Skip to main content
SpringerLink
Log in

Endothelial Progenitor Cells from Cord Blood: Magic Bullets Against Ischemia?

  • Chapter
  • First Online:
Regenerative Medicine Using Pregnancy-Specific Biological Substances

  • 772 Accesses

Abstract

The use of Endothelial Progenitor Cells (EPCs) in therapy is nowadays considered a feasible option to enhance neo-vascularization in the ischemic heart and lower limbs. Although autologous EPC sources such as the bone marrow (BM) and the peripheral blood (PB) have been already validated for their use to promote angiogenesis, heterologous sources such as the cord blood (CB) have not been yet approved for use in patients, due to risk for immune response induction. Studies in animal models of peripheral ischemia have shown, however, that protocols to pharmacologically suppress immune response allow a potentially successful use of cord-blood-derived CD34+ cells.

Since patients suffering cardiovascular diseases have a well-documented reduction of EPCs number and biological functions, the use of highly clonogenic EPCs, such as those obtained from the cord blood, may have an important therapeutic implication as an alternative option to promote angiogenesis in patients having a poor stem cell pool.

The present contribution will provide the EPC current definition(s), will discuss the fundamental biology of cord-blood-derived EPCs as potential “magic bullets” to combat consequences of ischemia and will report about potential risks and benefits arising from translation of cord-blood-derived EPCs into clinical practice.

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 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 249.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
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

Similar content being viewed by others

References

  1. Asahara T, Murohara T, Sullivan A, et al. Isolation of putative progenitor endothelial cells for angiogenesis. Science. 1997;275:964-967.

    Article  CAS  PubMed  Google Scholar 

  2. Takahashi T, Kalka C, Masuda H, et al. Ischemia- and cytokine-induced mobilization of bone marrow-derived endothelial progenitor cells for neovascularization. Nat Med. 1999;5:434-438.

    Article  CAS  PubMed  Google Scholar 

  3. Shi Q, Rafii S, Wu MH, et al. Evidence for circulating bone marrow-derived endothelial cells. Blood. 1998;92:362-367.

    CAS  PubMed  Google Scholar 

  4. Shintani S, Murohara T, Ikeda H, et al. Mobilization of endothelial progenitor cells in patients with acute myocardial infarction. Circulation. 2001;103:2776-2779.

    Article  CAS  PubMed  Google Scholar 

  5. Gill M, Dias S, Hattori K, et al. Vascular trauma induces rapid but transient mobilization of VEGFR2(+)AC133(+) endothelial precursor cells. Circ Res. 2001;88:167-174.

    CAS  PubMed  Google Scholar 

  6. Hill JM, Zalos G, Halcox JP, et al. Circulating endothelial progenitor cells, vascular function, and cardiovascular risk. N Engl J Med. 2003;348:593-600.

    Article  PubMed  Google Scholar 

  7. Liew A, Barry F, O’Brien T. Endothelial progenitor cells: diagnostic and therapeutic considerations. Bioessays. 2006;28:261-270.

    Article  PubMed  Google Scholar 

  8. Vasa M, Fichtlscherer S, Aicher A, et al. Number and migratory activity of circulating endothelial progenitor cells inversely correlate with risk factors for coronary artery disease. Circ Res. 2001;89:E1-E7.

    Article  CAS  PubMed  Google Scholar 

  9. Hur J, Yoon CH, Kim HS, et al. Characterization of two types of endothelial progenitor cells and their different ­contributions to neovasculogenesis. Arterioscler Thromb Vasc Biol. 2004;24:288-293.

    Article  CAS  PubMed  Google Scholar 

  10. Hur J, Yang HM, Yoon CH, et al. Identification of a novel role of T cells in postnatal vasculogenesis: characterization of endothelial progenitor cell colonies. Circulation. 2007;116:1671-1682.

    Article  PubMed  Google Scholar 

  11. Kuwana M, Okazaki Y, Kodama H, Satoh T, Kawakami Y, Ikeda Y. Endothelial differentiation potential of human monocyte-derived multipotential cells. Stem Cells. 2006;24:2733-2743.

    Article  CAS  PubMed  Google Scholar 

  12. Rehman J, Li J, Orschell CM, March KL. Peripheral blood “endothelial progenitor cells” are derived from monocyte/macrophages and secrete angiogenic growth factors. Circulation. 2003;107:1164-1169.

    Article  PubMed  Google Scholar 

  13. Rohde E, Bartmann C, Schallmoser K, et al. Immune cells mimic the morphology of endothelial progenitor colonies in vitro. Stem Cells. 2007;25:1746-1752.

    Article  CAS  PubMed  Google Scholar 

  14. Rohde E, Malischnik C, Thaler D, et al. Blood monocytes mimic endothelial progenitor cells. Stem Cells. 2006;24:357-367.

    Article  PubMed  Google Scholar 

  15. Romagnani P, Annunziato F, Liotta F, et al. CD14 + CD34low cells with stem cell phenotypic and functional features are the major source of circulating endothelial progenitors. Circ Res. 2005;97:314-322.

    Article  CAS  PubMed  Google Scholar 

  16. Urbich C, Heeschen C, Aicher A, Dernbach E, Zeiher AM, Dimmeler S. Relevance of monocytic features for neovascularization capacity of circulating endothelial progenitor cells. Circulation. 2003;108:2511-2516. Epub 2003 Oct 27.

    Article  PubMed  Google Scholar 

  17. Nagano M, Yamashita T, Hamada H, et al. Identification of functional endothelial progenitor cells suitable for the treatment of ischemic tissue using human umbilical cord blood. Blood. 2007;110:151-160.

    Article  CAS  PubMed  Google Scholar 

  18. Timmermans F, Van Hauwermeiren F, De Smedt M, et al. Endothelial outgrowth cells are not derived from CD133+ cells or CD45+ hematopoietic precursors. Arterioscler Thromb Vasc Biol. 2007;27:1572-1579.

    Article  CAS  PubMed  Google Scholar 

  19. Case J, Mead LE, Bessler WK, et al. Human CD34 + AC133 + VEGFR-2+ cells are not endothelial progenitor cells but distinct, primitive hematopoietic progenitors. Exp Hematol. 2007;35:1109-1118.

    Article  CAS  PubMed  Google Scholar 

  20. Prater DN, Case J, Ingram DA, Yoder MC. Working ­hypothesis to redefine endothelial progenitor cells. Leukemia. 2007;21:1141-1149.

    Article  CAS  PubMed  Google Scholar 

  21. Pelosi E, Valtieri M, Coppola S, et al. Identification of the hemangioblast in postnatal life. Blood. 2002;100:3203-3208.

    Article  CAS  PubMed  Google Scholar 

  22. Ziegler BL, Valtieri M, Porada GA, et al. KDR receptor: a key marker defining hematopoietic stem cells. Science. 1999;285:1553-1558.

    Article  CAS  PubMed  Google Scholar 

  23. Yoder MC, Mead LE, Prater D, et al. Redefining endothelial progenitor cells via clonal analysis and hematopoietic stem/progenitor cell principals. Blood. 2007;109:1801-1809.

    Article  CAS  PubMed  Google Scholar 

  24. Takakura N, Watanabe T, Suenobu S, et al. A role for hematopoietic stem cells in promoting angiogenesis. Cell. 2000;102:199-209.

    Article  CAS  PubMed  Google Scholar 

  25. Jones WS, Annex BH. Growth factors for therapeutic angiogenesis in peripheral arterial disease. Curr Opin Cardiol. 2007;22:458-463.

    Article  PubMed  Google Scholar 

  26. Asahara T, Masuda H, Takahashi T, et al. Bone marrow origin of endothelial progenitor cells responsible for postnatal vasculogenesis in physiological and pathological neovascularization. Circ Res. 1999;85:221-228.

    CAS  PubMed  Google Scholar 

  27. Asahara T, Takahashi T, Masuda H, et al. VEGF contributes to postnatal neovascularization by mobilizing bone marrow-derived endothelial progenitor cells. Embo J. 1999;18:3964-3972.

    Article  CAS  PubMed  Google Scholar 

  28. Kamihata H, Matsubara H, Nishiue T, et al. Implantation of bone marrow mononuclear cells into ischemic myocardium enhances collateral perfusion and regional function via side supply of angioblasts, angiogenic ligands, and cytokines. Circulation. 2001;104:1046-1052.

    Article  CAS  PubMed  Google Scholar 

  29. Murayama T, Tepper OM, Silver M, et al. Determination of bone marrow-derived endothelial progenitor cell ­significance in angiogenic growth factor-induced neovascularization in vivo. Exp Hematol. 2002;30:967-972.

    Article  CAS  PubMed  Google Scholar 

  30. Tepper OM, Capla JM, Galiano RD, et al. Adult vasculogenesis occurs through in situ recruitment, proliferation, and tubulization of circulating bone marrow-derived cells. Blood. 2005;105:1068-1077.

    Article  CAS  PubMed  Google Scholar 

  31. Ziegelhoeffer T, Fernandez B, Kostin S, et al. Bone marrow-derived cells do not incorporate into the adult growing ­vasculature. Circ Res. 2004;94:230-238.

    Article  CAS  PubMed  Google Scholar 

  32. Urbich C, Aicher A, Heeschen C, et al. Soluble factors released by endothelial progenitor cells promote migration of endothelial cells and cardiac resident progenitor cells. J Mol Cell Cardiol. 2005;39:733-742.

    Article  CAS  PubMed  Google Scholar 

  33. Dirkx AE, Oude Egbrink MG, Wagstaff J, Griffioen AW. Monocyte/macrophage infiltration in tumors: modulators of angiogenesis. J Leukoc Biol. 2006;80:1183-1196.

    Article  CAS  PubMed  Google Scholar 

  34. Sica A, Bronte V. Altered macrophage differentiation and immune dysfunction in tumor development. J Clin Invest. 2007;117:1155-1166.

    Article  CAS  PubMed  Google Scholar 

  35. Kajiguchi M, Kondo T, Izawa H, et al. Safety and efficacy of autologous progenitor cell transplantation for therapeutic angiogenesis in patients with critical limb ischemia. Circ J. 2007;71:196-201.

    Article  PubMed  Google Scholar 

  36. Tateishi-Yuyama E, Matsubara H, Murohara T, et al. Therapeutic angiogenesis for patients with limb ischaemia by autologous transplantation of bone-marrow cells: a pilot study and a randomised controlled trial. Lancet. 2002;360:427.

    Article  PubMed  Google Scholar 

  37. Fazel S, Cimini M, Chen L, et al. Cardioprotective c-kit + cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J Clin Invest. 2006;116:1865-1877.

    Article  CAS  PubMed  Google Scholar 

  38. Yoon CH, Hur J, Park KW, et al. Synergistic neovascularization by mixed transplantation of early endothelial progenitor cells and late outgrowth endothelial cells: the role of angiogenic cytokines and matrix metalloproteinases. Circulation. 2005;112:1618-1627.

    Article  PubMed  Google Scholar 

  39. Carmeliet P, Dor Y, Herbert JM, et al. Role of HIF-1alpha in hypoxia-mediated apoptosis, cell proliferation and tumour angiogenesis. Nature. 1998;394:485-490.

    Article  CAS  PubMed  Google Scholar 

  40. Ceradini DJ, Kulkarni AR, Callaghan MJ, et al. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat Med. 2004;10:858-864.

    Article  CAS  PubMed  Google Scholar 

  41. Abbott JD, Huang Y, Liu D, Hickey R, Krause DS, Giordano FJ. Stromal cell-derived factor-1alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation. 2004;110:3300-3305.

    Article  PubMed  Google Scholar 

  42. Askari AT, Unzek S, Popovic ZB, et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue ­regeneration in ischaemic cardiomyopathy. Lancet. 2003;362:697-703.

    Article  CAS  PubMed  Google Scholar 

  43. Ceradini DJ, Gurtner GC. Homing to hypoxia: HIF-1 as a mediator of progenitor cell recruitment to injured tissue. Trends Cardiovasc Med. 2005;15:57-63.

    Article  CAS  PubMed  Google Scholar 

  44. Staller P, Sulitkova J, Lisztwan J, Moch H, Oakeley EJ, Krek W. Chemokine receptor CXCR4 downregulated by von Hippel-Lindau tumour suppressor pVHL. Nature. 2003;425:307-311.

    Article  CAS  PubMed  Google Scholar 

  45. De Falco E, Porcelli D, Torella AR, et al. SDF-1 involvement in endothelial phenotype and ischemia-induced recruitment of bone marrow progenitor cells. Blood. 2004;104:3472-3482.

    Article  PubMed  Google Scholar 

  46. Hidalgo A, Sanz-Rodriguez F, Rodriguez-Fernandez JL, et al. Chemokine stromal cell-derived factor-1alpha modulates VLA-4 integrin-dependent adhesion to fibronectin and VCAM-1 on bone marrow hematopoietic progenitor cells. Exp Hematol. 2001;29:345-355.

    Article  CAS  PubMed  Google Scholar 

  47. Peled A, Kollet O, Ponomaryov T, et al. The chemokine SDF-1 activates the integrins LFA-1, VLA-4, and VLA-5 on immature human CD34(+) cells: role in transendothelial/stromal migration and engraftment of NOD/SCID mice. Blood. 2000;95:3289-3296.

    CAS  PubMed  Google Scholar 

  48. Petit I, Goichberg P, Spiegel A, et al. Atypical PKC-zeta regulates SDF-1-mediated migration and development of human CD34+ progenitor cells. J Clin Invest. 2005;115:168-176.

    CAS  PubMed  Google Scholar 

  49. Hiasa KI, Ishibashi M, Ohtani K, et al. Gene transfer of stromal cell-derived factor-1{alpha} enhances ischemic vasculogenesis and angiogenesis via vascular endothelial growth factor/endothelial nitric oxide synthase-related pathway. Next-generation chemokine therapy for therapeutic neovascularization. Circulation. 2004;17:17.

    Google Scholar 

  50. Lataillade JJ, Clay D, Bourin P, et al. Stromal cell-derived factor 1 regulates primitive hematopoiesis by suppressing apoptosis and by promoting G(0)/G(1) transition in CD34(+) cells: evidence for an autocrine/paracrine mechanism. Blood. 2002;99:1117-1129.

    Article  CAS  PubMed  Google Scholar 

  51. Callaghan MJ, Ceradini DJ, Gurtner GC. Hyperglycemia-induced reactive oxygen species and impaired endothelial progenitor cell function. Antioxid Redox Signal. 2005;7:1476-1482.

    Article  CAS  PubMed  Google Scholar 

  52. Chen YH, Lin SJ, Lin FY, Wu TC, Tsao CR, Huang PH, Liu PL, Chen YL, Chen JW. High glucose impairs early and late endothelial progenitor cells by modifying nitric oxide-related but not oxidative stress-mediated mechanisms. Diabetes. 2007;56(6):1559-1568.

    Google Scholar 

  53. Fadini GP, Miorin M, Facco M, et al. Circulating endothelial progenitor cells are reduced in peripheral vascular complications of type 2 diabetes mellitus. J Am Coll Cardiol. 2005;45:1449-1457.

    Article  CAS  PubMed  Google Scholar 

  54. Fadini GP, Sartore S, Schiavon M, et al. Diabetes impairs progenitor cell mobilisation after hindlimb ischaemia-reperfusion injury in rats. Diabetologia. 2006;49:3075-3084.

    Article  CAS  PubMed  Google Scholar 

  55. Ingram DA, Lien IZ, Mead LE, et al. In vitro hyperglycemia or a diabetic intrauterine environment reduces neonatal endothelial colony-forming cell numbers and function. Diabetes. 2008;57:724-731.

    Article  CAS  PubMed  Google Scholar 

  56. Krankel N, Adams V, Linke A, et al. Hyperglycemia reduces survival and impairs function of circulating blood-derived progenitor cells. Arterioscler Thromb Vasc Biol. 2005;25:698-703.

    Article  PubMed  Google Scholar 

  57. Loomans CJ, de Koning EJ, Staal FJ, et al. Endothelial progenitor cell dysfunction: a novel concept in the pathogenesis of vascular complications of type 1 diabetes. Diabetes. 2004;53:195-199.

    Article  CAS  PubMed  Google Scholar 

  58. Marchetti V, Menghini R, Rizza S, et al. Benfotiamine counteracts glucose toxicity effects on endothelial progenitor cell differentiation via Akt/FoxO signaling. Diabetes. 2006;55:2231-2237.

    Article  CAS  PubMed  Google Scholar 

  59. Seeger FH, Haendeler J, Walter DH, et al. p38 mitogen-activated protein kinase downregulates endothelial progenitor cells. Circulation. 2005;111:1184-1191.

    Article  CAS  PubMed  Google Scholar 

  60. Tepper OM, Galiano RD, Capla JM, et al. Human endothelial progenitor cells from type II diabetics exhibit impaired proliferation, adhesion, and incorporation into vascular structures. Circulation. 2002;106:2781-2786.

    Article  PubMed  Google Scholar 

  61. Thum T, Fraccarollo D, Schultheiss M, et al. Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes. 2007;56:66674.

    Article  Google Scholar 

  62. Chavakis E, Urbich C, Dimmeler S. Homing and engraftment of progenitor cells: a prerequisite for cell therapy. J Mol Cell Cardiol. 2008;45(4):514-522.

    Article  CAS  PubMed  Google Scholar 

  63. Seeger FH, Zeiher AM, Dimmeler S. Cell-enhancement strategies for the treatment of ischemic heart disease. Nat Clin Pract Cardiovasc Med. 2007;4(suppl 1):S110-S113.

    Article  CAS  PubMed  Google Scholar 

  64. Zemani F, Silvestre JS, Fauvel-Lafeve F, et al. Ex vivo priming of endothelial progenitor cells with SDF-1 before transplantation could increase their proangiogenic potential. Arterioscler Thromb Vasc Biol. 2008;28:644-650.

    Article  CAS  PubMed  Google Scholar 

  65. Delorme B, Basire A, Gentile C, et al. Presence of endothelial progenitor cells, distinct from mature endothelial cells, within human CD146+ blood cells. Thromb Haemost. 2005;94:1270-1279.

    CAS  PubMed  Google Scholar 

  66. Corselli M, Parodi A, Mogni M, et al. Clinical scale ex vivo expansion of cord blood-derived outgrowth endothelial progenitor cells is associated with high incidence of karyotype aberrations. Exp Hematol. 2008;36:340-349.

    Article  CAS  PubMed  Google Scholar 

  67. Pesce M, Orlandi A, Iachininoto MG, et al. Myoendothelial differentiation of human umbilical cord blood-derived stem cells in ischemic limb tissues. Circ Res. 2003;93:e51-e62.

    Article  PubMed  Google Scholar 

  68. Torrente Y, Belicchi M, Sampaolesi M, et al. Human circulating AC133(+) stem cells restore dystrophin expression and ameliorate function in dystrophic skeletal muscle. J Clin Invest. 2004;114:182-195.

    CAS  PubMed  Google Scholar 

  69. Horsley V, Jansen KM, Mills ST, Pavlath GK. IL-4 acts as a myoblast recruitment factor during mammalian muscle growth. Cell. 2003;113:483-494.

    Article  CAS  PubMed  Google Scholar 

  70. Au P, Daheron LM, Duda DG, et al. Differential in vivo potential of endothelial progenitor cells from human umbilical cord blood and adult peripheral blood to form functional long-lasting vessels. Blood. 2008;111:1302-1305.

    Article  CAS  PubMed  Google Scholar 

  71. Botta R, Gao E, Stassi G, et al. Heart infarct in NOD-SCID mice: therapeutic vasculogenesis by transplantation of human CD34+ cells and low dose CD34 + KDR + cells. Faseb J. 2004;18:1392-1394.

    CAS  PubMed  Google Scholar 

  72. Leor J, Guetta E, Feinberg MS, et al. Human umbilical cord blood-derived CD133+ cells enhance function and repair of the infarcted myocardium. Stem Cells. 2006;24:772-780.

    Article  PubMed  Google Scholar 

  73. Ma N, Ladilov Y, Moebius JM, et al. Intramyocardial delivery of human CD133+ cells in a SCID mouse cryoinjury model: bone marrow vs. cord blood-derived cells. Cardiovasc Res. 2006;71:158-169.

    Article  CAS  PubMed  Google Scholar 

  74. Melero-Martin JM, Khan ZA, Picard A, Wu X, Paruchuri S, Bischoff J. In vivo vasculogenic potential of human blood-derived endothelial progenitor cells. Blood. 2007;109:4761-4768.

    Article  CAS  PubMed  Google Scholar 

  75. Murohara T, Ikeda H, Duan J, et al. Transplanted cord blood-derived endothelial precursor cells augment postnatal neovascularization. J Clin Invest. 2000;105:1527-1536.

    Article  CAS  PubMed  Google Scholar 

  76. Ott I, Keller U, Knoedler M, et al. Endothelial-like cells expanded from CD34+ blood cells improve left ventricular function after experimental myocardial infarction. Faseb J. 2005;19:992-994.

    CAS  PubMed  Google Scholar 

  77. Lemarie C, Esterni B, Calmels B, et al. CD34(+) progenitors are reproducibly recovered in thawed umbilical grafts, and positively influence haematopoietic reconstitution after transplantation. Bone Marrow Transplant. 2007;39:453-460.

    Article  CAS  PubMed  Google Scholar 

  78. Bonanno G, Mariotti A, Procoli A, et al. Human cord blood CD133+ cells immunoselected by a clinical-grade apparatus differentiate in vitro into endothelial- and cardiomyocyte-like cells. Transfusion. 2007;47:280-289.

    Article  CAS  PubMed  Google Scholar 

  79. Jang JH, Kim SK, Choi JE, et al. Endothelial progenitor cell differentiation using cryopreserved, umbilical cord blood-derived mononuclear cells. Acta Pharmacol Sin. 2007;28:367-374.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The Authors wish to thank Dr. Ilaria Burba and Dr. Anita Gianella for critically reading the manuscript.

Author information

Authors and Affiliations

  1. Centro Cardiologico Monzino, Laboratorio di Biologia Vascolare e Terapia Genica, Milan, Italy

    Maurizio Pesce

  2. Centro Cardiologico Monzino IRCCS, Laboratorio di Biologia Vascolare e Terapia Genica, Via Parea 4, Milan, Italy

    Maurizio Pesce

Authors
  1. Maurizio Pesce
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Giulio Pompilio
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Maurizio C. Capogrossi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Maurizio Pesce .

Editor information

Editors and Affiliations

  1. Advanced Medical Research Inst., B.P.Poddar Hospital, Vidyasagar Hospital, Kolkata, India

    Niranjan Bhattacharya

  2. Dept. Obstetrics & Gynaecology, Boston University Medical Centre, E. Concord Street 85, Boston, 02118, Massachusetts, USA

    Phillip Stubblefield

Rights and permissions

Reprints and permissions

Copyright information

© 2011 Springer London

About this chapter

Cite this chapter

Pesce, M., Pompilio, G., Capogrossi, M.C. (2011). Endothelial Progenitor Cells from Cord Blood: Magic Bullets Against Ischemia?. In: Bhattacharya, N., Stubblefield, P. (eds) Regenerative Medicine Using Pregnancy-Specific Biological Substances. Springer, London. https://doi.org/10.1007/978-1-84882-718-9_21

Download citation

  • DOI: https://doi.org/10.1007/978-1-84882-718-9_21

  • Published:

  • Publisher Name: Springer, London

  • Print ISBN: 978-1-84882-717-2

  • Online ISBN: 978-1-84882-718-9

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation