Abstract
Mesenchymal stem cells (MSC) are a group of clonogenic cells present among the bone marrow stroma and capable of multilineage differentiation into mesoderm-type cells such as osteoblasts, adipocytes and chondrocytes. Due to their ease of isolation and their differentiation potential, MSC are being introduced into clinical medicine in variety of applications and through different ways of administration. Here, we discuss approaches for isolation, characterization and directing differentiation of human mesenchymal stem cells (hMSC). An update of the current clinical use of the cells is also provided.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$259.00 per year
only $21.58 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Dominici M, Le BK, Mueller I, Slaper-Cortenbach I, Marini F, Krause D et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8: 315–317.
Bianco P, Riminucci M, Gronthos S, Robey PG . Bone marrow stromal stem cells: nature, biology, and potential applications. Stem Cells 2001; 19: 180–192.
Dezawa M, Kanno H, Hoshino M, Cho H, Matsumoto N, Itokazu Y et al. Specific induction of neuronal cells from bone marrow stromal cells and application for autologous transplantation. J Clin Invest 2004; 113: 1701–1710.
Luk JM, Wang PP, Lee CK, Wang JH, Fan ST . Hepatic potential of bone marrow stromal cells: development of in vitro co-culture and intra-portal transplantation models. J Immunol Methods 2005; 305: 39–47.
Dexter TM . Haemopoiesis in long-term bone marrow cultures. A review. Acta Haematol 1979; 62: 299–305.
Friedenstein AJ . Osteogenic stem cells in the bone marrow. Bone Miner 1991; 7: 243–272.
Owen M . Marrow stromal stem cells. J Cell Sci Suppl 1988; 10: 63–76.
Friedenstein AJ, Chailakhjan RK, Lalykina KS . The development of fibroblast colonies in monolayer cultures of guinea-pig bone marrow and spleen cells. Cell Tissue Kinet 1970; 3: 393–403.
Luria EA, Panasyuk AF, Friedenstein AY . Fibroblast colony formation from monolayer cultures of blood cells. Transfusion 1971; 11: 345–349.
Abdallah BM, Haack-Sorensen M, Burns JS, Elsnab B, Jakob F, Hokland P et al. Maintenance of differentiation potential of human bone marrow mesenchymal stem cells immortalized by human telomerase reverse transcriptase gene despite [corrected] extensive proliferation. Biochem Biophys Res Commun 2005; 326: 527–538.
Foster LJ, Zeemann PA, Li C, Mann M, Jensen ON, Kassem M . Differential expression profiling of membrane proteins by quantitative proteomics in a human mesenchymal stem cell line undergoing osteoblast differentiation. Stem Cells 2005; 23: 1367–1377.
Kassem M, Mosekilde L, Eriksen EF . 1,25-dihydroxyvitamin D3 potentiates fluoride-stimulated collagen type I production in cultures of human bone marrow stromal osteoblast-like cells. J Bone Miner Res 1993; 8: 1453–1458.
Rickard DJ, Kassem M, Hefferan TE, Sarkar G, Spelsberg TC, Riggs BL . Isolation and characterization of osteoblast precursor cells from human bone marrow. J Bone Miner Res 1996; 11: 312–324.
Kuznetsov SA, Krebsbach PH, Satomura K, Kerr J, Riminucci M, Benayahu D et al. Single-colony derived strains of human marrow stromal fibroblasts form bone after transplantation in vivo. J Bone Miner Res 1997; 12: 1335–1347.
Gronthos S, Graves SE, Ohta S, Simmons PJ . The STRO-1+ fraction of adult human bone marrow contains the osteogenic precursors. Blood 1994; 84: 4164–4173.
Gronthos S, Zannettino AC, Hay SJ, Shi S, Graves SE, Kortesidis A et al. Molecular and cellular characterisation of highly purified stromal stem cells derived from human bone marrow. J Cell Sci 2003; 116: 1827–1835.
Quirici N, Soligo D, Bossolasco P, Servida F, Lumini C, Deliliers GL . Isolation of bone marrow mesenchymal stem cells by anti-nerve growth factor receptor antibodies. Exp Hematol 2002; 30: 783–791.
Miura Y, Miura M, Gronthos S, Allen MR, Cao C, Uveges TE et al. Defective osteogenesis of the stromal stem cells predisposes CD18-null mice to osteoporosis. Proc Natl Acad Sci USA 2005; 102: 14022–14027.
Gang EJ, Bosnakovski D, Figueiredo CA, Visser JW, Perlingeiro RC . SSEA-4 identifies mesenchymal stem cells from bone marrow. Blood 2007; 109: 1743–1751.
Johnstone B, Hering TM, Caplan AI, Goldberg VM, Yoo JU . In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells. Exp Cell Res 1998; 238: 265–272.
Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD et al. Multilineage potential of adult human mesenchymal stem cells. Science 1999; 284: 143–147.
Piersanti S, Sacchetti B, Funari A, Di Cesare S, Bonci D, Cherubini G et al. Lentiviral transduction of human postnatal skeletal (stromal, mesenchymal) stem cells: in vivo transplantation and gene silencing. Calcif Tissue Int 2006; 78: 372–384.
Reyes M, Lund T, Lenvik T, Aguiar D, Koodie L, Verfaillie CM . Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood 2001; 98: 2615–2625.
Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR et al. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418: 41–49.
Olmsted-Davis EA, Gugala Z, Camargo F, Gannon FH, Jackson K, Kienstra KA et al. Primitive adult hematopoiletic stem cells can function as osteoblast precursors. Proc Natl Acad Sci USA 2003; 100: 15877–15882.
D'ippolito G, Diabira S, Howard GA, Menei P, Roos BA, Schiller PC . Marrow-isolated adult multilineage inducible (MIAMI) cells, a unique population of postnatal young and old human cells with extensive expansion and differentiation potential. J Cell Sci 2004; 117: 2971–2981.
Lodie TA, Blickarz CE, Devarakonda TJ, He CF, Dash AB, Clarke J et al. Systematic analysis of reportedly distinct populations of multipotent bone marrow-derived stem cells reveals a lack of distinction. Tissue Eng 2002; 8: 739–751.
Kuznetsov SA, Mankani MH, Gronthos S, Satomura K, Bianco P, Robey PG . Circulating skeletal stem cells. J Cell Biol 2001; 153: 1133–1140.
Rosada C, Justesen J, Melsvik D, Ebbesen P, Kassem M . The human umbilical cord blood: a potential source for osteoblast progenitor cells. Calcif Tissue Int 2003; 72: 135–142.
De Bari C, Dell'Accio F, Tylzanowski P, Luyten FP . Multipotent mesenchymal stem cells from adult human synovial membrane. Arthritis Rheum 2001; 44: 1928–1942.
Miura M, Gronthos S, Zhao M, Lu B, Fisher LW, Robey PG et al. Stem cells from human exfoliated deciduous teeth. Proc Natl Acad Sci USA 2003; 100: 5807–5812.
De Coppi P, Bartsch Jr G, Siddiqui MM, Xu T, Santos CC, Perin L et al. Isolation of amniotic stem cell lines with potential for therapy. Nat Biotechnol 2007; 25: 100–106.
Wagner W, Wein F, Seckinger A, Frankhauser M, Wirkner U, Krause U et al. Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Exp Hematol 2005; 33: 1402–1416.
Kassem M, Ankersen L, Eriksen EF, Clark BF, Rattan SI . Demonstration of cellular aging and senescence in serially passaged long-term cultures of human trabecular osteoblasts. Osteoporosis Int 1997; 7: 514–524.
DiGirolamo CM, Stokes D, Colter D, Phinney DG, Class R, Prockop DJ . Propagation and senescence of human marrow stromal cells in culture: a simple colony-forming assay identifies samples with the greatest potential to propagate and differentiate. Br J Haematol 1999; 107: 275–281.
Stenderup K, Justesen J, Clausen C, Kassem M . Aging is associated with decreased maximal life span and accelerated senescence of bone marrow stromal cells. Bone 2003; 33: 919–926.
Rattan SIS . Aging outside the body: usefulneess of the Hayflick system. In: Kaul SC, Wadhwa R (eds). Aging of Cells in and Outside the Body. Kuwer Academic Publishers: London, 2003. pp 1–8.
Stenderup K, Justesen J, Eriksen EF, Rattan SI, Kassem M . Number and proliferative capacity of osteogenic stem cells are maintained during aging and in patients with osteoporosis. J Bone Miner Res 2001; 16: 1120–1129.
Sharpless NE, DePinho RA . How stem cells age and why this makes us grow old. Nat Rev Mol Cell Biol 2007; 8: 703–713.
Wright WE, Shay JW . Historical claims and current interpretations of replicative aging. Nat Biotechnol 2002; 20: 682–688.
Harley CB . Telomere loss: mitotic clock or genetic time bomb? Mutat Res 1991; 256: 271–282.
Simonsen JL, Rosada C, Serakinci N, Justesen J, Stenderup K, Rattan SI et al. Telomerase expression extends the proliferative life-span and maintains the osteogenic potential of human bone marrow stromal cells. Nat Biotechnol 2002; 20: 592–596.
Zimmermann S, Voss M, Kaiser S, Kapp U, Waller CF, Martens UM . Lack of telomerase activity in human mesenchymal stem cells. Leukemia 2003; 17: 1146–1149.
Chang MW, Grillari J, Mayrhofer C, Fortschegger K, Allmaier G, Marzban G et al. Comparison of early passage, senescent and hTERT immortalized endothelial cells. Exp Cell Res 2005; 309: 121–136.
Mckee JA, Banik SSR, Boyer MJ, Hamad NM, Lawson JH, Niklason LE et al. Human arteries engineered in vitro. EMBO Rep 2003; 4: 633–638.
Burns JS, Abdallah BM, Guldberg P, Rygaard J, Schroder HD, Kassem M . Tumorigenic heterogeneity in cancer stem cells evolved from long-term cultures of telomerase-immortalized human mesenchymal stem cells. Cancer Res 2005; 65: 3126–3135.
Serakinci N, Guldberg P, Burns J, Abdallah B, Schroedder H, Jensen T et al. Adult human mesenchymal stem cell as a target for neoplastic transformation. Oncogene 2004; 23: 5095–5098.
Serakinci N, Hoare SF, Kassem M, Atkinson SP, Keith WN . Telomerase promoter reprogramming and interaction with general transcription factors in the human mesenchymal stem cell. Regen Med 2006; 1: 125–131.
Bianchi G, Banfi A, Mastrogiacomo M, Notaro R, Luzzatto L, Cancedda R et al. Ex vivo enrichment of mesenchymal cell progenitors by fibroblast growth factor. Exp Cell Res 2003; 287: 98–105.
Ito T, Sawada R, Fujiwara Y, Seyama Y, Tsuchiya T . FGF-2 suppresses cellular senescence of human mesenchymal stem cells by down-regulation of TGF-beta2. Biochem Biophys Res Commun 2007; 359: 108–114.
Ren H, Cao Y, Zhao Q, Li J, Zhou C, Liao L et al. Proliferation and differentiation of bone marrow stromal cells under hypoxic conditions. Biochem Biophys Res Commun 2006; 347: 12–21.
Grayson WL, Zhao F, Izadpanah R, Bunnell B, Ma T . Effects of hypoxia on human mesenchymal stem cell expansion and plasticity in 3D constructs. J Cell Physiol 2006; 207: 331–339.
Komori T, Yagi H, Nomura S, Yamaguchi A, Sasaki K, Deguchi K et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell 1997; 89: 755–764.
Nakashima K, Zhou X, Kunkel G, Zhang Z, Deng JM, Behringer RR et al. The novel zinc finger-containing transcription factor osterix is required for osteoblast differentiation and bone formation. Cell 2002; 108: 17–29.
Qiu W, Andersen TE, Bollerslev J, Mandrup S, Abdallah BM, Kassem M . Patients with high bone mass phenotype exhibit enhanced osteoblast differentiation and inhibition of adipogenesis of human mesenchymal stem cells. J Bone Miner Res 2007; 22: 1720–1731.
Lecka-Czernik B, Moerman EJ, Grant DF, Lehmann JM, Manolagas SC, Jilka RL . Divergent effects of selective peroxisome proliferator-activated receptor-gamma 2 ligands on adipocyte versus osteoblast differentiation. Endocrinology 2002; 143: 2376–2384.
Ng LJ, Wheatley S, Muscat GE, Conway-Campbell J, Bowles J, Wright E et al. SOX9 binds DNA, activates transcription, and coexpresses with type II collagen during chondrogenesis in the mouse. Dev Biol 1997; 183: 108–121.
Luu HH, Song WX, Luo X, Manning D, Luo J, Deng ZL et al. Distinct roles of bone morphogenetic proteins in osteogenic differentiation of mesenchymal stem cells. J Orthop Res 2007; 25: 665–677.
Gaur T, Lengner CJ, Hovhannisyan H, Bhat RA, Bodine PV, Komm BS et al. Canonical WNT signaling promotes osteogenesis by directly stimulating Runx2 gene expression. J Biol Chem 2005; 280: 33132–33140.
Abdallah BM, Jensen CH, Gutierrez G, Leslie RG, Jensen TG, Kassem M . Regulation of human skeletal stem cells differentiation by Dlk1/Pref-1. J Bone Miner Res 2004; 19: 841–852.
Rifas L . The role of noggin in human mesenchymal stem cell differentiation. J Cell Biochem 2007; 100: 824–834.
Kratchmarova I, Blagoev B, Haack-Sorensen M, Kassem M, Mann M . Mechanism of divergent growth factor effects in mesenchymal stem cell differentiation. Science 2005; 308: 1472–1477.
Gao J, Dennis JE, Muzic RF, Lundberg M, Caplan AI . The dynamic in vivo distribution of bone marrow-derived mesenchymal stem cells after infusion. Cells Tissues Organs 2001; 169: 12–20.
Bentzon JF, Stenderup K, Hansen FD, Schroder HD, Abdallah BM, Jensen TG et al. Tissue distribution and engraftment of human mesenchymal stem cells immortalized by human telomerase reverse transcriptase gene. Biochem Biophys Res Commun 2005; 330: 633–640.
Francois S, Bensidhoum M, Mouiseddine M, Mazurier C, Allenet B, Semont A et al. Local irradiation not only induces homing of human mesenchymal stem cells at exposed sites but promotes their widespread engraftment to multiple organs: a study of their quantitative distribution after irradiation damage. Stem Cells 2006; 24: 1020–1029.
Bruder SP, Fink DJ, Caplan AI . Mesenchymal stem cells in bone development, bone repair, and skeletal regeneration therapy. J Cell Biochem 1994; 56: 283–294.
Ohgushi H, Goldberg VM, Caplan AI . Repair of bone defects with marrow cells and porous ceramic. Experiments in rats. Acta Orthop Scand 1989; 60: 334–339.
Quarto R, Mastrogiacomo M, Cancedda R, Kutepov SM, Mukhachev V, Lavroukov A et al. Repair of large bone defects with the use of autologous bone marrow stromal cells. N Engl J Med 2001; 344: 385–386.
Diduch DR, Jordan LC, Mierisch CM, Balian G . Marrow stromal cells embedded in alginate for repair of osteochondral defects. Arthroscopy 2000; 16: 571–577.
Tateishi-Yuyama E, Matsubara H, Murohara T, Ikeda U, Shintani S, Masaki H 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: 427–435.
Assmus B, Schachinger V, Teupe C, Britten M, Lehmann R, Dobert N et al. Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction—(TOPCARE-AMI). Circulation 2002; 106: 3009–3017.
Lee MS, Makker RR . Stem-cell transplantation in myocardial infarction: a status report. Ann Intern Med 2004; 140: 729–737.
Badiavas EV, Falanga V . Treatment of chronic wounds with bone marrow-derived cells. Arch Dermatol 2003; 139: 510–516.
Horwitz EM, Prockop DJ, Fitzpatrick LA, Koo WW, Gordon PL, Neel M et al. Transplantability and therapeutic effects of bone marrow-derived mesenchymal cells in children with osteogenesis imperfecta. Nat Med 1999; 5: 309–313.
Horwitz EM, Prockop DJ, Gordon PL, Koo WW, Fitzpatrick LA, Neel MD et al. Clinical responses to bone marrow transplantation in children with severe osteogenesis imperfecta. Blood 2001; 97: 1227–1231.
Horwitz EM, Gordon PL, Koo WKK, Marx JC, Neel MD, Mcnall RY et al. 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.
Le Blanc K, Gotherstrom C, Ringden O, Hassan M, McMahon R, Horwitz E 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.
Koc ON, Day J, Nieder M, Gerson SL, Lazarus HM, Krivit W . Allogeneic mesenchymal stem cell infusion for treatment of metachromatic leukodystrophy (MLD) and Hurler syndrome (MPS-IH). Bone Marrow Transplant 2002; 30: 215–222.
Fouillard L, Bensidhoum M, Bories D, Bonte H, Lopez M, Moseley AM et al. Engraftment of allogeneic mesenchymal stem cells in the bone marrow of a patient with severe idiopathic aplastic anemia improves stroma. Leukemia 2003; 17: 474–476.
Koc ON, Gerson SL, Cooper BW, Dyhouse SM, Haynesworth SE, Caplan AI et al. Rapid hematopoietic recovery after coinfusion of autologous-blood stem cells and culture-expanded marrow mesenchymal stem cells in advanced breast cancer patients receiving high-dose chemotherapy. J Clin Oncol 2000; 18: 307–316.
Dean RM, Bishop MR . Graft-versus-host disease: emerging concepts in prevention and therapy. Curr Hematol Rep 2003; 2: 287–294.
Ringden O, Uzunel M, Rasmusson I, Remberger M, Sundberg B, Lonnies H et al. Mesenchymal stem cells for treatment of therapy-resistant graft-versus-host disease. Transplantation 2006; 81: 1390–1397.
Le Blanc K, Gotherstrom C, Tammik C, Ringden O . HLA expression and immunologic properties of differentiated and undifferentiated adult and fetal mesenchymal stem cells. Bone Marrow Transplant 2003; 31: S244–S245.
Gelse K, von der MK, Aigner T, Park J, Schneider H . Articular cartilage repair by gene therapy using growth factor-producing mesenchymal cells. Arthritis Rheum 2003; 48: 430–441.
Park J, Ries J, Gelse K, Kloss F, von der MK, Wiltfang J et al. Bone regeneration in critical size defects by cell-mediated BMP-2 gene transfer: a comparison of adenoviral vectors and liposomes. Gene Therapy 2003; 10: 1089–1098.
Van Damme A, Chuah MK, Dell'Accio F, De Bari C, Luyten F, Collen D et al. Bone marrow mesenchymal cells for haemophilia A gene therapy using retroviral vectors with modified long-terminal repeats. Haemophilia 2003; 9: 94–103.
Allay JA, Dennis JE, Haynesworth SE, Majumdar MK, Clapp DW, Shultz LD et al. LacZ and interleukin-3 expression in vivo after retroviral transduction of marrow-derived human osteogenic mesenchymal progenitors. Hum Gene Ther 1997; 8: 1417–1427.
Stock UA, Vacanti JP . Tissue engineering: current state and prospects. Annu Rev Med 2001; 52: 443–451.
Bianco P, Robey PG . Stem cells in tissue engineering. Nature 2001; 414: 118–121.
Kon E, Muraglia A, Corsi A, Bianco P, Marcacci M, Martin I et al. Autologous bone marrow stromal cells loaded onto porous hydroxyapatite ceramic accelerate bone repair in critical-size defects of sheep long bones. J Biomed Mater Res 2000; 49: 328–337.
Robey PG, Bianco P . The use of adult stem cells in rebuilding the human face. J Am Dent Assoc 2006; 137: 961–972.
Acknowledgements
The study was supported by grants from the Danish Medical Research Council, the Novo Nordisk Foundation, the Vellux Foundation and Danish Center for Stem Cell Research.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Abdallah, B., Kassem, M. Human mesenchymal stem cells: from basic biology to clinical applications. Gene Ther 15, 109–116 (2008). https://doi.org/10.1038/sj.gt.3303067
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/sj.gt.3303067
Keywords
This article is cited by
-
Bone mineral density is associated with composite dietary antioxidant index among US adults: results from NHANES
Osteoporosis International (2023)
-
A TrkB agonist prodrug prevents bone loss via inhibiting asparagine endopeptidase and increasing osteoprotegerin
Nature Communications (2022)
-
Frequency-specific sensitivity of 3T3-L1 preadipocytes to low-intensity vibratory stimulus during adipogenesis
In Vitro Cellular & Developmental Biology - Animal (2022)
-
Mesenchymal Stem Cell–Based Therapy as a New Approach for the Treatment of Systemic Sclerosis
Clinical Reviews in Allergy & Immunology (2022)
-
The influence of association between aging and reduced protein intake on some immunomodulatory aspects of bone marrow mesenchymal stem cells: an experimental study
European Journal of Nutrition (2022)