Abstract
The prevention of perinatal neurological disabilities remains a major challenge for public health, and no neuroprotective treatment to date has proven clinically useful in reducing the lesions leading to these disabilities. Efforts are, therefore, urgently needed to test other neuroprotective strategies including cell therapies. Although stem cells have raised great hopes as an inexhaustible source of therapeutic products that could be used for neuroprotection and neuroregeneration in disorders affecting the brain and spinal cord, certain sources of stem cells are associated with potential ethical issues. The human umbilical cord (hUC) is a rich source of stem and progenitor cells including mesenchymal stem cells (MSCs) derived either from the cord or from cord blood. hUC MSCs (hUC-MSCs) have several advantages as compared to other types and sources of stem cells. In this review, we will summarize the most recent findings regarding the technical aspects and the preclinical investigation of these promising cells in neuroprotection and neuroregeneration, and their potential use in the developing human brain. However, extensive studies are needed to optimize the administration protocol, safety parameters, and potential preinjection cell manipulations before designing a controlled trial in human neonates.
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References
Larroque B, Ancel PY, Marret S, et al.; EPIPAGE Study group. Neurodevelopmental disabilities and special care of 5-year-old children born before 33 weeks of gestation (the EPIPAGE study): a longitudinal cohort study. Lancet 2008;371:813–20.
Marlow N, Wolke D, Bracewell MA, Samara M; EPICure Study Group. Neurologic and developmental disability at six years of age after extremely preterm birth. N Engl J Med 2005;352:9–19.
Volpe JJ . Neurobiology of periventricular leukomalacia in the premature infant. Pediatr Res 2001;50:553–62.
Pappa KI, Anagnou NP . Novel sources of fetal stem cells: where do they fit on the developmental continuum? Regen Med 2009;4:423–33.
Weiss ML, Medicetty S, Bledsoe AR, et al. Human umbilical cord matrix stem cells: preliminary characterization and effect of transplantation in a rodent model of Parkinson’s disease. Stem Cells 2006;24:781–92.
Yang CC, Shih YH, Ko MH, Hsu SY, Cheng H, Fu YS . Transplantation of human umbilical mesenchymal stem cells from Wharton’s jelly after complete transection of the rat spinal cord. PLoS ONE 2008;3:e3336.
Yu G, Borlongan CV, Stahl CE, et al. Systemic delivery of umbilical cord blood cells for stroke therapy: a review. Restor Neurol Neurosci 2009;27:41–54.
Zhang L, Li Y, Zhang C, Chopp M, Gosiewska A, Hong K . Delayed administration of human umbilical tissue-derived cells improved neurological functional recovery in a rodent model of focal ischemia. Stroke 2011;42:1437–44.
Sanberg PR, Willing AE, Garbuzova-Davis S, et al. Umbilical cord blood-derived stem cells and brain repair. Ann N Y Acad Sci 2005;1049:67–83.
Friedenstein AJ, Gorskaja JF, Kulagina NN . Fibroblast precursors in normal and irradiated mouse hematopoietic organs. Exp Hematol 1976;4:267–74.
Dazzi F, Horwood NJ . Potential of mesenchymal stem cell therapy. Curr Opin Oncol 2007;19:650–5.
Pittenger MF, Mackay AM, Beck SC, et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999;284:143–7.
Delorme B, Ringe J, Gallay N, et al. Specific plasma membrane protein phenotype of culture-amplified and native human bone marrow mesenchymal stem cells. Blood 2008;111:2631–5.
Silva WA Jr, Covas DT, Panepucci RA, et al. The profile of gene expression of human marrow mesenchymal stem cells. Stem Cells 2003;21:661–9.
Caplan AI, Dennis JE . Mesenchymal stem cells as trophic mediators. J Cell Biochem 2006;98:1076–84.
Rao MS, Mattson MP . Stem cells and aging: expanding the possibilities. Mech Ageing Dev 2001;122:713–34.
Campagnoli C, Roberts IA, Kumar S, Bennett PR, Bellantuono I, Fisk NM . Identification of mesenchymal stem/progenitor cells in human first-trimester fetal blood, liver, and bone marrow. Blood 2001;98:2396–402.
De Coppi P, Bartsch G Jr, Siddiqui MM, et al. Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol 2007;25:100–6.
Romanov YA, Svintsitskaya VA, Smirnov VN . Searching for alternative sources of postnatal human mesenchymal stem cells: candidate MSC-like cells from umbilical cord. Stem Cells 2003;21:105–10.
Sarugaser R, Lickorish D, Baksh D, Hosseini MM, Davies JE . Human umbilical cord perivascular (HUCPV) cells: a source of mesenchymal progenitors. Stem Cells 2005;23:220–9.
Tsai MS, Lee JL, Chang YJ, Hwang SM . Isolation of human multipotent mesenchymal stem cells from second-trimester amniotic fluid using a novel two-stage culture protocol. Hum Reprod 2004;19:1450–6.
Tuan RS, Boland G, Tuli R . Adult mesenchymal stem cells and cell-based tissue engineering. Arthritis Res Ther 2003;5:32–45.
Newcomb JD, Willing AE, Sanberg PR . Umbilical cord blood cells. Methods Mol Biol 2009;549:119–36.
Broxmeyer HE . Umbilical cord transplantation: epilogue. Semin Hematol 2010;47:97–103.
Kurtzberg J . Update on umbilical cord blood transplantation. Curr Opin Pediatr 2009;21:22–9.
Baksh D, Yao R, Tuan RS . Comparison of proliferative and multilineage differentiation potential of human mesenchymal stem cells derived from umbilical cord and bone marrow. Stem Cells 2007;25:1384–92.
Lu LL, Liu YJ, Yang SG, et al. Isolation and characterization of human umbilical cord mesenchymal stem cells with hematopoiesis-supportive function and other potentials. Haematologica 2006;91:1017–26.
Rocha V, Wagner JE Jr, Sobocinski KA, et al. Graft-versus-host disease in children who have received a cord-blood or bone marrow transplant from an HLA-identical sibling. Eurocord and International Bone Marrow Transplant Registry Working Committee on Alternative Donor and Stem Cell Sources. N Engl J Med 2000;342:1846–54.
Gluckman E, Rocha V, Chastang C . Peripheral stem cells in bone marrow transplantation. Cord blood stem cell transplantation. Baillieres Best Pract Res Clin Haematol 1999;12:279–92.
Karahuseyinoglu S, Cinar O, Kilic E, et al. Biology of stem cells in human umbilical cord stroma: in situ and in vitro surveys. Stem Cells 2007;25:319–31.
Manca MF, Zwart I, Beo J, et al. Characterization of mesenchymal stromal cells derived from full-term umbilical cord blood. Cytotherapy 2008;10:54–68.
Bjorklund LM, Sánchez-Pernaute R, Chung S, et al. Embryonic stem cells develop into functional dopaminergic neurons after transplantation in a Parkinson rat model. Proc Natl Acad Sci USA 2002;99:2344–9.
Titomanlio L, Bouslama M, Le Verche V, et al. Implanted neurosphere-derived precursors promote recovery after neonatal excitotoxic brain injury. Stem Cells Dev 2011;20:865–79.
Wright LS, Prowse KR, Wallace K, Linskens MH, Svendsen CN . Human progenitor cells isolated from the developing cortex undergo decreased neurogenesis and eventual senescence following expansion in vitro. Exp Cell Res 2006;312:2107–20.
Brederlau A, Correia AS, Anisimov SV, et al. Transplantation of human embryonic stem cell-derived cells to a rat model of Parkinson’s disease: effect of in vitro differentiation on graft survival and teratoma formation. Stem Cells 2006;24:1433–40.
Carson CT, Aigner S, Gage FH . Stem cells: the good, bad and barely in control. Nat Med 2006;12:1237–8.
Amariglio N, Hirshberg A, Scheithauer BW, et al. Donor-derived brain tumor following neural stem cell transplantation in an ataxia telangiectasia patient. PLoS Med 2009;6:e1000029.
Grinnemo KH, Kumagai-Braesch M, Månsson-Broberg A, et al. Human embryonic stem cells are immunogenic in allogeneic and xenogeneic settings. Reprod Biomed Online 2006;13:712–24.
Nussbaum J, Minami E, Laflamme MA, et al. Transplantation of undifferentiated murine embryonic stem cells in the heart: teratoma formation and immune response. FASEB J 2007;21:1345–57.
Lee OK, Kuo TK, Chen WM, Lee KD, Hsieh SL, Chen TH . Isolation of multipotent mesenchymal stem cells from umbilical cord blood. Blood 2004;103:1669–75.
Musina RA, Bekchanova ES, Belyavskii AV, Grinenko TS, Sukhikh GT . Umbilical cord blood mesenchymal stem cells. Bull Exp Biol Med 2007;143:127–31.
Secco M, Zucconi E, Vieira NM, et al. Multipotent stem cells from umbilical cord: cord is richer than blood! Stem Cells 2008;26:146–50.
Wexler SA, Donaldson C, Denning-Kendall P, Rice C, Bradley B, Hows JM . Adult bone marrow is a rich source of human mesenchymal ‘stem’ cells but umbilical cord and mobilized adult blood are not. Br J Haematol 2003;121:368–74.
Mareschi K, Biasin E, Piacibello W, Aglietta M, Madon E, Fagioli F . Isolation of human mesenchymal stem cells: bone marrow versus umbilical cord blood. Haematologica 2001;86:1099–100.
Zeddou M, Briquet A, Relic B, et al. The umbilical cord matrix is a better source of mesenchymal stem cells (MSC) than the umbilical cord blood. Cell Biol Int 2010;34:693–701.
Fong CY, Subramanian A, Biswas A, et al. Derivation efficiency, cell proliferation, freeze-thaw survival, stem-cell properties and differentiation of human Wharton’s jelly stem cells. Reprod Biomed Online 2010;21:391–401.
Fong CY, Richards M, Manasi N, Biswas A, Bongso A . Comparative growth behaviour and characterization of stem cells from human Wharton’s jelly. Reprod Biomed Online 2007;15:708–18.
Gonzalez R, Griparic L, Umana M, et al. An efficient approach to isolation and characterization of pre- and postnatal umbilical cord lining stem cells for clinical applications. Cell Transplant 2010;19:1439–49.
Kita K, Gauglitz GG, Phan TT, Herndon DN, Jeschke MG . Isolation and characterization of mesenchymal stem cells from the sub-amniotic human umbilical cord lining membrane. Stem Cells Dev 2010;19:491–502.
Montanucci P, Basta G, Pescara T, Pennoni I, Di Giovanni F, Calafiore R . New simple and rapid method for purification of mesenchymal stem cells from the human umbilical cord Wharton jelly. Tissue Eng Part A 2011;17:2651–61.
Tong CK, Vellasamy S, Tan BC, et al. Generation of mesenchymal stem cell from human umbilical cord tissue using a combination enzymatic and mechanical disassociation method. Cell Biol Int 2011;35:221–6.
Hatlapatka T, Moretti P, Lavrentieva A, et al. Optimization of culture conditions for the expansion of umbilical cord-derived mesenchymal stem or stromal cell-like cells using xeno-free culture conditions. Tissue Eng Part C Methods 2011;17:485–93.
Ennis J, Götherström C, Le Blanc K, Davies JE . In vitro immunologic properties of human umbilical cord perivascular cells. Cytotherapy 2008;10:174–81.
Weiss ML, Anderson C, Medicetty S, et al. Immune properties of human umbilical cord Wharton’s jelly-derived cells. Stem Cells 2008;26:2865–74.
Yoo KH, Jang IK, Lee MW, et al. Comparison of immunomodulatory properties of mesenchymal stem cells derived from adult human tissues. Cell Immunol 2009;259:150–6.
Azari MF, Mathias L, Ozturk E, Cram DS, Boyd RL, Petratos S . Mesenchymal stem cells for treatment of CNS injury. Curr Neuropharmacol 2010;8:316–23.
Bieback K, Brinkmann I . Mesenchymal stromal cells from human perinatal tissues: From biology to cell therapy. World J Stem Cells 2010;2:81–92.
Troyer DL, Weiss ML . Wharton’s jelly-derived cells are a primitive stromal cell population. Stem Cells 2008;26:591–9.
Fu YS, Cheng YC, Lin MY, et al. Conversion of human umbilical cord mesenchymal stem cells in Wharton’s jelly to dopaminergic neurons in vitro: potential therapeutic application for Parkinsonism. Stem Cells 2006;24:115–24.
Hou L, Cao H, Wang D, et al. Induction of umbilical cord blood mesenchymal stem cells into neuron-like cells in vitro. Int J Hematol 2003;78:256–61.
Wang HS, Hung SC, Peng ST, et al. Mesenchymal stem cells in the Wharton’s jelly of the human umbilical cord. Stem Cells 2004;22:1330–7.
Tsagias N, Koliakos I, Karagiannis V, Eleftheriadou M, Koliakos GG . Isolation of mesenchymal stem cells using the total length of umbilical cord for transplantation purposes. Transfus Med 2011;21:253–61.
Ishige I, Nagamura-Inoue T, Honda MJ, et al. Comparison of mesenchymal stem cells derived from arterial, venous, and Wharton’s jelly explants of human umbilical cord. Int J Hematol 2009;90:261–9.
Majore I, Moretti P, Stahl F, Hass R, Kasper C . Growth and differentiation properties of mesenchymal stromal cell populations derived from whole human umbilical cord. Stem Cell Rev 2011;7:17–31.
Petsa A, Gargani S, Felesakis A, Grigoriadis N, Grigoriadis I . Effectiveness of protocol for the isolation of Wharton’s Jelly stem cells in large-scale applications. In Vitro Cell Dev Biol Anim 2009;45:573–6.
Xu Y, Meng H, Li C, et al. Umbilical cord-derived mesenchymal stem cells isolated by a novel explantation technique can differentiate into functional endothelial cells and promote revascularization. Stem Cells Dev 2010;19:1511–22.
Hartmann I, Hollweck T, Haffner S, et al. Umbilical cord tissue-derived mesenchymal stem cells grow best under GMP-compliant culture conditions and maintain their phenotypic and functional properties. J Immunol Methods 2010;363:80–9.
Nekanti U, Mohanty L, Venugopal P, Balasubramanian S, Totey S, Ta M . Optimization and scale-up of Wharton’s jelly-derived mesenchymal stem cells for clinical applications. Stem Cell Res 2010;5:244–54.
De Bruyn C, Najar M, Raicevic G, et al. A rapid, simple, and reproducible method for the isolation of mesenchymal stromal cells from Wharton’s jelly without enzymatic treatment. Stem Cells Dev 2011;20:547–57.
Liu G, Ye X, Zhu Y, et al. Osteogenic differentiation of GFP-labeled human umbilical cord blood derived mesenchymal stem cells after cryopreservation. Cryobiology 2011;63:125–8.
Wang HY, Lun ZR, Lu SS . Cryopreservation of umbilical cord blood-derived mesenchymal stem cells without dimethyl sulfoxide. Cryo Letters 2011;32:81–8.
Ding DC, Shyu WC, Chiang MF, et al. Enhancement of neuroplasticity through upregulation of beta1-integrin in human umbilical cord-derived stromal cell implanted stroke model. Neurobiol Dis 2007;27:339–53.
Fu YS, Shih YT, Cheng YC, Min MY . Transformation of human umbilical mesenchymal cells into neurons in vitro. J Biomed Sci 2004;11:652–60.
Mitchell KE, Weiss ML, Mitchell BM, et al. Matrix cells from Wharton’s jelly form neurons and glia. Stem Cells 2003;21:50–60.
Montzka K, Lassonczyk N, Tschöke B, et al. Neural differentiation potential of human bone marrow-derived mesenchymal stromal cells: misleading marker gene expression. BMC Neurosci 2009;10:16.
Bertani N, Malatesta P, Volpi G, Sonego P, Perris R . Neurogenic potential of human mesenchymal stem cells revisited: analysis by immunostaining, time-lapse video and microarray. J Cell Sci 2005;118(Pt 17):3925–36.
Choi CB, Cho YK, Prakash KV, et al. Analysis of neuron-like differentiation of human bone marrow mesenchymal stem cells. Biochem Biophys Res Commun 2006;350:138–46.
Lu P, Blesch A, Tuszynski MH . Induction of bone marrow stromal cells to neurons: differentiation, transdifferentiation, or artifact? J Neurosci Res 2004;77:174–91.
Neuhuber B, Gallo G, Howard L, Kostura L, Mackay A, Fischer I . Reevaluation of in vitro differentiation protocols for bone marrow stromal cells: disruption of actin cytoskeleton induces rapid morphological changes and mimics neuronal phenotype. J Neurosci Res 2004;77:192–204.
Rooney GE, Howard L, O’Brien T, Windebank AJ, Barry FP . Elevation of cAMP in mesenchymal stem cells transiently upregulates neural markers rather than inducing neural differentiation. Stem Cells Dev 2009;18:387–98.
Hodgkinson CP, Gomez JA, Mirotsou M, Dzau VJ . Genetic engineering of mesenchymal stem cells and its application in human disease therapy. Hum Gene Ther 2010;21:1513–26.
Porada CD, Almeida-Porada G . Mesenchymal stem cells as therapeutics and vehicles for gene and drug delivery. Adv Drug Deliv Rev 2010;62:1156–66.
Lim JY, Park SH, Jeong CH, et al. Microporation is a valuable transfection method for efficient gene delivery into human umbilical cord blood-derived mesenchymal stem cells. BMC Biotechnol 2010;10:38.
Park SA, Ryu CH, Kim SM, et al. CXCR4-transfected human umbilical cord blood-derived mesenchymal stem cells exhibit enhanced migratory capacity toward gliomas. Int J Oncol 2011;38:97–103.
Shang AJ, Hong SQ, Xu Q, et al. NT-3-secreting human umbilical cord mesenchymal stromal cell transplantation for the treatment of acute spinal cord injury in rats. Brain Res 2011;1391:102–13.
Kermani AJ, Fathi F, Mowla SJ . Characterization and genetic manipulation of human umbilical cord vein mesenchymal stem cells: potential application in cell-based gene therapy. Rejuvenation Res 2008;11:379–86.
Ryu CH, Park SH, Park SA, et al. Gene therapy of intracranial glioma using interleukin 12-secreting human umbilical cord blood-derived mesenchymal stem cells. Hum Gene Ther 2011;22:733–43.
Friedman R, Betancur M, Boissel L, Tuncer H, Cetrulo C, Klingemann H . Umbilical cord mesenchymal stem cells: adjuvants for human cell transplantation. Biol Blood Marrow Transplant 2007;13:1477–86.
Burns TC, Ortiz-González XR, Gutiérrez-Pérez M, et al. Thymidine analogs are transferred from prelabeled donor to host cells in the central nervous system after transplantation: a word of caution. Stem Cells 2006;24:1121–7.
Coyne TM, Marcus AJ, Woodbury D, Black IB . Marrow stromal cells transplanted to the adult brain are rejected by an inflammatory response and transfer donor labels to host neurons and glia. Stem Cells 2006;24:2483–92.
Pawelczyk E, Jordan EK, Balakumaran A, et al. In vivo transfer of intracellular labels from locally implanted bone marrow stromal cells to resident tissue macrophages. PLoS ONE 2009;4:e6712.
Koh SH, Kim KS, Choi MR, et al. Implantation of human umbilical cord-derived mesenchymal stem cells as a neuroprotective therapy for ischemic stroke in rats. Brain Res 2008;1229:233–48.
Pluchino S, Cusimano M, Bacigaluppi M, Martino G . Remodelling the injured CNS through the establishment of atypical ectopic perivascular neural stem cell niches. Arch Ital Biol 2010;148:173–83.
Prowse AB, Chong F, Gray PP, Munro TP . Stem cell integrins: implications for ex-vivo culture and cellular therapies. Stem Cell Res 2011;6:1–12.
Liao W, Zhong J, Yu J, et al. Therapeutic benefit of human umbilical cord derived mesenchymal stromal cells in intracerebral hemorrhage rat: implications of anti-inflammation and angiogenesis. Cell Physiol Biochem 2009;24:307–16.
Hu SL, Luo HS, Li JT, et al. Functional recovery in acute traumatic spinal cord injury after transplantation of human umbilical cord mesenchymal stem cells. Crit Care Med 2010;38:2181–9.
Xiong N, Zhang Z, Huang J, et al. VEGF-expressing human umbilical cord mesenchymal stem cells, an improved therapy strategy for Parkinson’s disease. Gene Ther 2011;18:394–402.
Zhang L, Zhang HT, Hong SQ, Ma X, Jiang XD, Xu RX . Cografted Wharton’s jelly cells-derived neurospheres and BDNF promote functional recovery after rat spinal cord transection. Neurochem Res 2009;34:2030–9.
Coyne TM, Marcus AJ, Reynolds K, Black IB, Woodbury D . Disparate host response and donor survival after the transplantation of mesenchymal or neuroectodermal cells to the intact rodent brain. Transplantation 2007;84:1507–16.
Le Blanc K, Tammik L, Sundberg B, Haynesworth SE, Ringdén O . Mesenchymal stem cells inhibit and stimulate mixed lymphocyte cultures and mitogenic responses independently of the major histocompatibility complex. Scand J Immunol 2003;57:11–20.
Lim JY, Park SI, Kim SM, et al. Neural differentiation of brain-derived neurotrophic factor-expressing human umbilical cord blood-derived mesenchymal stem cells in culture via TrkB-mediated ERK and β-catenin phosphorylation and following transplantation into the developing brain. Cell Transplant 2011, in press.
Xia G, Hong X, Chen X, Lan F, Zhang G, Liao L . Intracerebral transplantation of mesenchymal stem cells derived from human umbilical cord blood alleviates hypoxic ischemic brain injury in rat neonates. J Perinat Med 2010;38:215–21.
Seo Y, Yang SR, Jee MK, et al. Human umbilical cord blood-derived mesenchymal stem cells protect against neuronal cell death and ameliorate motor deficits in Niemann Pick type C1 mice. Cell Transplant 2011;20:1033–47.
Ball LM, Bernardo ME, Roelofs H, et al. Cotransplantation of ex vivo expanded mesenchymal stem cells accelerates lymphocyte recovery and may reduce the risk of graft failure in haploidentical hematopoietic stem-cell transplantation. Blood 2007;110:2764–7.
Le Blanc K, Frassoni F, Ball L, et al.; Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008;371:1579–86.
Christopeit M, Schendel M, Föll J, Müller LP, Keysser G, Behre G . Marked improvement of severe progressive systemic sclerosis after transplantation of mesenchymal stem cells from an allogeneic haploidentical-related donor mediated by ligation of CD137L. Leukemia 2008;22:1062–4.
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Dalous, J., Larghero, J. & Baud, O. Transplantation of umbilical cord–derived mesenchymal stem cells as a novel strategy to protect the central nervous system: technical aspects, preclinical studies, and clinical perspectives. Pediatr Res 71, 482–490 (2012). https://doi.org/10.1038/pr.2011.67
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DOI: https://doi.org/10.1038/pr.2011.67
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