Advertisement

Cellular and Molecular Life Sciences

, Volume 68, Issue 12, pp 2141–2156 | Cite as

Mesenchymal stem cells or cardiac progenitors for cardiac repair? A comparative study

  • Remco Koninckx
  • Annick Daniëls
  • Severina Windmolders
  • Françoise Carlotti
  • Urbain Mees
  • Paul Steels
  • Jean-Luc Rummens
  • Marc Hendrikx
  • Karen HensenEmail author
Research Article

Abstract

In the past, clinical trials transplanting bone marrow–derived mononuclear cells reported a limited improvement in cardiac function. Therefore, the search for stem cells leading to more successful stem cell therapies continues. Good candidates are the so-called cardiac stem cells (CSCs). To date, there is no clear evidence to show if these cells are intrinsic stem cells from the heart or mobilized cells from bone marrow. In this study we performed a comparative study between human mesenchymal stem cells (hMSCs), purified c-kit+ CSCs, and cardiosphere-derived cells (CDCs). Our results showed that hMSCs can be discriminated from CSCs by their differentiation capacity towards adipocytes and osteocytes and the expression of CD140b. On the other hand, cardiac progenitors display a greater cardiomyogenic differentiation capacity. Despite a different isolation protocol, no distinction could be made between c-kit+ CSCs and CDCs, indicating that they probably derive from the same precursor or even are the same cells.

Keywords

Mesenchymal stem cells Cardiosphere-derived cells c-kit+ cardiac stem cells Heart failure Myocardial infarction Differentiation Coculture 

References

  1. 1.
    Bergmann O, Bhardwaj RD, Bernard S, Zdunek S, Barnabé-Heider F, Walsh S, Zupicich J, Alkass K, Buchholz BA, Druid H, Jovinge S, Frisén J (2009) Evidence for cardiomyocyte renewal in humans. Science 324:98–102PubMedCrossRefGoogle Scholar
  2. 2.
    Astorri E, Bolgognesi R, Colla B, Chizzola A, Visioli O (1977) Left ventricular hypertrophy: a cytometric study on 42 human hearts. J Mol Cell Cardiol 9:763–775PubMedCrossRefGoogle Scholar
  3. 3.
    Wollert KC, Meyer GP, Lotz J, Ringes-Lichtenberg S, Lippolt P, Breidenbach C, Fichtner S, Korte T, Hornig B, Messinger D, Arseniev L, Hertenstein B, Ganser A, Drexler H (2004) Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 364:141–148PubMedCrossRefGoogle Scholar
  4. 4.
    Janssens S, Dubois C, Bogaert J, Theunissen K, Deroose C, Desmet W, Kalantzi M, Herbots L, Sinnaeve P, Dens J, Martens J, Rademakers F, Dymarkowski S, Gheysens O, Van Cleemput J, Bormans G, Nuyts J, Belmans A (2006) Autologous bone marrow-derived stem-cell transfer in patients with ST-segment elevation myocardial infarction: double-blind, randomised controlled trial. Lancet 367:113–121PubMedCrossRefGoogle Scholar
  5. 5.
    Hendrikx M, Hensen K, Clijsters C, Jongen H, Koninckx R, Bijnens E, Ingels M, Jacobs A, Geukens R, Dendale P, Vijgen J, Dilling D, Steels P, Mees U, Rummens JL (2006) Recovery of regional but not global contractile function by the direct intramyocardial autologous bone marrow transplantation: results from a randomized controlled clinical trial. Circulation 114:101–107CrossRefGoogle Scholar
  6. 6.
    Schächinger V, Assmus B, Erbs S, Elsässer A, Haberbosch W, Hambrecht R, Yu J, Corti R, Mathey DG, Hamm CW, Tonn T, Dimmeler S, Zeiher AM, REPAIR-AMI Investigators (2006) Intracoronary bone marrow-derived progenitor cells in acute myocardial infarction. N Engl J Med 355:1210–1221PubMedCrossRefGoogle Scholar
  7. 7.
    Koninckx R, Hensen K, Daniëls A, Moreels M, Lambrichts I, Jongen H, Clijsters C, Mees U, Steels P, Hendrikx M, Rummens JL (2009) Plasticity of human bone marrow-derived stem cells after co-culture with neonatal rat cardiomyocytes: a realistic perspective. Cytotherapy 11:778–792PubMedCrossRefGoogle Scholar
  8. 8.
    Rose RA, Jiang H, Wang X, Helke S, Tsoporis JN, Gong N, Keating SC, Parker TG, Backx PH, Keating A (2008) Bone marrow-derived mesenchymal stromal cells express cardiac-specific markers, retain the stromal phenotype, and do not become functional cardiomyocytes in vitro. Stem Cells 26:2884–2892PubMedCrossRefGoogle Scholar
  9. 9.
    Cheng Z, Liu X, Ou L, Zhou X, Liu Y, Jia X, Zhang J, Li Y, Kong D (2008) Mobilization of mesenchymal stem cells by granulocyte colony-stimulating factor in rats with acute myocardial infarction. Cardiovasc Drugs Ther 22:363–371PubMedCrossRefGoogle Scholar
  10. 10.
    Hare J, Traverse J, Henry T, Dib N, Strumpf R, Schulman S, Gerstenblith G, DeMaria A, Denktas A, Gammon R, Hermiller J, Reisman M, Schaer G, Sherman W (2009) A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (prochymal) after acute myocardial infarction). J Am Coll Cardiol 54:2277–2286PubMedCrossRefGoogle Scholar
  11. 11.
    Noiseux N, Gnecchi M, Lopez-Ilasaca M, Zhang L, Solomon SD, Deb A, Dzau VJ, Pratt RE (2006) Mesenchymal stem cells overexpressing Akt dramatically repair infarcted myocardium and improve cardiac function despite infrequent cellular fusion or differentiation. Mol Ther 14:840–850PubMedCrossRefGoogle Scholar
  12. 12.
    Yokokawa M, Ohnishi S, Ishibashi-Ueda H, Obata H, Otani K, Miyahara Y, Tanaka K, Shimizu W, Nakazawa K, Kangawa K, Kamakura S, Kitamura S, Nagaya N (2008) Transplantation of mesenchymal stem cells improves atrioventricular conduction in a rat model of complete atrioventricular block. Cell Transplant 17:1145–1155PubMedCrossRefGoogle Scholar
  13. 13.
    Beltrami AP, Barlucchi L, Torella D, Baker M, Limana F, Chimenti S, Kasahara H, Rota M, Musso E, Urbanek K, Leri A, Kajstura J, Nadal-Ginard B, Anversa P (2003) Adult cardiac stem cells are multipotent and support myocardial regeneration. Cell 114:763–776PubMedCrossRefGoogle Scholar
  14. 14.
    Messina E, De Angelis L, Frati G, Morrone S, Chimenti S, Fiordaliso F, Salio M, Battaglia M, Latronico MV, Coletta M, Vivarelli E, Frati L, Cossu G, Giacomello A (2004) Isolation and expansion of adult cardiac stem cells from human and murine heart. Circ Res 95:911–921PubMedCrossRefGoogle Scholar
  15. 15.
    Smith RR, Barile L, Cho HC, Leppo MK, Hare JM, Messina E, Giacomello A, Abraham MR, Marbán E (2007) Regenerative potential of cardiosphere-derived cells expanded from percutaneous endomyocardial biopsy specimens. Circulation 115:896–908PubMedCrossRefGoogle Scholar
  16. 16.
    Bearzi C, Rota M, Hosoda T, Tillmanns J, Nascimbene A, De Angelis A, Yasuzawa-Amano S, Trofimova I, Siggins RW, Lecapitaine N, Cascapera S, Beltrami AP, D’Alessandro DA, Zias E, Quaini F, Urbanek K, Michler RE, Bolli R, Kajstura J, Leri A, Anversa P (2007) Human cardiac stem cells. Proc Natl Acad Sci USA 104:14068–14073PubMedCrossRefGoogle Scholar
  17. 17.
    Goumans MJ, de Boer TP, Smits AM, van Laake LW, van Vliet P, Metz CH, Korfage TH, Kats KP, Hochstenbach R, Pasterkamp G, Verhaar MC, van der Heyden MA, de Kleijn D, Mummery CL, van Veen TA, Sluijter JP, Doevendans PA (2007) TGF-β1 induces efficient differentiation of human cardiomyocyte progenitor cells into functional cardiomyocytes in vitro. Stem Cell Res 1:138–149PubMedCrossRefGoogle Scholar
  18. 18.
    Itzhaki-Alfia A, Leor J, Raanani E, Sternik L, Spiegelstein D, Netser S, Holbova R, Pevsner-Fischer M, Lavee J, Barbash IM (2009) Patient characteristics and cell source determine the number of isolated human cardiac progenitor cells. Circulation 120:2559–2566PubMedCrossRefGoogle Scholar
  19. 19.
    Tateishi K, Ashihara E, Honsho S, Takehara N, Nomura T, Takahashi T, Ueyama T, Yamagishi M, Yaku H, Matsubara H, Oh H (2007) Human cardiac stem cells exhibit mesenchymal features and are maintained through Akt/GSK-3β signaling. Biochem Biophys Res Commun 352:635–641PubMedCrossRefGoogle Scholar
  20. 20.
    Tokcaer-Keskin Z, Akar AR, Ayaloglu-Butun F, Terzioglu-Kara E, Durdu S, Ozyurda U, Ugur M, Akcali KC (2009) Timing of induction of cardiomyocyte differentiation for in vitro cultured mesenchymal stem cells: a perspective for emergencies. Can J Physiol Pharmacol 87:143–150PubMedCrossRefGoogle Scholar
  21. 21.
    Widera D, Zander C, Heidbreder M, Kasperek Y, Noll T, Seitz O, Saldamli B, Sudhoff H, Sader R, Kaltschmidt C, Kaltschmidt B (2009) Adult palatum as a novel source of neural crest-related stem cells. Stem Cells 27:1899–1910PubMedCrossRefGoogle Scholar
  22. 22.
    Carlotti F, Bazuine M, Kekarainen T, Seppen J, Pognonec P, Maassen JA, Hoeben RC (2004) Lentiviral vectors efficiently transduce quiescent mature 3T3–L1 adipocytes. Mol Ther 9:209–217PubMedCrossRefGoogle Scholar
  23. 23.
    Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S, Marshak DR (1999) Multilineage potential of adult human mesenchymal stem cells. Science 284:143–147PubMedCrossRefGoogle Scholar
  24. 24.
    Prockop D, Sekiya I, Colter D (2001) Isolation and characterization of rapidly self-renewing stem cells from cultures of human marrow stromal cells. Cytotherapy 3:393–396PubMedCrossRefGoogle Scholar
  25. 25.
    Bartosh T, Wang Z, Rosales A, Dimitrijevich S, Rogue R (2008) 3D-model of adult cardiac stem cells promotes cardiac differentiation and resistance to oxidative stress. J Cell Biochem 105:612–623PubMedCrossRefGoogle Scholar
  26. 26.
    Kawaguchi N, Machida M, Matsuoka R, Takagaki Y (2008) Proteomic analysis of cardiac stem cells derived from adult rat hearts: comparison of the sphere and adherent states of a cardiosphere forming cell clone by protein profiling. Circulation 118: S_281 (abstract) Google Scholar
  27. 27.
    Gwak SJ, Bhang SH, Yang HS, Kim SS, Lee DH, Lee SH, Kim BS (2009) In vitro cardiomyogenic differentiation of adipose-derived stromal cells using transforming growth factor-beta1. Cell Biochem Funct 27:148–154PubMedCrossRefGoogle Scholar
  28. 28.
    Ip HS, Wilson DB, Heikinheimo M, Tang Z, Ting CN, Simon MC, Leiden JM, Parmacek MS (1994) The GATA-4 transcription factor activates the cardiac muscle-specific troponin C promoter-enhancer in nonmuscle cells. Mol Cell Biol 14:7517–7526PubMedGoogle Scholar
  29. 29.
    Charron F, Paradis P, Bronchain O, Nemer G, Nemer M (1999) Cooperative interaction between GATA-4 and GATA-6 regulates myocardial gene expression. Mol Cell Biol 19:4355–4365PubMedGoogle Scholar
  30. 30.
    Manginas A, Goussetis E, Koutelou M, Karatasakis G, Peristeri I, Theodorakos A, Leontiadis E, Plessas N, Theodosaki M, Graphakos S, Cokkinos DV (2007) Pilot study to evaluate the safety and feasibility of intracoronary CD133(+) and CD133(−) CD34(+) cell therapy in patients with nonviable anterior myocardial infarction. Catheter Cardiovasc Interv 69:773–781PubMedCrossRefGoogle Scholar
  31. 31.
    Klein HM, Ghodsizad A, Marktanner R, Poll L, Voelkel T, Mohammad Hasani MR, Piechaczek C, Feifel N, Stockschlaeder M, Burchardt ER, Kar BJ, Gregoric I, Gams E (2007) Intramyocardial implantation of CD133+ stem cells improved cardiac function without bypass surgery. Heart Surg Forum 10:E66–E69PubMedCrossRefGoogle Scholar
  32. 32.
    Makino S, Fukuda K, Miyoshi S, Konishi F, Kodama H, Pan J, Sano M, Takahashi T, Hori S, Abe H, Hata J, Umezawa A, Ogawa S (1999) Cardiomyocytes can be generated from marrow stromal cells in vitro. J Clin Invest 103:93–98CrossRefGoogle Scholar
  33. 33.
    Toma C, Pittenger M, Cahill K, Byrne B, Kessler P (2002) Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation 105:93–98PubMedCrossRefGoogle Scholar
  34. 34.
    Yoon J, Ming B, Kim Y, Shim W, Ro Y, Lim D (2005) Differentiation, engraftment and functional effects of pre-treated mesenchymal stem cells in a rat myocardial infarct model. Acta Cardiol 690:277–284CrossRefGoogle Scholar
  35. 35.
    Lien C, Wu C, Mercer B, Webb R, Richardson J, Olson E (1999) Control of early cardiac-specific transcription of Nkx2–5 by a GATA-dependent enhancer. Development 126:75–84PubMedGoogle Scholar
  36. 36.
    Jahn T, Seipel P, Coutinho S, Urschel S, Schwarz K, Miething C, Serve H, Peschel C, Duyster J (2002) Analysing c-kit internalization using a functional c-kit-EGFP chimera containing the fluorochrome within the extracellular domain. Oncogene 21:4508–4520PubMedCrossRefGoogle Scholar
  37. 37.
    Gargett C, Schwab K, Zillwood R, Nguygen H, Wu D (2009) Isolation and culture of epithelial progenitors and mesenchymal stem cells from human endometrium. Biol Reprod 80:1136–1145PubMedCrossRefGoogle Scholar
  38. 38.
    Vogel W, Grünebach F, Messam C, Kanz L, Brugger W, Bühring H (2003) Heterogeneity among human bone marrow-derived mesenchymal stem cells and neural progenitors. Haematologica 88:126–133PubMedGoogle Scholar
  39. 39.
    Fierro F, Illmer T, Jing D, Schleyer E, Ehninger G, Boxberger S, Bornhäuser M (2007) Inhibition of platelet-derived growth factor receptor beta by imatinib mesylate suppresses proliferation and alters differentiation of human mesenchymal stem cells in vitro. Cell Prolif 40:355–366PubMedCrossRefGoogle Scholar
  40. 40.
    Urbanek K, Rota M, Cascapera S, Bearzi C, Nascimbene A, De Angelis A, Hosoda 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
  41. 41.
    Hattan N, Kawaguchi H, Ando K, Kuwabara E, Fujita J, Murata M, Suematsu M, Mori H, Fukuda K (2005) Purified cardiomyocytes from bone marrow mesenchymal stem cells produce stable intercardiac grafts in mice. Cardiovasc Res 65:334–344PubMedCrossRefGoogle Scholar
  42. 42.
    Zhou Y, Wang S, Yu Z, Hoyt R, Sachdev V, Vincent P, Arai A, Kwak M, Burkett S, Horvath K (2009) Direct injection of autologous mesenchymal stromal cells improves myocardial function. Biochem Biophys Res Commun 390:902–907PubMedCrossRefGoogle Scholar
  43. 43.
    Andersen D, Andersen P, Schneider M, Jensen H, Sheikh S (2009) Murine “cardiospheres” are not a source of stem cells with cardiomyogenic potential. Stem Cells 27:1571–1581PubMedCrossRefGoogle Scholar
  44. 44.
    Koninckx R, Hensen K, Rummens JL, Hendrikx M (2008) Cardiac stem cells in the real world. J Thorac Cardiovasc Surg 136:797–798PubMedCrossRefGoogle Scholar
  45. 45.
    Davis D, Smith R, Marbàn E (2010) Human cardiospheres are a source of stem cells with cardiomyogenic potential. Stem Cells 28:903–904PubMedGoogle Scholar
  46. 46.
    Davis D, Zhang Y, Smith R, Cheng K, Terrovitis J, Malliaras K, Li T, White A, Makkar R, Marbàn E (2009) Validation of the cardiosphere method to culture cardiac progenitor cells from myocardial tissue. Plos One 9:e7195CrossRefGoogle Scholar

Copyright information

© Springer Basel AG 2010

Authors and Affiliations

  • Remco Koninckx
    • 1
    • 2
  • Annick Daniëls
    • 1
  • Severina Windmolders
    • 1
    • 2
  • Françoise Carlotti
    • 3
  • Urbain Mees
    • 4
  • Paul Steels
    • 2
  • Jean-Luc Rummens
    • 1
    • 2
  • Marc Hendrikx
    • 2
    • 4
  • Karen Hensen
    • 1
    Email author
  1. 1.Laboratory of Experimental HematologyJessa HospitalHasseltBelgium
  2. 2.Laboratory of Physiology, Faculty of Medicine, and School of Life SciencesHasselt University, Biomedical Research Institute and Transnational University LimburgDiepenbeekBelgium
  3. 3.Department of Molecular Cell BiologyLeiden University Medical CenterLeidenThe Netherlands
  4. 4.Department of Cardiothoracic SurgeryJessa HospitalHasseltBelgium

Personalised recommendations