Stem Cell Reviews

, Volume 3, Issue 4, pp 239–248 | Cite as

Mesenchymal Stem Cell Preparations—Comparing Apples and Oranges

  • Wolfgang Wagner
  • Anthony D. HoEmail author


Mesenchymal stem cells (MSC) represent a type of adult stem cells that can easily be isolated from various tissues and expanded in vitro. Past reports on their pluripotency and possible clinical applications have raised hopes and interest in MSC. Multiple designations have been given to different MSC preparations. So far MSC are poorly defined by a combination of physical, phenotypical and functional properties. As MSC could be derived from different tissues as starting material, by diverse isolation protocols, cultured and expanded in different media and conditions, the MSC preparations from different laboratories are highly heterogeneous. All of these variables might have implications (1) on the selection of cell types and the composition of heterogeneous subpopulations; (2) they can selectively favor expansion of different cell populations with totally different potentials; or (3) they might alter the long term fate of adult stem cells upon in vitro culture. The recent controversy on the multilineage differentiation potentials of some specific MSC preparations might be attributed to this lack of common standards. More precise molecular and cellular markers to define subsets of MSC and to standardize the protocols for expansion of MSC are urgently needed.


Mesenchymal stem cell Culture conditions Microenvironment Differentiation Hematopoietic stem cells Cell–cell interaction 



The authors thank Patrick Horn and Anke Diehlmann for their support in MSC culture and photo documentation. This work was supported by the German Ministry of Education and Research (BMBF) within the National Genome Research Network NGFN-2 (EP-S19T01) and within the supporting program “cell based regenerative medicine” (START-MSC), the German Research Foundation DFG (HO 914/7-1), the Joachim Siebeneicher-Stiftung and the Academy of Sciences and Humanities, Heidelberg (WIN-Kolleg).


  1. 1.
    Dominici, M., Le Blanc, K., Mueller, I., et al. (2006). Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy, 8, 315–317.PubMedCrossRefGoogle Scholar
  2. 2.
    Wagner, W., Wein, F., Seckinger, A., et al. (2005). Comparative characteristics of mesenchymal stem cells from human bone marrow, adipose tissue, and umbilical cord blood. Experimental Hematology, 33, 1402–1416.PubMedCrossRefGoogle Scholar
  3. 3.
    Caplan, A. I. (1991). Mesenchymal stem cells. Journal of Orthopaedic Research, 9, 641–650.PubMedCrossRefGoogle Scholar
  4. 4.
    Friedenstein, A. J., Petrakova, K. V., Kurolesova, A. I., & Frolova, G. P. (1968). Heterotopic of bone marrow. Analysis of precursor cells for osteogenic and hematopoietic tissues. Transplantation, 6, 230–247.PubMedCrossRefGoogle Scholar
  5. 5.
    Friedenstein, A. J., Chailakhyan, R. K., Latsinik, N. V., Panasyuk, A. F., & Keiliss-Borok, I. V. (1974). Stromal cells responsible for transferring the microenvironment of the hemopoietic tissues. Cloning in vitro and retransplantation in vivo. Transplantation, 17, 331–340.PubMedCrossRefGoogle Scholar
  6. 6.
    Nakahara, H., Bruder, S. P., Haynesworth, S. E., et al. (1990). Bone and cartilage formation in diffusion chambers by subcultured cells derived from the periosteum. Bone, 11, 181–188.PubMedCrossRefGoogle Scholar
  7. 7.
    Horwitz, E. M., & Keating A. (2000). Nonhematopoietic mesenchymal stem cells: What are they? Cytotherapy, 2, 387–388.PubMedCrossRefGoogle Scholar
  8. 8.
    Horwitz, E. M., Le, B. K., Dominici, M., et al. (2005). Clarification of the nomenclature for MSC: The International Society for Cellular Therapy position statement. Cytotherapy, 7, 393–395.PubMedCrossRefGoogle Scholar
  9. 9.
    Erices, A., Conget, P., & Minguell, J. J. (2000). Mesenchymal progenitor cells in human umbilical cord blood. British Journal of Haematology, 109, 235–242.PubMedCrossRefGoogle Scholar
  10. 10.
    Johnstone, B., Hering, T. M., Caplan, A. I., Goldberg, V. M., & Yoo, J. U. (1998). In vitro chondrogenesis of bone marrow-derived mesenchymal progenitor cells. Experimental Cell Research, 238, 265–272.PubMedCrossRefGoogle Scholar
  11. 11.
    Jiang, Y., Jahagirdar, B. N., Reinhardt, R. L., et al. (2002). Pluripotency of mesenchymal stem cells derived from adult marrow. Nature, 418, 41–49.PubMedCrossRefGoogle Scholar
  12. 12.
    Kogler, G., Sensken, S., Airey, J. A., et al. (2004). A new human somatic stem cell from placental cord blood with intrinsic pluripotent differentiation potential. Journal of Experimental Medicine, 200, 123–135.PubMedCrossRefGoogle Scholar
  13. 13.
    Reyes, M., Lund, T., Lenvik, T., Aguiar, D., Koodie, L., & Verfaillie, C. M. (2001). Purification and ex vivo expansion of postnatal human marrow mesodermal progenitor cells. Blood, 98, 2615–2625.PubMedCrossRefGoogle Scholar
  14. 14.
    Petersen, B. E., Bowen, W. C., Patrene, K. D., et al. (1999). Bone marrow as a potential source of hepatic oval cells. Science, 284, 1168–1170.PubMedCrossRefGoogle Scholar
  15. 15.
    Schwartz, R. E., Reyes, M., Koodie, L., et al. (2002). Multipotent adult progenitor cells from bone marrow differentiate into functional hepatocyte-like cells. Journal of Clinical Investigation, 109, 1291–1302.PubMedCrossRefGoogle Scholar
  16. 16.
    Bjornson, C. R., Rietze, R. L., Reynolds, B. A., Magli, M. C., & Vescovi, A. L. (1999). Turning brain into blood: a hematopoietic fate adopted by adult neural stem cells in vivo. Science, 283, 534–537.PubMedCrossRefGoogle Scholar
  17. 17.
    Mezey, E., Chandross, K. J., Harta, G., Maki, R. A., & McKercher, S. R. (2000). Turning blood into brain: cells bearing neuronal antigens generated in vivo from bone marrow. Science, 290, 1779–1782.PubMedCrossRefGoogle Scholar
  18. 18.
    Ying, Q. L., Nichols, J., Evans, E. P., & Smith, A. G. (2002). Changing potency by spontaneous fusion. Nature, 416, 545–548.PubMedCrossRefGoogle Scholar
  19. 19.
    Terada, N., Hamazaki, T., Oka, M., et al. (2002). Bone marrow cells adopt the phenotype of other cells by spontaneous cell fusion. Nature, 416, 542–545.PubMedCrossRefGoogle Scholar
  20. 20.
    Jiang, Y., Vaessen, B., Lenvik, T., Blackstad, M., Reyes, M., & Verfaillie, C. M. (2002). Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. Experimental Hematology, 30, 896–904.PubMedCrossRefGoogle Scholar
  21. 21.
    Zeng, L., Rahrmann, E., Hu, Q., et al. (2006). Multipotent adult progenitor cells from swine bone marrow. Stem Cells, 24, 2355–2366.PubMedCrossRefGoogle Scholar
  22. 22.
    Jiang, Y., Henderson, D., Blackstad, M., Chen, A., Miller, R. F., & Verfaillie, C. M. (2003). Neuroectodermal differentiation from mouse multipotent adult progenitor cells. Proceedings of the National Academy of Sciences of the United States of America, 100(Suppl 1), 11854–11860.PubMedCrossRefGoogle Scholar
  23. 23.
    Serafini, M., Dylla, S. J., Oki, M., et al. (2007). Hematopoietic reconstitution by multipotent adult progenitor cells: precursors to long-term hematopoietic stem cells. Journal of Experimental Medicine, 204, 129–139.PubMedCrossRefGoogle Scholar
  24. 24.
    Hochedlinger, K., & Jaenisch, R. (2006). Nuclear reprogramming and pluripotency. Nature, 441, 1061–1067.PubMedCrossRefGoogle Scholar
  25. 25.
    Morshead, C. M., Benveniste, P., Iscove, N. N., & van der, Kooy, D. (2002). Hematopoietic competence is a rare property of neural stem cells that may depend on genetic and epigenetic alterations. Nature Medicine, 8, 268–273.PubMedCrossRefGoogle Scholar
  26. 26.
    Raedt, R., Pinxteren, J., Van Dycke, A., et al. (2007). Differentiation assays of bone marrow-derived Multipotent Adult Progenitor Cell (MAPC)-like cells towards neural cells cannot depend on morphology and a limited set of neural markers. Experimental Neurology, 203, 542–554.PubMedCrossRefGoogle Scholar
  27. 27.
    Wagner, W., Roderburg, C., Wein, F., et al. (2007). Molecular and secretory profiles of human mesenchymal stromal cells and their abilities to maintain primitive hematopoietic progenitors. Stem Cells 2007.Google Scholar
  28. 28.
    Simmons, P. J., & Torok-Storb, B. (1991). Identification of stromal cell precursors in human bone marrow by a novel monoclonal antibody, STRO-1. Blood, 78, 55–62.PubMedGoogle Scholar
  29. 29.
    Quirici, N., Soligo, D., Bossolasco, P., Servida, F., Lumini, C., & Deliliers, G. L. (2002). Isolation of bone marrow mesenchymal stem cells by anti-nerve growth factor receptor antibodies. Experimental Hematology, 30, 783–791.PubMedCrossRefGoogle Scholar
  30. 30.
    Sabatini, F., Petecchia, L., Tavian, M., Jodon, d. V. V, Rossi, G. A., & Brouty-Boye, D. (2005). Human bronchial fibroblasts exhibit a mesenchymal stem cell phenotype and multilineage differentiating potentialities. Laboratory Investigation, 85, 962–971.PubMedCrossRefGoogle Scholar
  31. 31.
    Buhring, H. J., Battula, V. L., Treml, S., Schewe, B., Kanz, L., & Vogel, W. (2007). Novel markers for the prospective isolation of human MSC. Annals of the New York Academy of Sciences, 2007.Google Scholar
  32. 32.
    Pittenger, M. F., Mackay, A. M., Beck, S. C., et al. (1999). Multilineage potential of adult human mesenchymal stem cells. Science, 284, 143–147.PubMedCrossRefGoogle Scholar
  33. 33.
    Wagner, W., Feldmann, R. E., Jr., Seckinger, A., et al. (2006). The heterogeneity of human mesenchymal stem cell preparations—Evidence from simultaneous analysis of proteomes and transcriptomes. Experimental Hematology, 34, 536–548.PubMedCrossRefGoogle Scholar
  34. 34.
    Colter, D. C., Sekiya, I., & Prockop, D. J. (2001). Identification of a subpopulation of rapidly self-renewing and multipotential adult stem cells in colonies of human marrow stromal cells. Proceedings of the National Academy of Sciences of the United States of America, 98, 7841–7845.PubMedCrossRefGoogle Scholar
  35. 35.
    Javazon, E. H., Colter, D. C., Schwarz, E. J., & Prockop, D. J. (2001). Rat marrow stromal cells are more sensitive to plating density and expand more rapidly from single-cell-derived colonies than human marrow stromal cells. Stem Cells, 19, 219–225.PubMedCrossRefGoogle Scholar
  36. 36.
    Friedenstein, A. J., Piatetzky-Shapiro, I. I., & Petrakova, K. V. (1966). Osteogenesis in transplants of bone marrow cells. Journal of Embryology and Experimental Morphology, 16, 381–390.PubMedGoogle Scholar
  37. 37.
    Zuk, P. A., Zhu, M., Mizuno, H., et al. (2001). Multilineage cells from human adipose tissue: Implications for cell-based therapies. Tissue Engineering, 7, 211–228.PubMedCrossRefGoogle Scholar
  38. 38.
    Bieback, K., Kern, S., Kluter, H., & Eichler, H. (2004). Critical parameters for the isolation of mesenchymal stem cells from umbilical cord blood. Stem Cells, 22, 625–634.PubMedCrossRefGoogle Scholar
  39. 39.
    Kuznetsov, S. A., Mankani, M. H., Gronthos, S., Satomura, K., Bianco, P., & Robey, P. G. (2001). Circulating skeletal stem cells. Journal of Cell Biology, 153, 1133–1140.PubMedCrossRefGoogle Scholar
  40. 40.
    da Silva, M. L., Chagastelles, P. C., & Nardi, N. B. (2006). Mesenchymal stem cells reside in virtually all post-natal organs and tissues. Journal of Cell Science, 119, 2204–2213.CrossRefGoogle Scholar
  41. 41.
    Kern, S., Eichler, H., Stoeve, J., Kluter, H., & Bieback, K. (2006). Comparative analysis of mesenchymal stem cells from bone marrow, umbilical cord blood, or adipose tissue. Stem Cells, 24, 1294–1301.PubMedCrossRefGoogle Scholar
  42. 42.
    Anderson, D. G., Levenberg, S., & Langer, R. (2004). Nanoliter-scale synthesis of arrayed biomaterials and application to human embryonic stem cells. Nature Biotechnology, 22, 863–866.PubMedCrossRefGoogle Scholar
  43. 43.
    Engler, A. J., Sen, S., Sweeney, H. L., & Discher D. E. (2006). Matrix elasticity directs stem cell lineage specification. Cell, 126, 677–689.PubMedCrossRefGoogle Scholar
  44. 44.
    Ren, H., Cao, Y., Zhao, Q., et al. (2006). Proliferation and differentiation of bone marrow stromal cells under hypoxic conditions. Biochemical and Biophysical Research Communications, 347, 12–21.PubMedCrossRefGoogle Scholar
  45. 45.
    Lange, C., Cakiroglu, F., Spiess, A. N., Cappallo-Obermann, H., Dierlamm, J., & Zander, A. R. (2007). Accelerated and safe expansion of human mesenchymal stromal cells in animal serum-free medium for transplantation and regenerative medicine. Journal of Cellular Physiology, 213, 18–26.PubMedCrossRefGoogle Scholar
  46. 46.
    Muller, I., Kordowich, S., Holzwarth, C., et al. (2006). Animal serum-free culture conditions for isolation and expansion of multipotent mesenchymal stromal cells from human BM. Cytotherapy, 8, 437–444.PubMedCrossRefGoogle Scholar
  47. 47.
    Stute, N., Holtz, K., Bubenheim, M., Lange, C., Blake, F., & Zander, A. R. (2004). Autologous serum for isolation and expansion of human mesenchymal stem cells for clinical use. Experimental Hematology, 32, 1212–1225.PubMedCrossRefGoogle Scholar
  48. 48.
    Kocaoemer, A., Kern, S., Kluter, H., & Bieback, K. (2007). Human AB serum and thrombin-activated platelet-rich plasma are suitable alternatives to fetal calf serum for the expansion of mesenchymal stem cells from adipose tissue. Stem Cells, 25, 1270–1278.PubMedCrossRefGoogle Scholar
  49. 49.
    DiGirolamo, C. M., Stokes, D., Colter, D., Phinney, D. G., Class, R., & Prockop, D. J. (1999). 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. British Journal of Haematology, 107, 275–281.PubMedCrossRefGoogle Scholar
  50. 50.
    Fehrer, C., Laschober, G., & Lepperdinger, G. (2006). Aging of murine mesenchymal stem cells. Annals of the New York Academy of Sciences, 1067, 235–242.PubMedCrossRefGoogle Scholar
  51. 51.
    Javazon, E. H., Beggs, K. J., & Flake, A. W. (2004). Mesenchymal stem cells: Paradoxes of passaging. Experimental Hematology, 32, 414–425.PubMedCrossRefGoogle Scholar
  52. 52.
    Sotiropoulou, P. A., Perez, S. A., Salagianni, M., Baxevanis, C. N., & Papamichail, M. (2005). Characterization of the optimal culture conditions for clinical scale production of human mesenchymal stem cells. Stem Cells, 24, 462–471.PubMedCrossRefGoogle Scholar
  53. 53.
    Gregory, C. A., Singh, H., Perry, A. S., & Prockop, D. J. (2003). The Wnt signaling inhibitor dickkopf-1 is required for reentry into the cell cycle of human adult stem cells from bone marrow. Journal of Biological Chemistry, 278, 28067–28078.PubMedCrossRefGoogle Scholar
  54. 54.
    Wang, H., & Scott, R. E. (1993). Inhibition of distinct steps in the adipocyte differentiation pathway in 3T3 T mesenchymal stem cells by dimethyl sulphoxide (DMSO). Cell Proliferation, 26, 55–66.PubMedGoogle Scholar
  55. 55.
    Kotobuki, N., Hirose, M., Machida, H., et al. (2005). Viability and osteogenic potential of cryopreserved human bone marrow-derived mesenchymal cells. Tissue Engineering, 11, 663–673.PubMedCrossRefGoogle Scholar
  56. 56.
    Wuchter, P., Boda-Heggemann, J., Straub, B. K., et al. (2007). Processus and recessus adhäerentes: Giant adherens cell junction systems connect and attract human mesenchymal stem cells. Cell Tissue Research, 328, 499–514.PubMedCrossRefGoogle Scholar
  57. 57.
    Franke, W. W., Grund, C., Jackson, B. W., & Illmensee K. (1983). Formation of cytoskeletal elements during mouse embryogenesis. IV. Ultrastructure of primary mesenchymal cells and their cell–cell interactions. Differentiation, 25, 121–141.PubMedCrossRefGoogle Scholar
  58. 58.
    Schofield, R. (1978). The relationship between the spleen colony-forming cell and the haemopoietic stem cell. Blood Cells, 4, 7–25.PubMedGoogle Scholar
  59. 59.
    Ho, A. D., & Wagner, W. (2007). The beauty of asymmetry–asymmetric divisions and self-renewal in the hematopoietic system. Current Opinion in Hematology, 14, 330–336.PubMedCrossRefGoogle Scholar
  60. 60.
    Wagner, W., Wein, F., Roderburg, C., et al. (2007). Adhesion of hematopoietic progenitor cells to human mesenchymal stem cells as a model for cell–cell interaction. Experimental Hematology, 35, 314–325.PubMedCrossRefGoogle Scholar
  61. 61.
    Gottschling, S., Saffrich, R., Seckinger, A., et al. (2007). Human mesenchymal stroma cells regulate initial self-renewing divisions of hematopoietic progenitor cells by a beta1-integrin-dependent mechanism. Stem Cells, 25, 798–806.PubMedCrossRefGoogle Scholar
  62. 62.
    Zhang, J., Niu, C., Ye, L., et al. (2003). Identification of the haematopoietic stem cell niche and control of the niche size. Nature, 425, 836–841.PubMedCrossRefGoogle Scholar
  63. 63.
    Wilson, A., & Trumpp, A. (2006). Bone-marrow haematopoietic-stem-cell niches. Nature Reviews. Immunology, 6, 93–106.PubMedCrossRefGoogle Scholar
  64. 64.
    Forsberg, E. C., Prohaska, S. S., Katzman, S., Heffner, G. C., Stuart, J. M., & Weissman, I. L. (2005). Differential expression of novel potential regulators in hematopoietic stem cells. PLoS Genet, 1, e28.PubMedCrossRefGoogle Scholar
  65. 65.
    Wineman, J., Moore, K., Lemischka, I., & Muller-Sieburg, C. (1996). Functional heterogeneity of the hematopoietic microenvironment: Rare stromal elements maintain long-term repopulating stem cells. Blood, 87, 4082–4090.PubMedGoogle Scholar
  66. 66.
    Gan, O. I., Murdoch, B., Larochelle, A., & Dick, J. E. (1997). Differential maintenance of primitive human SCID-repopulating cells, clonogenic progenitors, and long-term culture-initiating cells after incubation on human bone marrow stromal cells. Blood, 90, 641–650.PubMedGoogle Scholar
  67. 67.
    Kadereit, S., Deeds, L. S., Haynesworth, S. E., et al. (2002). Expansion of LTC-ICs and maintenance of p21 and BCL-2 expression in cord blood CD34(+)/CD38(−) early progenitors cultured over human MSCs as a feeder layer. Stem Cells, 20, 573–582.PubMedCrossRefGoogle Scholar
  68. 68.
    Jang, Y. K., Jung, D. H., Jung, M. H., et al. (2006). Mesenchymal stem cells feeder layer from human umbilical cord blood for ex vivo expanded growth and proliferation of hematopoietic progenitor cells. Annals of Hematology, 85, 212–225.PubMedCrossRefGoogle Scholar
  69. 69.
    Robinson, S. N., Ng, J., Niu, T., et al. (2006). Superior ex vivo cord blood expansion following co-culture with bone marrow-derived mesenchymal stem cells. Bone Marrow Transplant, 37, 359–366.PubMedCrossRefGoogle Scholar
  70. 70.
    Punzel, M., Liu, D., Zhang, T., Eckstein, V., Miesala, K., & Ho, A. D. (2003). The symmetry of initial divisions of human hematopoietic progenitors is altered only by the cellular microenvironment. Experimental Hematology, 31, 339–347.PubMedCrossRefGoogle Scholar
  71. 71.
    Dexter, T. M., Allen, T. D., & Lajtha, L. G. (1977). Conditions controlling the proliferation of haemopoietic stem cells in vitro. Journal of Cellular Physiology, 91, 335–344.PubMedCrossRefGoogle Scholar
  72. 72.
    Yamaguchi, M., Hirayama, F., Murahashi, H., et al. (2002). Ex vivo expansion of human UC blood primitive hematopoietic progenitors and transplantable stem cells using human primary BM stromal cells and human AB serum. Cytotherapy, 4, 109–118.PubMedCrossRefGoogle Scholar
  73. 73.
    Wagner, W., Saffrich, R., Wirkner, U., et al. (2005). Hematopoietic progenitor cells and cellular microenvironment: Behavioral and molecular changes upon interaction. Stem Cells, 23, 1180–1191.PubMedCrossRefGoogle Scholar
  74. 74.
    Ho, A. D. (2005). Kinetics and symmetry of divisions of hematopoietic stem cells. Experimental Hematology, 33, 1–8.PubMedCrossRefGoogle Scholar
  75. 75.
    Wagner, W., Wein, F., Roderburg, C., et al. (2007). Adhesion of human hematopoietic progenitor cells to mesenchymal stromal cells involves CD44. Cells Tissues Organs, (in press).Google Scholar
  76. 76.
    Caplan, A. I., & Dennis, J. E. (2006). Mesenchymal stem cells as trophic mediators. Journal of Cellular Biochemistry, 98, 1076–1084.PubMedCrossRefGoogle Scholar
  77. 77.
    Stamm, C., Liebold, A., Steinhoff, G., & Strunk, D. (2006). Stem cell therapy for ischemic heart disease: Beginning or end of the road? Cell Transplant, 15(Suppl 1), S47–S56.PubMedGoogle Scholar
  78. 78.
    Mazhari, R., & Hare, J. M. (2007). Mechanisms of action of mesenchymal stem cells in cardiac repair: Potential influences on the cardiac stem cell niche. Nature Clinical Practice. Cardiovascular Medicine, 4(Suppl 1), S21–S26.PubMedCrossRefGoogle Scholar
  79. 79.
    Grinnemo, K. H., Mansson-Broberg, A., Leblanc, K., et al. (2006). Human mesenchymal stem cells do not differentiate into cardiomyocytes in a cardiac ischemic xenomodel. Annals of Medicine, 38, 144–153.PubMedCrossRefGoogle Scholar
  80. 80.
    Adewumi, O., Aflatoonian, B., Ahrlund-Richter, L., et al. (2007). Characterization of human embryonic stem cell lines by the International Stem Cell Initiative. Nature Biotechnology, 25, 803–816.PubMedCrossRefGoogle Scholar

Copyright information

© Humana Press Inc. 2007

Authors and Affiliations

  1. 1.Department of Medicine VUniversity of HeidelbergHeidelbergGermany
  2. 2.Department of Physiology and PathophysiologyUniversity of HeidelbergHeidelbergGermany

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