Basic Research in Cardiology

, Volume 103, Issue 3, pp 265–273 | Cite as

Stem cell factor/c-kit signaling mediated cardiac stem cell migration via activation of p38 MAPK

  • Dong Kuang
  • Xia Zhao
  • Guixiang Xiao
  • Juan Ni
  • Youmei Feng
  • Renliang Wu
  • Guoping WangEmail author



It was reported that there are cardiac stem cells (CSCs) in the rat heart, and they could reconstitute well-differentiated myocardium that are formed by blood-carrying new vessels and myocytes. However, how do the CSCs migrate into the peri-infarcted areas after myocardial infarction (MI)? It remains entirely unknown about the signal transduction involved in the migration of CSCs.

Methods and results

Rat heart MI was induced by left coronary artery ligation. Both immunohistochemical staining and Western blotting analysis was performed to detect the expression of SCF protein, and RT-PCR was conducted for the expression of SCF mRNA. Cardiac stem cells were isolated from rat hearts, and a cardiac stem cell migration assay was performed using a 48-well chemotaxis chamber system. On day 5 after MI in rats, the expression of stem cell factor (SCF) mRNA and protein was significantly increased in the peri-infarcted area, which was matched with more accumulation of CSCs in the region and improvement of cardiac function, which was blocked by p38 MAPK selective inhibitor SB203580. In in vitro experiments, SCF induced CSC migration in a concentration-dependent manner, and the antibody against SCF receptor (c-kit) blocked the SCF-induced CSC migration. Western blot analysis showed that the phosphorylated p38 MAPK (Phospho-p38 MAPK) was highly increased in the SCF-treated CSCs, and the inhibition of p38 MAPK activity significantly attenuated SCF-induced the migration of CSCs.


It demonstrated that SCF/c-kit signaling may mediate the migration of CSCs via activation of p38 MAPK.

Key words

cardiac stem cell stem cell factor migration myocardial infarction 



This study was supported in part by research grants 30470710 from the National Natural Science Foundation of China, NCET-04-0711 from the Program for New Century Excellent Talents in University, and 2005ABB009 from the Natural Science Foundation of Hubei.


  1. 1.
    Anversa P, Kajstura J, Nadal-Ginard B, Leri A (2003) Primitive cells and tissue regeneration. Circ Res 92:579–582PubMedCrossRefGoogle Scholar
  2. 2.
    Ayach BB, Yoshimitsu M, Dawood F, Sun M, Arab S, Chen M, Higuchi K, Siatskas C, Lee P, Lim H, Zhang J, Cukerman E, Stanford W, Medin JA, Liu PP (2006) Stem cell factor receptor induces progenitor and natural killer cell-mediated cardiac survival and repair after myocardial infarction. Proc Natl Acad Sci USA 103:2304–2309PubMedCrossRefGoogle Scholar
  3. 3.
    Barbash IM, Chouraqui P, Baron J, Feinberg MS, Etzion S, Tessone A, Miller L, Guetta E, Zipori D, Kedes LH, Kloner RA, Leor J (2003) Systemic delivery of bone marrow-derived mesenchymal stem cells to the infracted myocardium: feasibility, cell migration and body distribution. Circulation 108:863–868PubMedCrossRefGoogle Scholar
  4. 5.
    Beltrami AP, Urbanek K, Kajstura J, Yan SM, Finato N, Bussani R, Nadal-Ginard B, Silvestri F, Leri A, Beltrami CA, Anversa P (2001) Evidence that human cardiac myocytes divide after myocardial infarction. N Engl J Med 344:1750–1757PubMedCrossRefGoogle Scholar
  5. 4.
    Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Nadal-Ginard B, Anversa P (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114:763–776PubMedCrossRefGoogle Scholar
  6. 6.
    Cai CL, Liang X, Shi Y, Chu PH, Pfaff SL, Chen J, Evans S (2003) Isl1 identifies a cardiac progenitor population that proliferates prior to differentiation and contributes a majority of cells to the heart. Dev Cell 5:877–889PubMedCrossRefGoogle Scholar
  7. 7.
    Chimenti C, Kajstura J, Torella D, Urbanek K, Heleniak H, Colussi C, Di Meglio F, Nadal-Ginard B, Frustaci A, Leri A, Maseri A, Anversa P (2003) Senescence and death of primitive cells and myocytes lead to premature cardiac aging and heart failure. Circ Res 93:604–613PubMedCrossRefGoogle Scholar
  8. 8.
    Dawn B, Stein AB, Urbanek K, Rota M, Whang B, Rastaldo R, Torella D, Tang XL, Rezazadeh A, Kajstura J, Leri A, Hunt G, Varma J, Prabhu SD, Anversa P, Bolli R (2005) Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc Natl Acad Sci USA 102:3766–3771PubMedCrossRefGoogle Scholar
  9. 9.
    Duronio V, Welham MJ, Abraham S, Dryden P, Schrader JW (1992) p21ras activation via hemopoietin receptors and c-kit requires tyrosine kinase activity but not tyrosine phosphorylation of p21ras GTPase-activating protein. Proc Natl Acad Sci USA 89:1587–1591PubMedCrossRefGoogle Scholar
  10. 10.
    Engel FB, Hsieh PC, Lee RT, Keating MT (2006) FGF1/p38 MAP kinase inhibitor therapy induces cardiomyocyte mitosis, reduces scarring, and rescues function after myocardial infarction. Proc Natl Acad Sci USA 103:15546–15551PubMedCrossRefGoogle Scholar
  11. 11.
    Fazel S, Cimini M, Chen L, Li S, Angoulvant D, Fedak P, Verma S, Weisel RD, Keating A, Li RK (2006) Cardioprotective c-kit+ cells are from the bone marrow and regulate the myocardial balance of angiogenic cytokines. J Clin Invest 116:1865–1877PubMedCrossRefGoogle Scholar
  12. 12.
    Galli SJ, Zsebo KM, Geissler EN (1994) The kit ligand, stem cell factor. Adv Immunol 55:1–96PubMedGoogle Scholar
  13. 13.
    Histov M, Weber C (2006) The therapeutic potential of progenitor cells in ischemic heart diseases—past, present and future. Basic Res Cardiol 101:1–7CrossRefGoogle Scholar
  14. 14.
    Konard L, Munir Keilani M, Cordes A, Voulck-Badouin E, Laible L, Albrecht M, Renneberg N, Aumouller G (2005) Rat sertoli cells express epithelial but also mesenchymal genes after immortalization with SV40. Biochim Biophy Acta 1722:6–14Google Scholar
  15. 15.
    Kunisada T, Yoshida H, Yamakazi H, Miyamoto A, Hemmi H, Nishimura E, Shultz LD, Nishikawa S, Hayashi S (1998) Transgene expression of steel factor in the basal layer of epidermis promotes survival, proliferation, differentiation and migration of melanocyte precursors. Development 125: 2915–2293PubMedGoogle Scholar
  16. 16.
    Laflamme MA, Myerson D, Saffitz JE, Murry CE (2002) Evidence for cardiomyocyte repopulation by extracardiac progenitors in transplanted human hearts. Circ Res 90:634–640PubMedCrossRefGoogle Scholar
  17. 17.
    Lam V, Kalesnikoff J, Lee CW, Hernandez-Hansen V, Wilson BS, Oliver JM, Krystal G (2003) IgE alone stimulates mast cell adhesion to fibronectin via pathways similar to those used by IgE + antigen but distinct from those used by Steel factor. Blood 102:1405–1413PubMedCrossRefGoogle Scholar
  18. 18.
    Leri A, Kajstura J, Anversa P (2005) Cardiac stem cells and mechanisms of myocardial regeneration. Physiol Rev 5:1373–416CrossRefGoogle Scholar
  19. 19.
    Linke A, Mueller P, Nurzynska D, Casarsa C, Torella D, Nascimbene A, Castaldo C, Cascapera S, Bohm M, Quaini F, Urbanek K, Leri A, Hintze TH, Kajstura J, Anversa P (2005) Cardiac stem cells in the dog heart regenerate infarcted myocardium improving cardiac performance. Proc Natl Acad Sci USA 102:8966–8971PubMedCrossRefGoogle Scholar
  20. 20.
    Linnekin D, DeBerry CS, Mou S (1997) Lyn associates with the juxtamembrane region of c-Kit and is activated by stem cell factor in hematopoietic cell lines and normal progenitor cells. J Biol Chem 272:27450–27455PubMedCrossRefGoogle Scholar
  21. 21.
    Lewis TS, Shapiro PS, Ahn NG (1998) Signal transduction through MAP kinase cascades. Adv Cancer Res 74:49–139PubMedCrossRefGoogle Scholar
  22. 22.
    Lyngbaek S, Schneider M, Hansen JL, Sheikh SP (2007) Cardiac regeneration by resident stem and progenitor cells in the adult heart. Basic Res Cardiol 102:101–114PubMedCrossRefGoogle Scholar
  23. 23.
    Nadal-Ginard B, Kajstura J, Anversa P, Leri A (2003) A matter of life and death: cardiac myocyte apoptosis and regeneration. J Clin Invest 111:1457–1459PubMedGoogle Scholar
  24. 24.
    Oh H, Bradfute SB, Gallardo TD, Nakamura T, Gaussin V, Mishina Y, Pocius J, Michael LH, Behringer RR, Garry DJ, Entman ML, Schneider MD (2003) Cardiac progenitor cells from adult myocardium: homing, differentiation, and fusion after infarction. Proc Natl Acad Sci USA 100:12313–12318PubMedCrossRefGoogle Scholar
  25. 25.
    O’Laughlin-Bunner B, Radosevic N, Taylor ML, Shivakrupa, DeBerry C, Metcalfe DD, Zhou M, Lowell C, Linnekin D (2001) Lyn is required for normal stem cell factor-induced proliferation and chemotaxis of primary hematopoietic cells. Blood 98:343–350Google Scholar
  26. 26.
    Qiu FH, Ray P, Brown K, Barker PE, Jhanwar S, Ruddle FH, Besmer P (1988) Primary structure of c-kit: relationship with the CSF-1/PDGF receptor kinase family—oncogenic activation of v-kit involves deletion of extracellular domain and C terminus. EMBO J 7:1003–1011PubMedGoogle Scholar
  27. 27.
    Sattler M, Salgia R, Shrikhande G, Verma S, Pisick E, Prasad KV Griffin JD (1997) Steel factor induces tyrosine phosphorylation of CRKL and binding of CRKL to a complex containing ckit, phosphatidylinositol 3-kinase, and p120(CBL). J Biol Chem 272:10248–10253PubMedCrossRefGoogle Scholar
  28. 28.
    Serve H, Hsu YC, Besmer P (1994) Tyrosine residue 719 of the c-kit receptor is essential for binding of the P85 subunit of phosphatidylinositol (PI) 3-kinase and for c-kit- associated PI 3-kinase activity in COS-1 cells. J Biol Chem 269:6026–6030PubMedGoogle Scholar
  29. 29.
    Song ZH, Zhong M (2000) CB1 cannabinoid receptor-mediated cell migration. J Pharmacol Exp Ther 294:204–209PubMedGoogle Scholar
  30. 30.
    Sun L, Lee J, Fine HA (2004) Neuronally expressed stem cell factor induces neural stem cell migration to areas of brain injury. J Clin Invest 113:1364–1374PubMedGoogle Scholar
  31. 31.
    Sundstrom M, Alfredsson J, Olsson N, Nilsson G (2001) Stem cell factor-induced migration of mast cells requires p38 mitogen-activated protein kinase activity. Exp Cell Res 267:144–151PubMedCrossRefGoogle Scholar
  32. 32.
    Suto H, Nakae S, Kakurai M, Sedgwick JD, Tsai M, Galli SJ (2006) Mast cell-associated TNF promotes dendritic cell migration. J Immunol 176:4102–4112PubMedGoogle Scholar
  33. 33.
    Teyssier-Le Discorde M, Prost S, Nandrot E, Kirzenbaum M (1999) Spatial and temporal mapping of c-kit and its ligand, stem cell factor expression during human embryonic haemopoiesis. Br J Haematol 107:247–253PubMedCrossRefGoogle Scholar
  34. 34.
    Templin C, Kotlarz D, Marquart F, Faulhaber J, Brendecke V, Schaefer A, Tsikas D, Bonda T, Hilfiker-Kleiner D, Ohl L, Naim HY, Foerster R, Drexler H, Limbourg FP (2006) Transcoronary delivery of bone marrow cells to the infarcted murine myocardium: feasibility, cellular kinetics, and improvement in cardiac function. Basic Res Cardiol 101:301–310PubMedCrossRefGoogle Scholar
  35. 35.
    Ueda S, Mizuki M, Ikeda H, Tsujimura T, Matsumura I, Nakano K, Daino H, Honda Zi Z, Sonoyama J, Shibayama H, Sugahara H, Machii T, Kanakura Y (2002) Critical roles of c-Kit tyrosine residues 567 and 719 in stem cell factor-induced chemotaxis: contribution of src family kinase and PI3-kinase on calcium mobilization and cell migration. Blood 99:3342–3349PubMedCrossRefGoogle Scholar
  36. 36.
    Urbanek K, Rota M, Cascapera S, Bearzi C, Nascimbene A, De Angelis A, Hosota T, Chimenti S, Baker M, Limana F, Nurzynska D, Torella D, Rotatori F, Rastaldo R, Musso E, Quaini F, Leri A, Kajstura J, Anversa P (2005) Cardiac stem cells possess growth factor-receptor systems that after activation regenerate the infarcted myocardium, improving ventricular function and long-term survival. Circ Res 97:663–673PubMedCrossRefGoogle Scholar
  37. 37.
    Urbanek K, Torella D, Sheikh F, Nurzynska D, Silvestri F, Beltrami CA, Bussani R, Beltrami AP, Quaini F, Bolli R, Leri A, Kajstura J, Anversa P (2005) Myocardial regeneration by activation of multipotent cardiac stem cells in ischemic heart failure. Proc Natl Acad Sci USA 102:8692–8697PubMedCrossRefGoogle Scholar
  38. 38.
    van Dijk TB, van Den Akker E, Amelsvoort MP, Mano H, Lowenberg B, von Lindern M (2000) Stem cell factor induces phosphatidylinositol 3-kinase-dependent Lyn/Tec/Dok-1 complex formation in hematopoietic cells. Blood 96:3406–3413PubMedGoogle Scholar
  39. 39.
    Vosseller K, Stella G, Yee NS, Besmer P (1997) c-kit receptor signaling through its phosphatidylinositide-3′-kinase-binding site and protein kinase C: role in mast cell enhancement of degranulation, adhesion, and membrane ruffling. Mol Biol Cell 8:909–922PubMedGoogle Scholar
  40. 40.
    Wang G, Lei M, Lu X, Feng Q (2004) Bone marrow stem cell migration to the infracted myocardium: role of TNF. Faseb J 18:A1286Google Scholar
  41. 41.
    Wang R, Li J, Yashpal N (2004) Phenotypic analysis of c-kit expression in epithelial monolayers derived from postnatal rat pancreatic islets. J Endocrinol 182:113–122PubMedCrossRefGoogle Scholar
  42. 42.
    Witte ON (1990) Steel locus defines new multipotent growth factor. Cell 63:5–6PubMedCrossRefGoogle Scholar
  43. 43.
    Yarden Y, Kuang WJ, Yang-Feng T, Coussens L, Munemitsu S, Dull TJ, Chen E, Schlessinger J, Francke U, Ullrich A (1987) Human proto-oncogene c-kit: a new cell surface receptor tyrosine kinase for an unidentified ligand. EMBO J 6:3341–3351PubMedGoogle Scholar

Copyright information

© Springer 2007

Authors and Affiliations

  • Dong Kuang
    • 1
  • Xia Zhao
    • 1
  • Guixiang Xiao
    • 1
  • Juan Ni
    • 1
  • Youmei Feng
    • 2
  • Renliang Wu
    • 1
  • Guoping Wang
    • 1
    Email author
  1. 1.Institute of Pathology, Tongji Hospital, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanPeople’s Republic of China
  2. 2.Dept. of Biochemistry, Tongji Medical CollegeHuazhong University of Science and TechnologyWuhanChina

Personalised recommendations