generation lentiviral vectors. Mol Ther. 2000;1:566–573. doi: 10.1006/mthe.2000.0077. [DOI] [PubMed] [Google Scholar]
- Gutiérrez-Rodríguez M, Reyes-Maldonado E, Mayani H. Characterization of the adherent cells developed in Dexter-type long-term cultures from human umbilical cord blood. Stem Cells. 2000;18:46–52. doi: 10.1634/stemcells.18-1-46. [DOI] [PubMed] [Google Scholar]
- Ha Y, Choi JU, Yoon DH, Yeon DS, Lee JJ, Kim HO, Cho YE. Neural phenotype expression of cultured human cord blood cells in vitro. Neuroreport. 2001;12:3523–3527. doi: 10.1097/00001756-200111160-00030. [DOI] [PubMed] [Google Scholar]
- Henschler R, Brugger W, Luft T, Frey T, Mertelsmann R, Kanz L. Maintenance of transplantation potential in ex vivo expanded CD34(+)-selected human peripheral blood progenitor cells. Blood. 1994;84:2898–2903. [PubMed] [Google Scholar]
- Hows JM, Bradley BA, Marsh JC, Luft T, Coutinho L, Testa NG, Dexter TM. Growth of human umbilical-cord blood in longterm haemopoietic cultures. Lancet. 1992;340:73–76. doi: 10.1016/0140-6736(92)90396-K. [DOI] [PubMed] [Google Scholar]
- Hows JM. Status of umbilical cord blood transplantation in the year 2001. J Clin Pathol. 2001;54:428–434. doi: 10.1136/jcp.54.6.428. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kohn DB, Hershfield MS, Carbonaro D, Shigeoka A, Brooks J, Smogorzewska EM, Barsky LW, Chan R, Burotto F, Annett G, Nolta JA, Crooks G, Kapoor N, Elder M, Wara D, Bowen T, Madsen E, Snyder FF, Bastian J, Muul L, Blaese RM, Weinberg K, Parkman R. T lymphocytes with a normal ADA gene accumulate after transplantation of transduced autologous umbilical cord blood CD34+ cells in ADA-deficient SCID neonates. Nat Med. 1998;4:775–780. doi: 10.1038/nm0798-775. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Koller M, Manchel I, Maher R, Goltry K, Armstrong R, Smith A. Clinical scale human umbilical cord blood cell expansion in a novel automated perfusion culture system. Bone Marrow Transplant. 1998;21:653–663. doi: 10.1038/sj.bmt.1701157. [DOI] [PubMed] [Google Scholar]
- Kopen GC, Prockop DJ, Phinney DG. Marrow stromal cells migrate throughout forebrain and cerebellum, and they differentiate into astrocytes after injection into neonatal mouse brains. Proc Natl Acad Sci USA. 1999;96:10711–10716. doi: 10.1073/pnas.96.19.10711. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Kurtzberg J, Laughlin M, Graham ML, Smith C, Olson JF, Halperin EC, Ciocci G, Carrier C, Stevens CE, Rubinstein P. Placental blood as a source of hematopoietic stem cells for transplantation into unrelated recipients. N Engl J Med. 1996;335:157–166. doi: 10.1056/NEJM199607183350303. [DOI] [PubMed] [Google Scholar]
- Lewis ID, Almeida-Poradr G, Du J, Lemischka IR, Moore KA, Zanjani ED, Verfaillie CM. Umbilical cord blood cells capable of engrafting in primary, secondary, and tertiary xenogeneic hosts are preserved after ex vivo culture in a noncontact system. Blood. 2001;97:3441–3449. doi: 10.1182/blood.V97.11.3441. [DOI] [PubMed] [Google Scholar]
- Liu E, Tu W, Law HK, Lau YL. Decreased yield, phenotypic expression and function of immature monocyte-derived dendritic cells in cord blood. Br J Haematol. 2001;113:240–246. doi: 10.1046/j.1365-2141.2001.02720.x. [DOI] [PubMed] [Google Scholar]
- Liu A, Takahashi TM, Narita M, Zheng Z, Kanazawa N, Abe T, Nikkuni K, Furukawa T, Toba K, Fuse I, Aizawa Y. Generation of functional and mature dendritic cells from cord blood and bone marrow CD34+ cells by two-step culture combined with calcium ionophore treatment. J Immunol Methods. 2002;261:49–63. doi: 10.1016/S0022-1759(01)00545-2. [DOI] [PubMed] [Google Scholar]
- McNiece I, Kubegov D, Kerzic P, Shpall EJ, Gross S. Increased expansion and differentiation of cord blood products using a two-step expansion culture. Exp Hematol. 2000;28:1181–1186. doi: 10.1016/S0301-472X(00)00520-8. [DOI] [PubMed] [Google Scholar]
- Miyoshi H, Smith KA, Mosier DE, Verma IM, Torbett BE. Transduction of human CD34+ cells that mediate long-term engraftment of NOD/SCID mice by HIV vectors. Science. 1999;283:682–686. doi: 10.1126/science.283.5402.682. [DOI] [PubMed] [Google Scholar]
- Murohara T. Therapeutic vasculogenesis using human cord blood-derived endothelial progenitors. Trends Cardiovasc Medicine. 2001;11:303–307. doi: 10.1016/S1050-1738(01)00128-1. [DOI] [PubMed] [Google Scholar]
- Neildez-Nguyen TMA, Wajcman H, Marden MC, Bensidhoum M, Moncollin V, Giarratana M-C, Kobari L, Thierry D, Douay L. Human erythroid cells produced ex vivo at large scale differentiate into red blood cells. Nat Biotech. 2002;20:467–472. doi: 10.1038/nbt0502-467. [DOI] [PubMed] [Google Scholar]
- Nieda M, Nicol A, Denning-Kendall P, Sweetenham J, Bradley B, Hows J. Endothelial cell precursors are normal components of human umbilical cord blood. Br J Haematol. 1997;98:775–777. doi: 10.1046/j.1365-2141.1997.2583074.x. [DOI] [PubMed] [Google Scholar]
- Nishikawa SI. A complex linkage in the developmental pathway of endothelial and hematopoietic cells. Curr Opin Cell Biol. 2001;13:673–678. doi: 10.1016/S0955-0674(00)00270-2. [DOI] [PubMed] [Google Scholar]
- Ohkawara JI, Ikebuchi K, Fujihara M, Sato N, Hirayama F, Yamaguchi M, Mori KJ, Sekiguchi S. Culture system for extensive production of CD19+IgM+ cells by human cord blood CD34+ progenitors. Leukemia. 1998;12:764–771. doi: 10.1038/sj.leu.2401004. [DOI] [PubMed] [Google Scholar]
- Pereira RF, O'Hara MD, Laptev AV, Halford KW, Pollard MD, Class R, Simon D, Livezey K, Prockop DJ. Marrow stromal cells as a source of progenitor cells for nonhematopoietic tissues in transgenic mice with a phenotype of osteogenesis imperfecta. Proc Natl Acad Sci USA. 1998;95:1142–1147. doi: 10.1073/pnas.95.3.1142. [DOI] [PMC free article] [PubMed] [Google Scholar]
- Piacibello W, Sanavio F, Garetto L, Severino A, Bergandi D, Ferrario J, Fagioli F, Berger M, Aglietta M. Extensive amplification and self-renewal of human primitive hematopoietic stem cells from cord blood. Blood. 1997;89:2644–2653. [PubMed] [Google Scholar]
- Piacibello W, Sanavio F, Garetto L, Severino A, Dane A, Gammaitoni L, Aglietta M. Differential growth factor requirement of primitive cord blood hematopoietic stem cell for self-renewal and amplification vs proliferation and differentiation. Leukemia. 1998;12:718–727. doi: 10.1038/sj.leu.2401003. [DOI] [PubMed] [Google Scholar]
- Pick M, Nagler A, Grisaru D, Eldor A, Deutsch V. Expansion of megaryocyte progenitors from human umbilical cord blood using a new two-step separation procedure. Br J Haematol. 1998;103:639–650. doi: 10.1046/j.1365-2141.1998.01055.x. [DOI] [PubMed] [Google Scholar]
- Pick M, Eldor A, Grisaru D, Zander AR, Shenhav M, Deutsch VR. Ex-vivo expansion of megakaryocyte progenitors from cryopreserved umbilical cord blood: A potential source of maegakaryocytes for transplantation. Exp Hematol. 2002;30:1079–1087. doi: 10.1016/S0301-472X(02)00884-6. [DOI] [PubMed] [Google Scholar]
- Prockop DJ. Marrow stromal cells as stem cells for nonhematopoietic tissues. Science. 1997;276:71–74. doi: 10.1126/science.276.5309.71. [DOI] [PubMed] [Google Scholar]
- Robinson KL, Ayello J, Hughes R, van de Ven C, Issitt L, Kurtzberg J, Cairo MS. Ex vivo expansion, maturation, and activation of umbilical cord blood-derived T lymphocytes with IL-2, IL-12, anti-CD3, and IL-7. Potential for adoptive cellular immunotherapy post-umbilical cord blood transplantation. Exp Hematol. 2002;30:245–251. doi: 10.1016/S0301-472X(01)00781-0. [DOI] [PubMed] [Google Scholar]
- Salmon P, Kindler V, Ducrey O, Chapuis B, Zubler RH, Trono D. High-level transgene expression in human hematopoietic progenitors and differentiated blood lineages after transduction with improved lentiviral vectors. Blood. 2000;96:3392–3398. [PubMed] [Google Scholar]
- Schilz AJ, Schiedlmeier B, Kuhlcke K, Fruehauf S, Lindemann C, Zeller WJ, Grez M, Fauser AA, Baum C, Eckert HG. MDR1 gene expression in NOD/SCID repopulating cells after retroviral gene transfer under clinically relevant conditions. Mol Ther. 2000;2:609–618. doi: 10.1006/mthe.2000.0216. [DOI] [PubMed] [Google Scholar]
- Shpall EJ, Quinones R, Giller R, Zeng C, Baron AE, Jones RB, Bearman SI, Nieto Y, Freed B, Madinger N, Hogan CJ, Slat-Vasquez V, Russell P, Blunk B, Schissel D, Hild E, Malcolm J, Ward W, McNiece IK. Transplantation of ex vivo expanded cord blood. Biol Blood Marrow Transplant. 2002;8:368–376. doi: 10.1053/bbmt.2002.v8.pm12171483. [DOI] [PubMed] [Google Scholar]
- Tao H, Gandry L, Rice A, Chong B. Cord blood is better than bone marrow for generating megakaryocyte progenitor cells. Exp Hematol. 1999;27:293–301. doi: 10.1016/S0301-472X(98)00050-2. [DOI] [PubMed] [Google Scholar]
- Traycoff CM, Abboud MR, Laver J, Clapp DW, Srour EF. Rapid exit from G0/G1 phases of cell cycle in response to stem cell factor confers on umbilical cord blood CD34+ cells an enhanced ex vivo expansion potential. Exp Hematol. 1994;22:1264–1272. [PubMed] [Google Scholar]
- Traycoff CM, Kosak ST, Grigsby S, Srour EF. Evaluation of ex vivo expansion potential of cord blood and bone marrow hematopoietic progenitor cells using cell tracking and limiting dilution analysis. Blood. 1995;85:2059–2068. [PubMed] [Google Scholar]
- Wagner JE, Rosenthal J, Sweetman R, Shu XO, Davies SM, Ramsay NK, McGlave PB, Sender L, Cairo MS. Successful transplantation of HLA-matched and HLA-mismatched umbilical cord blood from unrelated donors: Analysis of engraftment and acute graft-versus-host disease. Blood. 1996;88:795–802. [PubMed] [Google Scholar]
- Wagner JE, Barker JN, DeFor TE, Baker KS, Blazar BR, Eide C, Goldman A, Kersey J, Krivit W, MacMillan ML, Orchard PJ, Peters C, Weisdorf DJ, Ramsay NKC, Davies SM. Transplantation of unrelated donor umbilical cord blood in 102 patients with malignant and nonmalignant diseases: Influence of CD34 cell dose and HLA disparity on treatment-related mortality and survival. Blood. 2002;100:1611–1618. doi: 10.1182/blood-2002-01-0294. [DOI] [PubMed] [Google Scholar]
- Woods N-B, Muessig A, Schmidt M, Flygare J, Olsson J, Salmon P, Trono D, Von Kalle C, Karlsson S. Lentiviral vector transduction of NOD/SCID repopulating cells results in multiple vector integrations per transduced cell: risk of insertional mutagenesis. Blood. 2000;96:3725–3733. doi: 10.1182/blood-2002-07-2238. [DOI] [PubMed] [Google Scholar]
- DeWynter E, Ploemacher RE. Assays for the assessment of human hematopoietic stem cells. J Biol Regul Homeost Agents. 2001;15:23–27. [PubMed] [Google Scholar]
- Zandstra PW, Conneally E, Petzer AL, Piret JM, Eaves CJ. Cytokine manipulation of primitive human hematopoietic cell self-renewal. Proc Natl Acad Sci USA. 1997;94:4698–4703. doi: 10.1073/pnas.94.9.4698. [DOI] [PMC free article] [PubMed] [Google Scholar]
