Stem Cell Reviews and Reports

, Volume 8, Issue 1, pp 243–250 | Cite as

The Role of Chemokines in Mesenchymal Stem Cell Homing to Myocardium



A growing body of preclinical evidence suggests that mesenchymal stem cells (MSCs) are effective for the structural and functional recovery of the infracted heart. Accordingly, clinical trials are underway to determine the benefit of MSC-based therapies. While systemic administration of MSCs is an attractive strategy, and is the route currently used for the administration of MSCs in clinical studies for myocardial infarction, the majority of infused cells do not appear to localize to infracted myocardium in animal studies. Recently, important progress has been made in identifying chemokine receptors critical for the migration and homing of MSCs. Here, we review recent literature regarding mechanisms of MSC homing and recruitment to the ischemic myocardium, and discuss potential influences of low engraftment rates of systemically administered MSCs to the infracted heart tissue on the effects of MSC-based therapies on myocardial infarction.


Mesenchymal stem cells Homing Chemokines CCR Myocardial infarction 



We thank Xusheng Wang and Ying Zhou for assistances in drawing graphs and collecting data. This work was supported by grants from Natural Science Foundation of China (No. 30871273, 30971496, U1032003) to Y Wu.


The authors indicate no potential conflicts of interest.


  1. 1.
    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
  2. 2.
    Prockop, D. J. (1997). Marrow stromal cells as stem cells for nonhematopoietic tissues. Science, 276, 71–74.PubMedCrossRefGoogle Scholar
  3. 3.
    Horwitz, E. M. (2006). MSC: A coming of age in regenerative medicine. Cytotherapy, 8, 194–195.PubMedCrossRefGoogle Scholar
  4. 4.
    Charwat, S., Gyongyosi, M., Lang, I., et al. (2008). Role of adult bone marrow stem cells in the repair of ischemic myocardium: Current state of the art. Experimental Hematology, 36, 672–680.PubMedCrossRefGoogle Scholar
  5. 5.
    Salem, H. K., & Thiemermann, C. (2010). Mesenchymal stromal cells: Current understanding and clinical status. Stem Cells, 28, 585–596.PubMedGoogle Scholar
  6. 6.
    Amado, L. C., Saliaris, A. P., Schuleri, K. H., et al. (2005). Cardiac repair with intramyocardial injection of allogeneic mesenchymal stem cells after myocardial infarction. Proceedings of the National Academy of Sciences of the United States of America, 102, 11474–11479.PubMedCrossRefGoogle Scholar
  7. 7.
    Ip, J. E., Wu, Y., Huang, J., Zhang, L., Pratt, R. E., & Dzau, V. J. (2007). Mesenchymal stem cells use integrin beta1 not CXC chemokine receptor 4 for myocardial migration and engraftment. Molecular Biology of the Cell, 18, 2873–2882.PubMedCrossRefGoogle Scholar
  8. 8.
    Barbash, I. M., Chouraqui, P., Baron, J., et al. (2003). Systemic delivery of bone marrow-derived mesenchymal stem cells to the infracted myocardium: Feasibility, cell migration, and body distribution. Circulation, 108, 863–868.PubMedCrossRefGoogle Scholar
  9. 9.
    LaPar, D. J., Kron, I. L., & Yang, Z. (2009). Stem cell therapy for ischemic heart disease: Where are we? Current Opinion in Organ Transplantation, 14, 79–84.PubMedCrossRefGoogle Scholar
  10. 10.
    Lapidot, T., Dar, A., & Kollet, O. (2005). How do stem cells find their way home? Blood, 106, 1901–1910.PubMedCrossRefGoogle Scholar
  11. 11.
    Hare, J. M., Traverse, J. H., Henry, T. D., et al. (2009). A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction. Journal of the American College of Cardiology, 54, 2277–2286.PubMedCrossRefGoogle Scholar
  12. 12.
    Rombouts, W. J., & Ploemacher, R. E. (2003). Primary murine MSC show highly efficient homing to the bone marrow but lose homing ability following culture. Leukemia, 17, 160–170.PubMedCrossRefGoogle Scholar
  13. 13.
    Assis, A. C., Carvalho, J. L., Jacoby, B. A., et al. (2010). Time-dependent migration of systemically delivered bone marrow mesenchymal stem cells to the infracted heart. Cell Transplantation, 19, 219–230.PubMedCrossRefGoogle Scholar
  14. 14.
    Kraitchman, D. L., Tatsumi, M., Gilson, W. D., et al. (2005). Dynamic imaging of allogeneic mesenchymal stem cells trafficking to myocardial infarction. Circulation, 112, 1451–1461.PubMedCrossRefGoogle Scholar
  15. 15.
    Vos, O., Luiten, F., & Ploemacher, R. E. (1980). Lodging of CFU(S) under various circumstances in bone marrow, spleen and liver. Experimental Hematology, 8, 860–866.PubMedGoogle Scholar
  16. 16.
    Freyman, T., Polin, G., Osman, H., et al. (2006). A quantitative, randomized study evaluating three methods of mesenchymal stem cell delivery following myocardial infarction. European Heart Journal, 27, 1114–1122.PubMedCrossRefGoogle Scholar
  17. 17.
    Honczarenko, M., Le, Y., Swierkowski, M., Ghiran, I., Glodek, A. M., & Silberstein, L. E. (2006). Human bone marrow stromal cells express a distinct set of biologically functional chemokine receptors. Stem Cells, 24, 1030–1041.PubMedCrossRefGoogle Scholar
  18. 18.
    Mangi, A. A., Noiseux, N., Kong, D., et al. (2003). Mesenchymal stem cells modified with Akt prevent remodeling and restore performance of infracted hearts. Nature Medicine, 9, 1195–1201.PubMedCrossRefGoogle Scholar
  19. 19.
    Schneider, C., Krause, K., Jaquet, K., et al. (2008). Intramyocardial transplantation of bone marrow-derived stem cells: Ultrasonic strain rate imaging in a model of hibernating myocardium. Journal of Cardiac Failure, 14, 861–872.PubMedCrossRefGoogle Scholar
  20. 20.
    Miyahara, Y., Nagaya, N., Kataoka, M., et al. (2006). Monolayered mesenchymal stem cells repair scarred myocardium after myocardial infarction. Nature Medicine, 12, 459–465.PubMedCrossRefGoogle Scholar
  21. 21.
    Perin, E. C., Silva, G. V., Assad, J. A., et al. (2008). Comparison of intracoronary and transendocardial delivery of allogeneic mesenchymal cells in a canine model of acute myocardial infarction. Journal of Molecular and Cellular Cardiology, 44, 486–495.PubMedCrossRefGoogle Scholar
  22. 22.
    Heldman, A. W., & Hare, J. M. (2008). Cell therapy for myocardial infarction: Special delivery. Journal of Molecular and Cellular Cardiology, 44, 473–476.PubMedCrossRefGoogle Scholar
  23. 23.
    Chavakis, E., Urbich, C., & Dimmeler, S. (2008). Homing and engraftment of progenitor cells: A prerequisite for cell therapy. Journal of Molecular and Cellular Cardiology, 45, 514–522.PubMedCrossRefGoogle Scholar
  24. 24.
    Ruster, B., Gottig, S., Ludwig, R. J., et al. (2006). Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells. Blood, 108, 3938–3944.PubMedCrossRefGoogle Scholar
  25. 25.
    McEver, R. P. (2010). Rolling back neutrophil adhesion. Nature Immunology, 11, 282–284.PubMedCrossRefGoogle Scholar
  26. 26.
    Imhof, B. A., & Aurrand-Lions, M. (2004). Adhesion mechanisms regulating the migration of monocytes. Nature Reviews Immunology, 4, 432–444.PubMedCrossRefGoogle Scholar
  27. 27.
    Kamei, M., & Carman, C. V. (2010). New observations on the trafficking and diapedesis of monocytes. Current Opinion in Hematology, 17, 43–52.PubMedCrossRefGoogle Scholar
  28. 28.
    Katayama, Y., Hidalgo, A., Furie, B. C., Vestweber, D., Furie, B., & Frenette, P. S. (2003). PSGL-1 participates in E-selectin-mediated progenitor homing to bone marrow: Evidence for cooperation between E-selectin ligands and {alpha}4 integrin. Blood, 102, 2060–2067.PubMedCrossRefGoogle Scholar
  29. 29.
    Hynes, R. O. (2002). Integrins: Bidirectional, allosteric signaling machines. Cell, 110, 673–687.PubMedCrossRefGoogle Scholar
  30. 30.
    Muller, W. A. (2009). Mechanisms of transendothelial migration of leukocytes. Circulation Research, 105, 223–230.PubMedCrossRefGoogle Scholar
  31. 31.
    Sorokin, L. (2010). The impact of the extracellular matrix on inflammation. Nature Reviews Immunology, 10, 712–723.PubMedCrossRefGoogle Scholar
  32. 32.
    Wu, Y., Ip, J. E., Huang, J., et al. (2006). Essential role of ICAM-1/CD18 in mediating EPC recruitment, angiogenesis, and repair to the infracted myocardium. Circulation Research, 99, 315–322.PubMedCrossRefGoogle Scholar
  33. 33.
    Frangogiannis, N. G. (2004). Chemokines in the ischemic myocardium: From inflammation to fibrosis. Inflammation Research, 53, 585–595.PubMedCrossRefGoogle Scholar
  34. 34.
    Herrera, M. B., Bussolati, B., Bruno, S., et al. (2007). Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury. Kidney International, 72, 430–441.PubMedCrossRefGoogle Scholar
  35. 35.
    Viswanathan, A., Painter, R. G., Lanson, N. A., Jr., & Wang, G. (2007). Functional expression of N-formyl peptide receptors in human bone marrow-derived mesenchymal stem cells. Stem Cells, 25, 1263–1269.PubMedCrossRefGoogle Scholar
  36. 36.
    Ponte, A. L., Marais, E., Gallay, N., et al. (2007). The in vitro migration capacity of human bone marrow mesenchymal stem cells: Comparison of chemokine and growth factor chemotactic activities. Stem Cells, 25, 1737–1745.PubMedCrossRefGoogle Scholar
  37. 37.
    Brooke, G., Tong, H., Levesque, J. P., & Atkinson, K. (2008). Molecular trafficking mechanisms of multipotent mesenchymal stem cells derived from human bone marrow and placenta. Stem Cells and Development, 17, 929–940.PubMedCrossRefGoogle Scholar
  38. 38.
    Bromley, S. K., Mempel, T. R., & Luster, A. D. (2008). Orchestrating the orchestrators: Chemokines in control of T cell traffic. Nature Immunology, 9, 970–980.PubMedCrossRefGoogle Scholar
  39. 39.
    Lazennec, G., & Richmond, A. (2010). Chemokines and chemokine receptors: New insights into cancer-related inflammation. Trends in Molecular Medicine, 16, 133–144.PubMedCrossRefGoogle Scholar
  40. 40.
    Schenk, S., Mal, N., Finan, A., et al. (2007). Monocyte chemotactic protein-3 is a myocardial mesenchymal stem cell homing factor. Stem Cells, 25, 245–251.PubMedCrossRefGoogle Scholar
  41. 41.
    Shi, M., Li, J., Liao, L., et al. (2007). Regulation of CXCR4 expression in human mesenchymal stem cells by cytokine treatment: Role in homing efficiency in NOD/SCID mice. Haematologica, 92, 897–904.PubMedCrossRefGoogle Scholar
  42. 42.
    Chamberlain, G., Wright, K., Rot, A., Ashton, B., & Middleton, J. (2008). Murine mesenchymal stem cells exhibit a restricted repertoire of functional chemokine receptors: Comparison with human. PloS One, 3, e2934.PubMedCrossRefGoogle Scholar
  43. 43.
    McQuibban, G. A., Gong, J. H., Tam, E. M., McCulloch, C. A., Clark-Lewis, I., & Overall, C. M. (2000). Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. Science, 289, 1202–1206.PubMedCrossRefGoogle Scholar
  44. 44.
    Huang, J., Zhang, Z., Guo, J., et al. (2010). Genetic modification of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circulation Research, 106, 1753–1762.PubMedCrossRefGoogle Scholar
  45. 45.
    Belema-Bedada, F., Uchida, S., Martire, A., Kostin, S., & Braun, T. (2008). Efficient homing of multipotent adult mesenchymal stem cells depends on FROUNT-mediated clustering of CCR2. Cell Stem Cell, 2, 566–575.PubMedCrossRefGoogle Scholar
  46. 46.
    Belema Bedada, F., Technau, A., Ebelt, H., Schulze, M., & Braun, T. (2005). Activation of myogenic differentiation pathways in adult bone marrow-derived stem cells. Molecular and Cellular Biology, 25, 9509–9519.PubMedCrossRefGoogle Scholar
  47. 47.
    Abbott, J. D., Huang, Y., Liu, D., Hickey, R., Krause, D. S., & Giordano, F. J. (2004). Stromal cell-derived factor-1 alpha plays a critical role in stem cell recruitment to the heart after myocardial infarction but is not sufficient to induce homing in the absence of injury. Circulation, 110, 3300–3305.PubMedCrossRefGoogle Scholar
  48. 48.
    Askari, A. T., Unzek, S., Popovic, Z. B., et al. (2003). Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. The Lancet, 362, 697–703.CrossRefGoogle Scholar
  49. 49.
    Wynn, R. F., Hart, C. A., Corradi-Perini, C., et al. (2004). A small proportion of mesenchymal stem cells strongly expresses functionally active CXCR4 receptor capable of promoting migration to bone marrow. Blood, 104, 2643–2645.PubMedCrossRefGoogle Scholar
  50. 50.
    Sordi, V., Malosio, M. L., Marchesi, F., et al. (2005). Bone marrow mesenchymal stem cells express a restricted set of functionally active chemokine receptors capable of promoting migration to pancreatic islets. Blood, 106, 419–427.PubMedCrossRefGoogle Scholar
  51. 51.
    Cheng, Z., Ou, L., Zhou, X., et al. (2008). Targeted migration of mesenchymal stem cells modified with CXCR4 gene to infracted myocardium improves cardiac performance. Molecular Therapy, 16, 571–579.PubMedCrossRefGoogle Scholar
  52. 52.
    Wojakowski, W., Tendera, M., Michalowska, A., et al. (2004). Mobilization of CD34/CXCR4+, CD34/CD117+, c-met + stem cells, and mononuclear cells expressing early cardiac, muscle, and endothelial markers into peripheral blood in patients with acute myocardial infarction. Circulation, 110, 3213–3220.PubMedCrossRefGoogle Scholar
  53. 53.
    Wang, Y., Johnsen, H. E., Mortensen, S., et al. (2006). Changes in circulating mesenchymal stem cells, stem cell homing factor, and vascular growth factors in patients with acute ST elevation myocardial infarction treated with primary percutaneous coronary intervention. Heart, 92, 768–774.PubMedCrossRefGoogle Scholar
  54. 54.
    Binger, T., Stich, S., Andreas, K., et al. (2009). Migration potential and gene expression profile of human mesenchymal stem cells induced by CCL25. Experimental Cell Research, 315, 1468–1479.PubMedCrossRefGoogle Scholar
  55. 55.
    Zhu, J., Zhou, Z., Liu, Y., & Zheng, J. (2009). Fractalkine and CX3CR1 are involved in the migration of intravenously grafted human bone marrow stromal cells toward ischemic brain lesion in rats. Brain Research, 1287, 173–183.PubMedCrossRefGoogle Scholar
  56. 56.
    Hung, S. C., Pochampally, R. R., Hsu, S. C., et al. (2007). Short-term exposure of multipotent stromal cells to low oxygen increases their expression of CX3CR1 and CXCR4 and their engraftment in vivo. PloS One, 2, e416.PubMedCrossRefGoogle Scholar
  57. 57.
    Ringe, J., Strassburg, S., Neumann, K., et al. (2007). Towards in situ tissue repair: Human mesenchymal stem cells express chemokine receptors CXCR1, CXCR2 and CCR2, and migrate upon stimulation with CXCL8 but not CCL2. Journal of Cellular Biochemistry, 101, 135–146.PubMedCrossRefGoogle Scholar
  58. 58.
    Von, L. I., Notohamiprodjo, M., Wechselberger, A., et al. (2005). Human adult CD34- progenitor cells functionally express the chemokine receptors CCR1, CCR4, CCR7, CXCR5, and CCR10 but not CXCR4. Stem Cells and Development, 14, 329–336.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  1. 1.Life Science DivisionTsinghua University Graduate School at ShenzhenShenzhenChina
  2. 2.Center of Excellence in Tissue Engineering, Department of Cell Biology, Institute of Basic Medical SciencesChinese Academy of Medical Sciences and School of Basic Medicine, Peking Union Medical CollegeBeijingChina
  3. 3.Tsinghua University Graduate School at ShenzhenShenzhenChina

Personalised recommendations