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Human mesenchymal stem cells: From immunophenotyping by flow cytometry to clinical applications

  1. Arthur A. Nery1,
  2. Isis C. Nascimento2,
  3. Talita Glaser1,
  4. Vinicius Bassaneze3,
  5. José E. Krieger3,
  6. Henning Ulrich1,*

Article first published online: 1 OCT 2012

DOI: 10.1002/cyto.a.22205

Issue

Cytometry Part A

Cytometry Part A

Special Issue: Cytometry in Stem Cell Research

Volume 83A, Issue 1, pages 48–61, January 2013

Additional Information

How to Cite

Nery, A. A., Nascimento, I. C., Glaser, T., Bassaneze, V., Krieger, J. E. and Ulrich, H. (2013), Human mesenchymal stem cells: From immunophenotyping by flow cytometry to clinical applications. Cytometry, 83A: 48–61. doi: 10.1002/cyto.a.22205

Author Information

  1. 1

    Departamento de Bioquímica, Universidade de São Paulo, São Paulo, Brazil

  2. 2

    Departamento de Neurologia e Neurocirurgia, Universidade Federal de São Paulo, São Paulo, SP, Brazil

  3. 3

    Laboratory of Genetics and Molecular Cardiology, InCor—HC, Universidade de São Paulo, São Paulo, Brazil

*Departamento de Bioquímica, Instituto de Química, Universidade de São Paulo, Avenida Professor Lineu Prestes, 748, CEP 05513-970, São Paulo, Brazil

Publication History

  1. Issue published online: 19 DEC 2012
  2. Article first published online: 1 OCT 2012
  3. Manuscript Accepted: 22 AUG 2012
  4. Manuscript Revised: 15 AUG 2012
  5. Manuscript Received: 9 MAR 2012

Funded by

  • Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP). Grant Number: 2006/61285-9
  • Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and the Provost's Office for Research of the University of São Paulo (Programa de à Pesquisa), Brazil. Grant Number: 2011.1.9333.1.3 (NAPNA-USP)
  • FAPESP

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Literature Cited

  • 1
    Spencer ND,Gimble JM,Lopez MJ. Mesenchymal stromal cells: Past, present, and future. Vet Surg 2011; 40: 129–139.
    Direct Link:
  • 2
    Gimble JM,Katz AJ,Bunnell BA. Adipose-derived stem cells for regenerative medicine. Circ Res 2007; 100: 1249–1260.
  • 3
    Gersh BJ,Simari RD,Behfar A,Terzic CM,Terzic A. Cardiac cell repair therapy: A clinical perspective. Mayo Clin Proc 2009; 84: 876–892.
  • 4
    Gyurkocza B,Rezvani A,Storb RF. Allogeneic hematopoietic cell transplantation: The state of the art. Expert Rev Hematol 2010; 3: 285–299.
  • 5
    Tárnok A,Ulrich H,Bocsi J. Phenotypes of stem cells from diverse origin. Cytometry Part A 2010; 77A: 6–10.
    Direct Link:
  • 6
    Marino G,Rosso F,Ferdinando P,Grimaldi A,De Biasio G,Cafiero G,Barbarisi M,Barbarisi A. Growth and endothelial differentiation of adipose stem cells on polycaprolactone. J Biomed Mater Res A 2012; 100: 543–548.
  • 7
    Gardin C,Vindigni V,Bressan E,Ferroni L,Nalesso E,Puppa AD,D'Avella D,Lops D,Pinton P,Zavan B. Hyaluronan and fibrin biomaterial as scaffolds for neuronal differentiation of adult stem cells derived from adipose tissue and skin. Int J Mol Sci 2011; 12: 6749–6764.
  • 8
    Park D,Spencer JA,Koh BI,Kobayashi T,Fujisaki J,Clemens TL,Lin CP,Kronenberg HM,Scadden DT. Endogenous bone marrow MSCs are dynamic, fate-restricted participants in bone maintenance and regeneration. Cell Stem Cell 2012; 10: 259–272.
  • 9
    Dezawa M,Ishikawa H,Itokazu Y,Yoshihara T,Hoshino M,Takeda S,Ide C,Nabeshima Y. Bone marrow stromal cells generate muscle cells and repair muscle degeneration. Science 2005; 309: 314–317.
  • 10
    Betchen SA,Kaplitt M. Future and current surgical therapies in Parkinson's disease. Curr Opin Neurol 2003; 16: 487–493.
  • 11
    Abdel Abdel-Latif A,Bolli R,Tleyjeh IM,Montori VM,Perin EC,Hornung CA,Zuba-Surma EK,Al-Mallah M,Dawn B. Adult bone marrow-derived cells for cardiac repair: A systematic review and meta-analysis. Arch Intern Med 2007; 167: 989–997.
  • 12
    Vilas-Boas F,Feitosa GS,Soares MB,Mota A,Pinho-Filho JA,Almeida AJ,Andrade MV,Carvalho HG,Dourado-Oliveira A,Ribeiro-dos-Santos R. Early results of bone marrow cell transplantation to the myocardium of patients with heart failure due to Chagas disease. Arq Bras Cardiol 2006; 87: 159–166.
  • 13
    Miranville A,Heeschen C,Sengenes C,Curat CA,Busse R,Bouloumie A. Improvement of postnatal neovascularization by human adipose tissue-derived stem cells. Circulation 2004; 110: 349–355.
  • 14
    Montiel-Eulefi E,Nery AA,Rodrigues LC,Sánchez R,Romero F,Ulrich H. Neural differentiation of rat aorta pericyte cells. Cytometry Part A 2012; 81A: 65–71.
    Direct Link:
  • 15
    Cao Y,Sun Z,Liao L,Meng Y,Han Q,Zhao RC. Human adipose tissue-derived stem cells differentiate into endothelial cells in vitro and improve postnatal neovascularization in vivo. Biochem Biophys Res Commun 2005; 332: 370–379.
  • 16
    Léobon B,Roncalli J,Joffre C,Mazo M,Boisson M,Barreau C,Calise D,Arnaud E,André M,Pucéat M, et al. Adipose-derived cardiomyogenic cells: in vitro expansion and functional improvement in a mouse model of myocardial infarction. Cardiovasc Res 2009; 83: 757–767.
  • 17
    Crisan M,Yap S,Casteilla L,Chen CW,Corselli M,Park TS,Andriolo G,Sun B,Zheng B,Zhang L, et al. A perivascular origin for mesenchymal stem cells in multiple human organs. Cell Stem Cell 2008; 3: 301–313.
  • 18
    Tropel P,Plate N,Platel JC,Noel D,Albrieux M,Benabid AL,Berger F. Functional neuronal differentiation of bone-marrow derived mesenchymal stem cells. Stem Cells 2006; 24: 2868–2876.
    Direct Link:
  • 19
    Zuk PA,Zhu M,Ashjian P,De Ugarte DA,Huang JI,Mizuno H,Alfonso ZC,Fraser JK,Benhaim P,Hedrick MH. Human adipose tissue is a source of multipotent stem cells. Mol Biol Cell 2002; 13: 4279–4295.
  • 20
    Niehage C,Steenblock C,Pursche T,Bornhäuser M,Corbeil D,Hoflack B. The cell surface proteome of human mesenchymal stromal cells. PLoS One 2011; 6: e20399.
  • 21
    Jones EA,Kinsey SE,English A,Jones RA,Straszynski L,Meredith DM,Markham AF,Jack A,Emery P,McGonagle D. Isolation and characterization of bone marrow multipotential mesenchymal progenitor cells. Arthritis Rheum 2002; 46: 3349–3360.
    Direct Link:
  • 22
    Brooke G,Tong H,Levesque JP,Atkinson K. Molecular trafficking mechanisms of multipotent mesenchymal stem cells derived from human bone marrow and placenta. Stem Cells Dev 2008; 17: 929–940.
  • 23
    Mariotti E,Mirabelli P,Abate G,Schiattarella M,Martinelli P,Fortunato G,Di Noto R,Del Vecchio L. Comparative characteristics of mesenchymal stem cells from human bone marrow and placenta: CD10, CD49d, and CD56 make a difference. Stem Cells Dev 2008; 17: 1039–1041.
  • 24
    Yoshimura K,Shigeura T,Matsumoto D,Sato T,Takaki Y,Aiba-Kojima E,Sato K,Inoue K,Nagase T,Koshima I, et al. Characterization of freshly isolated and cultured cells derived from the fatty and fluid portions of liposuction aspirates. J Cell Physiol 2006; 208: 64–76.
    Direct Link:
  • 25
    Wagner W,Wein F,Seckinger A,Frankhauser M,Wirkner U,Krause U,Blake J,Schwager C,Eckstein V,Ansorge W, et al. Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp Hematol 2005; 33: 1402–1416.
  • 26
    Fickert S,Fiedler J,Brenner RE. Identification, quantification and isolation of mesenchymal progenitor cells from osteoarthritic synovium by fluorescence automated cell sorting. Osteoarthritis Cartilage 2003; 11: 790–800.
  • 27
    Kestendjieva S,Kyurkchiev D,Tsvetkova G,Mehandjiev T,Dimitrov A,Nikolov A,Kyurkchiev S. Characterization of mesenchymal stem cells isolated from the human umbilical cord. Cell Biol Int 2008; 32: 724–732.
  • 28
    Qiao C,Xu W,Zhu W,Hu J,Qian H,Yin Q,Jiang R,Yan Y,Mao F,Yang H, et al. Human mesenchymal stem cells isolated from the umbilical cord. Cell Biol Int 2008; 32: 8–15.
  • 29
    Pivoriuūnas A,Surovas A,Borutinskaite V,Matuzeviccius D,Treigyte G,Savickiene J,Tunaitis V,Aldonyte R,Jarmalavicciuūte A,Suriakaite K, et al. Proteomic analysis of stromal cells derived from the dental pulp of human exfoliated deciduous teeth. Stem Cells Dev 2010; 19: 1081–1093.
  • 30
    Zimmerlin L,Donnenberg VS,Pfeifer ME,Meyer EM,Péault B,Rubin JP,Donnenberg AD. Stromal vascular progenitors in adult human adipose tissue. Cytometry Part A 2010; 77A: 22–30.
  • 31
    Schäffler A,Büchler C. Concise review: Adipose tissue-derived stromal cells--Basic and clinical implications for novel cell-based therapies. Stem Cells 2007; 25: 818–827.
    Direct Link:
  • 32
    Mitchell JB,McIntosh K,Zvonic S,Garrett S,Floyd ZE,Kloster A,Di Halvorsen Y,Storms RW,Goh B,Kilroy G, et al. Immunophenotype of human adipose-derived cells: Temporal changes in stromal-associated and stem cell-associated markers. Stem Cells 2006; 24: 376–385.
    Direct Link:
  • 33
    Dominici M,Le Blanc K,Mueller I,Slaper-Cortenbach I,Marini F,Krause D,Deans R,Keating A,Prockop DJ,Horwitz E. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8: 315–317.
  • 34
    Lin CS,Xin ZC,Deng CH,Ning H,Lin G,Lue TF. Defining adipose tissue-derived stem cells in tissue and in culture. Histol Histopathol 2010; 25: 807–815.
  • 35
    Chapon C,Jackson JS,Aboagye EO,Herlihy AH,Jones WA,Bhakoo KK. An in vivo multimodal imaging study using MRI and PET of stem cell transplantation after myocardial infarction in rats. Mol Imaging Biol 2009; 11: 31–38.
  • 36
    Bossolasco P,Cova L,Levandis G,Diana V,Cerri S,Deliliers GL,Polli E,Silani V,Blandini F,Armentero M. Noninvasive near-infrared live imaging of human adult mesenchymal stem cells transplanted in a rodent model of Parkinson's disease. Int J Nanomed 2012; 7: 435–447.
  • 37
    Lee Z,Dennis J,Welter J,Caplan A. Imaging stem cell differentiation for cell-based tissue repair. Methods Enzymol 2012; 506: 247–263.
  • 38
    Horwitz EM,Prockop DJ,Fitzpatrick LA,Koo WW,Gordon PL,Neel M,Sussman M,Orchard P,Marx JC,Pyeritz RE, et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 1999; 5: 309–313.
  • 39
    Horwitz EM,Prockop DJ,Gordon PL,Koo WW,Fitzpatrick LA,Neel MD,McCarville ME,Orchard PJ,Pyeritz RE,Brenner MK. Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood 2001; 97: 1227–1231.
  • 40
    Horwitz EM,Gordon PL,Koo WK,Marx JC,Neel MD,McNall RY,Muul L,Hofmann T. Isolated allogeneic bone marrow-derived mesenchymal cells engraft and stimulate growth in children with osteogenesis imperfecta: Implications for cell therapy of bone. Proc Natl Acad Sci USA 2002; 99: 8932–8937.
  • 41
    Le Blanc K,Götherström C,Ringdén O,Hassan M,McMahon R,Horwitz E,Anneren G,Axelsson O,Nunn J,Ewald U, et al. Fetal mesenchymal stem-cell engraftment in bone after in utero transplantation in a patient with severe osteogenesis imperfecta. Transplantation 2005; 79: 1607–1614.
  • 42
    Whyte MP,Kurtzberg J,McAlister WH,Mumm S,Podgornik MN,Coburn SP,Ryan LM,Miller CR,Gottesman GS,Smith AK, et al. Marrow cell transplantation for infantile hypophosphatasia. J Bone Miner Res 2003; 18: 624–636.
    Direct Link:
  • 43
    Cahill RA,Wenkert D,Perlman SA,Steele A,Coburn SP,McAlister WH,Mumm S,Whyte MP. Infantile hypophosphatasia: transplantation therapy trial using bone fragments and cultured osteoblasts. J Clin Endocrinol Metab 2007; 92: 2923–2930.
  • 44
    Tadokoro M,Kanai R,Taketani T,Uchio Y,Yamaguchi S,Ohgushi H. New bone formation by allogeneic mesenchymal stem cell transplantation in a patient with perinatal hypophosphatasia. J Pediatr 2009; 154: 924–930.
  • 45
    Pak J. Regeneration of human bones in hip osteonecrosis and human cartilage in knee osteoarthritis with autologous adipose-tissue-derived stem cells: A case series. J Med Case Reports 2011; 5: 296.
  • 46
    Quarto R,Mastrogiacomo M,Cancedda R,Kutepov SM,Mukhachev V,Lavroukov A,Kon E,Marcacci M. Repair of large bone defects with the use of autologous bone marrow stromal cells. N Engl J Med 2001; 344: 385–386.
  • 47
    Marcacci M,Kon E,Moukhachev V,Lavroukov A,Kutepov S,Quarto R,Mastrogiacomo M,Cancedda R. Stem cells associated with macroporous bioceramics for long bone repair: 6- to 7-year outcome of a pilot clinical study. Tissue Eng 2007; 13: 947–955.
  • 48
    Hernigou P,Poignard A,Beaujean F,Rouard H. Percutaneous autologous bone-marrow grafting for nonunions: Influence of the number and concentration of progenitor cells. J Bone Joint Surg Am 2005; 87: 1430–1437.
  • 49
    Goldring MB,Marcu KB. Cartilage homeostasis in health and rheumatic diseases. Arthritis Res Ther 2009; 11: 224.
  • 50
    Chen J,Li Y,Wang L,Lu M,Zhang X,Chopp M. Therapeutic benefit of intracerebral transplantation of bone marrow stromal cells after cerebral ischemia in rats. J Neurol Sci 2001; 189: 49–57.
  • 51
    Clarke D,Frise'n J. Differentiation potential of adult stem cells. Curr Opin Genet Dev 2001; 11: 575–580.
  • 52
    Poulsom R,Alison MR,Forbes SJ,Wright NA. Adult stem cell plasticity. J Pathol 2002; 197: 441–456.
    Direct Link:
  • 53
    Prockop DJ. Adult stem cells gradually come of age. Nat Biotechnol 2002; 20: 791–792.
  • 54
    Scolding N. New cells from old. Lancet 2001; 357: 329–330.
  • 55
    Deng W,Obrocka M,Fischer I,Prockop DJ. In vitro differentiation of human marrow stromal cells into early progenitors of neural cells by conditions that increase intracellular cyclic AMP. Biochem Biophys Res Commun 2001; 282: 148–152.
  • 56
    Gordon D,Glover CP,Merrison AM,Uney JB,Scolding NJ. Enhanced green fluorescent proteinYexpressing human mesenchymal stem cells retain neural marker expression. J Neuroimmunol 2008; 193: 59–67.
  • 57
    Kim BJ,Seo JH,Bubien JK,Oh YS. Differentiation of adult bone marrow stem cells into neuroprogenitor cells in vitro. Neuroreport 2002; 13: 1185–1188.
  • 58
    Sanchez-Ramos J,Song S,Cardozo-Pelaez F,Hazzi C,Stedeford T,Willing A,Freeman TB,Saporta S,Janssen W,Patel N, et al. Adult bone marrow stromal cells differentiate into neural cells in vitro. Exp Neurol 2000; 164: 247–256.
  • 59
    Woodbury D,Schwarz EJ,Prockop DJ,Black IB. Adult rat and human bone marrow stromal cells differentiate into neurons. J Neurosci Res 2000; 61: 364–370.
    Direct Link:
  • 60
    Bae JS,Han HS,Youn DH,Carter JE,Modo M,Schuchman EH,Jin HK. Bone marrow-derived mesenchymal stem cells promote neuronal networks with functional synaptic transmission after transplantation into mice with neurodegeneration. Stem Cells 2007; 25: 1307–1316.
    Direct Link:
  • 61
    Zhao J,Zhang N,Prestwich GD,Wen X. Recruitment of endogenous stem cells for tissue repair. Macromol Biosci 2008; 8: 836–842.
    Direct Link:
  • 62
    Ohta M,Suzuki Y,Noda T,Ejiri Y,Dezawa M,Kataoka K,Chou H,Ishikawa N,Matsumoto N,Iwashita Y, et al. Bone marrow stromal cells infused into the cerebrospinal fluid promote functional recovery of the injured rat spinal cord with reduced cavity formation. Exp Neurol 2004; 187: 266–278.
  • 63
    Chen J,Li Y,Wang L,Zhang Z,Lu D,Lu M,Chopp M. Therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats. Stroke 2001; 32: 1005–1011.
  • 64
    Torrente Y,Polli E. Mesenchymal stem cell transplantation for neurodegenerative diseases. Cell Transplant 2008; 17: 1103–1113.
  • 65
    Akiyama Y,Radtke C,Kocsis JD. Remyelination of the rat spinal cord by transplantation of identified bone marrow stromal cells. J Neurosci 2002; 22: 6623–6630.
  • 66
    Sasaki M,Honmou O,Akiyama Y,Uede T,Hashi K,Kocsis JD. Transplantation of an acutely isolated bone marrow fraction repairs demyelinated adult rat spinal cord axons. Glia 2001; 35: 26–34.
    Direct Link:
  • 67
    Li Y,Chen J,Chen XG,Wang L,Gautam SC,Xu YX,Katakowski M,Zhang LJ,Lu M,Janakiraman N, et al. Human marrow stromal cell therapy for stroke in rat: Neurotrophins and functional recovery. Neurology 2002; 59: 514–523.
  • 68
    Chopp M,Zhang XH,Li Y,Wang L,Chen J,Lu D,Lu M,Rosenblum M. Spinal cord injury in rat: Treatment with bone marrow stromal cell transplantation. Neuroreport 2000; 11: 3001–3005.
  • 69
    Li Y,Chen J,Wang L,Zhang L,Lu M,Chopp M. Intracerebral transplantation of bone marrow stromal cells in a 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine mouse model of Parkinson's disease. Neurosci Lett 2001; 316: 67–70.
  • 70
    Schwarz EJ,Alexander GM,Prockop DJ,Azizi SA. Multipotential marrow stromal cells transduced to produce L-DOPA: Engraftment in a rat model of Parkinson disease. Hum Gene Ther 1999; 10: 2539–2549.
  • 71
    Brittan M,Hunt T,Jeffery R,Poulsom R,Forbes SJ,Hodivala-Dilke K,Goldman J,Alison MR,Wright NA. Bone marrow derivation of pericryptal myofibroblasts in the mouse and human small intestine and colon. Gut 2002; 50: 752–757.
  • 72
    Kuznetsov SA,Mankani MH,Gronthos S,Satomura K,Bianco P,Robey PG. Circulating skeletal stem cells. J Cell Biol 2001; 153: 1133–1140.
  • 73
    Simonsen JL,Rosada C,Serakinci N,Justesen J,Stenderup K,Rattan SI,Jensen TG,Kassem M. Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nat Biotechnol 2002; 20: 592–599.
  • 74
    Klinge PM,Harmening K,Miller MC,Heile A,Wallrapp C,Geigle P,Brinker T. Encapsulated native and glucagon-like peptide-1 transfected human mesenchymal stem cells in a transgenic mouse model of Alzheimer's disease. Neurosci Lett 2011; 497: 6–10.
  • 75
    Walker PA,Harting MT,Jimenez F,Shah SK,Pati S,Dash PK,Cox CSJr. Direct intrathecal implantation of mesenchymal stromal cells leads to enhanced neuroprotection via an NF-kappaB mediated increase in Interleukin 6 (IL-6) production. Stem Cells Dev 2010; 19: 867–876.
  • 76
    Benveniste EN. Cytokine actions in the central nervous system. Cytokine Growth Factor Rev 1998; 9: 259–275.
  • 77
    Uccelli A,Moretta L,Pistoia V. Mesenchymal stem cells in health and disease. Nat Rev Immunol 2008; 8: 726–736.
  • 78
    Akiyama Y,Radtke C,Honmou O,Kocsis JD. Remyelination of the spinal cord following intravenous delivery of bone marrow cells. Glia 2002; 39: 229–236.
    Direct Link:
  • 79
    Inoue M,Honmou O,Oka S,Houkin K,Hashi K,Kocsis JD. Comparative analysis of remyelinating potential of focal and intravenous administration of autologous bone marrow cells into the rat demyelinated spinal cord. Glia 2003; 44: 111–118.
    Direct Link:
  • 80
    Galindo LT,Filippo TR,Semedo P,Ariza CB,Moreira CM,Camara NO,Porcionatto MA. Mesenchymal stem cell therapy modulates the inflammatory response in experimental traumatic brain injury. Neurol Res Int 2011; 2011: 564089.
  • 81
    Bai L,Lennon DP,Eaton V,Maier K,Caplan AI,Miller SD,Miller RH. Human bone marrow-derived mesenchymal stem cells induce Th2-polarized immune response and promote endogenous repair in animal models of multiple sclerosis. Glia 2009; 57: 1192–1203.
    Direct Link:
  • 82
    Bai L,Caplan A,Lennon D,Miller RH. Human mesenchymal stem cells signals regulate neural stem cell fate. Neurochem Res 2007; 32: 353–362.
  • 83
    Rivera FJ,Couillard-Despres S,Pedre X,Ploetz S,Caioni M,Lois C,Bogdahn U,Aigner L. Mesenchymal stem cells instruct oligodendrogenic fate decision on adult neural stem cells. Stem Cells 2006; 24: 2209–2219.
    Direct Link:
  • 84
    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.
  • 85
    Devine SM,Cobbs C,Jennings M,Bartholomew A,Hoffman R. Mesenchymal stem cells distribute to a wide range of tissues following systemic infusion into non-human primates. Blood 2003; 101: 2999–3001.
  • 86
    Hemmer B,Archelos JJ,Hartung HP. New concepts in the immunopathogenesis of multiple sclerosis. Nat Rev Neurosci 2002; 3: 291–301.
  • 87
    Hemmer B,Cepok S,Nessler S,Sommer N. Pathogenesis of multiple sclerosis: An update on immunology. Curr Opin Neurol 2002; 15: 227–231.
  • 88
    Lucchinetti C,Brück W,Parisi J,Scheithauer B,Rodriguez M,Lassmann H. Heterogeneity of multiple sclerosis lesions: Implications for the pathogenesis of demyelination. Ann Neurol 2000; 47: 707–717.
    Direct Link:
  • 89
    Zappia E,Casazza S,Pedemonte E,Benvenuto F,Bonanni I,Gerdoni E,Giunti D,Ceravolo A,Cazzanti F,Frassoni F, et al. Mesenchymal stem cells ameliorate experimental autoimmune encephalomyelitis inducing T cell anergy. Blood 2005; 106: 1755–1761.
  • 90
    Gerdoni E,Gallo B,Casazza S,Musio S,Bonanni I,Pedemonte E,Mantegazza R,Frassoni F,Mancardi G,Pedotti R, et al. Mesenchymal stem cells effectively modulate pathogenic immune response in experimental autoimmune encephalomyelitis. Ann Neurol 2007; 61: 219–227.
    Direct Link:
  • 91
    Zhang J,Li Y,Chen J,Cui Y,Lu M,Elias SB,Mitchell JB,Hammill L,Vanguri P,Chopp M. Human bone marrow stromal cell treatment improves neurological functional recovery in EAE mice. Exp Neurol 2005; 195: 16–26.
  • 92
    Trujillo CA,Schwindt TT,Martins AH,Alves JM,Mello LE,Ulrich H. Novel perspectives of neural stem cell differentiation: From neurotransmitters to therapeutics. Cytometry Part A 2009; 75A: 38–53.
    Direct Link:
  • 93
    Winkler C,Kirik D,Björklund A,Dunnett SB. Transplantation in the rat model of Parkinson's disease: Ectopic versus homotopic graft placement. Prog Brain Res 2000; 127: 233–265.
  • 94
    Annett LE. Functional studies of neural grafts in Parkinsonian primates. Transl Res 1994; 71–102.
  • 95
    Thomas MG,Stone L,Evill L,Ong S,Ziman M,Hool L. Bone marrow stromal cells as replacement cells for Parkinson's disease: Generation of an anatomical but not functional neuronal phenotype. Transl Res 2011; 157: 56–63.
  • 96
    Bang OY,Lee JS,Lee PH,Lee G. Autologous mesenchymal stem cell transplantation in stroke patients. Ann Neurol 2005; 57: 874–882.
    Direct Link:
  • 97
    Suárez-Monteagudo C,Hernández-Ramírez P,Alvarez-González L,García-Maeso I,de la Cuétara-Bernal K,Castillo-Díaz L,Bringas-Vega ML,Martínez-Aching G,Morales-Chacón LM,Báez-Martín MM, et al. Autologous bone marrow stem cell neurotransplantation in stroke patients. An open study. Restor Neurol Neurosci 2009; 27: 151–161.
  • 98
    Harting MT,Jimenez F,Xue H,Fischer UM,Baumgartner J,Dash PK,Cox CS. Intravenous mesenchymal stem cell therapy for traumatic brain injury Intravenous mesenchymal stem cell therapy for traumatic brain injury. J Neurosurg 2009; 110: 1189–1197.
  • 99
    Karussis D,Karageorgiou C,Vaknin-Dembinsky A,Gowda-Kurkalli B,Gomori JM,Kassis I,Bulte JW,Petrou P,Ben-Hur T,Abramsky O, et al. Safety and immunological effects of mesenchymal stem cell transplantation in patients with multiple sclerosis and amyotrophic lateral sclerosis. Arch Neurol 2010; 67: 1187–1194.
  • 100
    Hofstetter CP,Schwarz EJ,Hess D,Widenfalk J,El Manira A,Prockop DJ,Olson L. Marrow stromal cells from guiding strands in the injured spinal cord and promote recovery. Proc Natl Acad Sci USA 2002; 99: 2199–2204.
  • 101
    Zurita M,Vaquero J. Functional recovery in chronic paraplegia after bone marrow stromal cells transplantation. Neuroreport 2004; 15: 1105–1108.
  • 102
    Eftekharpour E,Karimi-Abdolrezaee S,Fehlings MG. Current status of experimental cell replacement approaches to spinal cord injury. Neurosurg Focus 2008; 24: E19.
  • 103
    Mazzini L,Fagioli F,Boccaletti R,Mareschi K,Oliveri G,Olivieri C,Pastore I,Marasso R,Madon E. Stem cell therapy in amyotrophic lateral sclerosis: A methodological approach in humans. Amyotroph Lateral Scler Other Motor Neuron Disord 2003; 4: 158–161.
  • 104
    Sykova E,Homola A,Mazanec R,Lachmann H,Konradova SL,Kobylka P,Padr R,Neuwirth J,Komrska V,Vavra V, et al. Autologous bone marrow transplantation in patients with subacute and chronic spinal cord injury. Cell Transplant 2006; 15: 675–687.
  • 105
    Okrainec K,Banerjee DK,Eisenberg MJ. Coronary artery disease in the developing world. Am Heart J 2004; 48: 7–15.
  • 106
    Farias N,Souza JMP,Laurenti R,Alencar SM. Mortalidade Cardiovascular por Sexo e Faixa Etária em São Paulo, Brasil: 1996 a 1998 e 2003 a 2005. Arq Bras Cardiol 2009; 93: 498–505.
  • 107
    Loehr LR,Rosamond WD,Chang PP,Folsom AR,Chambless LE. Heart failure incidence and survival (from the Atherosclerosis Risk in Communities study). Am J Cardiol 2008; 101: 1016–1022.
  • 108
    Bergmann O,Bhardwaj RD,Bernard S,Zdunek S,Barnabe-Heider F,Walsh S,Zupicich J,Alkass K,Buchholz BA,Druid H, et al. Evidence for cardiomyocyte renewal in humans. Science 2009; 324: 98–102.
  • 109
    Hsieh PC,Segers VF,Davis ME,MacGillivray C,Gannon J,Molkentin JD,Robbins J,Lee RT. Evidence from a genetic fate-mapping study that stem cells refresh adult mammalian cardiomyocytes after injury. Nat Med 2007; 13: 970–974.
  • 110
    Hu X,Wang J,Chen J,Luo R,He A,Xie X,Li J. Optimal temporal delivery of bone marrow mesenchymal stem cells in rats with myocardial infarction. Eur J Cardiothorac Surg 2007; 31: 438–443.
  • 111
    Dow J,Simkhovich BZ,Kedes L,Kloner RA. Washout of transplanted cells from the heart: A potential new hurdle for cell transplantation therapy. Cardiovasc Res 2005; 67: 301–307.
  • 112
    Zhang M,Methot D,Poppa V,Fujio Y,Walsh K,Murry CE. Cardiomyocyte grafting for cardiac repair: graft cell death and anti-death strategies. J Mol Cell Cardiol 2001; 33: 907–921.
  • 113
    Zhang X,Wang H,Ma X,Adila A,Wang B,Liu F,Chen B,Wang C,Ma Y. Preservation of the cardiac function in infarcted rat hearts by the transplantation of adipose-derived stem cells with injectable fibrin scaffolds. Exp Biol Med (Maywood) 2010; 235: 1505–1515.
  • 114
    Danoviz ME,Nakamuta JS,Marques FL,dos Santos L,Alvarenga EC,dos Santos AA,Antonio EL,Schettert IT,Tucci PJ,Krieger JE. Rat adipose tissue-derived stem cells transplantation attenuates cardiac dysfunction post infarction and biopolymers enhance cell retention. PLoS One 2010; 5: e12077.
  • 115
    Shimizu T,Sekine H,Yamato M,Okano T. Cell sheet-based myocardial tissue engineering: new hope for damaged heart rescue. Curr Pharm Des 2009; 15: 2807–2814.
  • 116
    Miyahara Y,Nagaya N,Kataoka M,Yanagawa B,Tanaka K,Hao H,Ishino K,Ishida H,Shimizu T,Kangawa K, et al. Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nat Med 2006; 12: 459–465.
  • 117
    Wang CC,Chen CH,Lin WW,Hwang SM,Hsieh PC,Lai PH,Yeh YC,Chang Y,Sung HW. Direct intramyocardial injection of mesenchymal stem cell sheet fragments improves cardiac functions after infarction. Cardiovasc Res 2008; 77: 515–524.
  • 118
    van der Spoel TI,Jansen of Lorkeers SJ,Agostoni P,van Belle E,Gyongyosi M,Sluijter JP,Cramer MJ,Doevendans PA,Chamuleau SA. Human relevance of pre-clinical studies in stem cell therapy: systematic review and meta-analysis of large animal models of ischaemic heart disease. Cardiovasc Res 2011; 91: 649–658.
  • 119
    Sanz-Ruiz R,Gutierrez Ibanes E,Arranz AV,Fernandez Santos ME,Fernandez PL,Fernandez-Aviles F. Phases I-III clinical trials using adult stem cells. Stem Cells Int 2010; 2010: 579142.
  • 120
    Toma C,Pittenger MF,Cahill KS,Byrne BJ,Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 2002; 105: 93–98.
  • 121
    Davani S,Marandin A,Mersin N,Royer B,Kantelip B,Herve P,Etievent JP,Kantelip JP. Mesenchymal progenitor cells differentiate into an endothelial phenotype, enhance vascular density, and improve heart function in a rat cellular cardiomyoplasty model. Circulation 2003; 108( Suppl 1): II253–II258.
  • 122
    Nygren JM,Jovinge S,Breitbach M,Sawen P,Roll W,Hescheler J,Taneera J,Fleischmann BK,Jacobsen SE. Bone marrow-derived hematopoietic cells generate cardiomyocytes at a low frequency through cell fusion, but not transdifferentiation. Nat Med 2004; 10: 494–501.
  • 123
    Ying QL,Nichols J,Evans EP,Smith AG. Changing potency by spontaneous fusion. Nature 2002; 416: 545–548.
  • 124
    Planat-Benard V,Menard C,Andre M,Puceat M,Perez A,Garcia-Verdugo JM,Penicaud L,Casteilla L. Spontaneous cardiomyocyte differentiation from adipose tissue stroma cells. Circ Res 2004; 94: 223–229.
  • 125
    Rangappa S,Fen C,Lee EH,Bongso A,Sim EK. Transformation of adult mesenchymal stem cells isolated from the fatty tissue into cardiomyocytes. Ann Thorac Surg 2003; 75: 775–779.
  • 126
    Makino S,Fukuda K,Miyoshi S,Konishi F,Kodama H,Pan J,Sano M,Takahashi T,Hori S,Abe H, et al. Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 1999; 103: 697–705.
  • 127
    Xu W,Zhang X,Qian H,Zhu W,Sun X,Hu J,Zhou H,Chen Y. Mesenchymal stem cells from adult human bone marrow differentiate into a cardiomyocyte phenotype in vitro. Exp Biol Med (Maywood) 2004; 229: 623–631.
  • 128
    Yoon J,Min BG,Kim YH,Shim WJ,Ro YM,Lim DS. Differentiation, engraftment and functional effects of pre-treated mesenchymal stem cells in a rat myocardial infarct model. Acta Cardiol 2005; 60: 277–284.
  • 129
    Orlic D,Kajstura J,Chimenti S,Bodine DM,Leri A,Anversa P. Bone marrow stem cells regenerate infarcted myocardium. Pediatr Transplant 2003; 7( Suppl 3): 86–88.
    Direct Link:
  • 130
    Di Nicola M,Carlo-Stella C,Magni M,Milanesi M,Longoni PD,Matteucci P,Grisanti S,Gianni AM. Human bone marrow stromal cells suppress T-lymphocyte proliferation induced by cellular or nonspecific mitogenic stimuli. Blood 2002; 99: 3838–3843.
  • 131
    Ren G,Zhang L,Zhao X,Xu G,Zhang Y,Roberts AI,Zhao RC,Shi Y. Mesenchymal stem cell-mediated immunosuppression occurs via concerted action of chemokines and nitric oxide. Cell Stem Cell 2008; 2: 141–150.
  • 132
    He A,Jiang Y,Gui C,Sun Y,Li J,Wang JA. The antiapoptotic effect of mesenchymal stem cell transplantation on ischemic myocardium is enhanced by anoxic preconditioning. Can J Cardiol 2009; 25: 353–358.
  • 133
    Nakamura T,Mizuno S,Matsumoto K,Sawa Y,Matsuda H. Myocardial protection from ischemia/reperfusion injury by endogenous and exogenous HGF. J Clin Invest 2000; 106: 1511–1519.
  • 134
    Tang YL,Zhao Q,Zhang YC,Cheng L,Liu M,Shi J,Yang YZ,Pan C,Ge J,Phillips MI. Autologous mesenchymal stem cell transplantation induce VEGF and neovascularization in ischemic myocardium. Regul Pept 2004; 117: 3–10.
  • 135
    Wang M,Crisostomo PR,Herring C,Meldrum KK,Meldrum DR. Human progenitor cells from bone marrow or adipose tissue produce VEGF, HGF, and IGF-I in response to TNF by a p38 MAPK-dependent mechanism. Am J Physiol Regul Integr Comp Physiol 2006; 291: R880–R884.
  • 136
    Hung SC,Pochampally RR,Chen SC,Hsu SC,Prockop DJ. Angiogenic effects of human multipotent stromal cell conditioned medium activate the PI3K-Akt pathway in hypoxic endothelial cells to inhibit apoptosis, increase survival, and stimulate angiogenesis. Stem Cells 2007; 25: 2363–2370.
    Direct Link:
  • 137
    Rehman J,Traktuev D,Li J,Merfeld-Clauss S,Temm-Grove CJ,Bovenkerk JE,Pell CL,Johnstone BH,Considine RV,March KL. Secretion of angiogenic and antiapoptotic factors by human adipose stromal cells. Circulation 2004; 109: 1292–1298.
  • 138
    Mangi AA,Noiseux N,Kong D,He H,Rezvani M,Ingwall JS,Dzau VJ. Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infarcted hearts. Nat Med 2003; 9: 1195–1201.
  • 139
    Au P,Tam J,Fukumura D,Jain RK. Bone marrow-derived mesenchymal stem cells facilitate engineering of long-lasting functional vasculature. Blood 2008; 111: 4551–4558.
  • 140
    Zimmerlin L,Donnenberg VS,Rubin JP,Donnenberg AD. Mesenchymal markers on human adipose stem/progenitor cells. Cytometry Part A 2013; 83A: 134–140.
    Direct Link:
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