TRANSPLANTATION OF GENETIC MODIFIED STEM CELLS OVEREXPRESSING THERAPEUTIC GROWTH FACTORSFOR THE TREATMENT OF EXPERIMENTAL RAT MYOCARDIAL INFARCTION

Cover Page


Cite item

Full Text

Abstract

We tested the hypothesis that simultaneous transgenic overexpression of a select quartet of growth factors activates diverse signaling pathways for mobilization and participation of various stem/progenitor cells for cardiogenesis in the infarcted heart. IGF-1, VEGF, SDF-1α, and HGF plasmids were synthesized and transfected into rat skeletal myoblasts (SM). Overexpression of growth factors in transfected SM (TransSM) was confirmed by reverse transcription PCR, western blotting, and fluorescence immunostaining. The conditioned medium (CM) from TransSM was cytoprotective for cardiomyocytes following H 2O 2 treatment, promoted a higher transwell migration of HUVEC cells and in vitro tube formation. Intramyocardial transplantation of 1.5×10 6 TransSM in a rat model of acute myocardial infarction induced extensive mobilization of stem/progenitor cells into the infarcted heart on day 7 and improved integration of TransSM in the heart compared to NatSM. Extensive neomyogenesis and angiogenesis with resultant attenuation of infarct size and improvement in global heart function was observed at 8 weeks. In conclusion, simultaneous activation of diverse signaling pathways by overexpression of multiple growth factors caused massive mobilization and homing of stem/progenitor cells from peripheral circulation, the bone marrow, and the heart for accelerated repair of the infarcted myocardium.

Full Text

ТРАНСПЛАНТАЦИЯ ГЕНЕТИЧЕСКИ МОДИФИЦИРОВАННЫХ СТВОЛОВЫХ КЛЕТОК, ПОВЫШЕННО ЭКСПРЕССИРУЮЩИХ ТЕРАПЕВТИЧЕСКИЕ РОСТОВЫЕ ФАКТОРЫ,ПРИ ЛЕЧЕНИИ ЭКСПЕРИМЕНТАЛЬНОГО ИНФАРКТА МИОКАРДА КРЫС
×

References

  1. Singla DK. Stem cells in the infarcted heart. J Cardiovasc Transl Res 2010; 3:73-78.
  2. P Menasche , A A Hagege, M Scorsin, B Pouzet, M Desnos, et al. Myoblast transplantation for heart failure. Lancet 2001;357: 279-280.
  3. P Menasche , O Alfieri, S Janssens, W McKenna, H Reichenspurner, L Trinquart, et al. The Myoblast Autologous Grafting in Ischemic Cardiomyopathy (MAGIC) trial: first randomized placebo-controlled study of myoblast transplantation. Circulation 2008; 117:1189-1200.
  4. KC Wollert, GP Meyer, J Lotz, S Ringes- Lichtenberg, P Lippolt, C Breidenbach, S Fichtner, et al. Intracoronary autologous bone-marrow cell transfer after myocardial infarction: the BOOST randomised controlled clinical trial. Lancet 2004;364:141-148.
  5. BZ Atkins, MT Hueman, J Meuchel, KA Hutcheson, et al. Cellular cardiomyoplasty improves diastolic properties of injured heart. J Surg Res 1999; 85:234-242.
  6. DA Taylor, BZ Atkins, P Hungspreugs, TR Jones, MC Reedy, KA Hutcheson, et al. Regenerating functional myocardium: improved performance after skeletal myoblast transplantation. Nat Med 1998; 4: 929-933.
  7. M Perez-Ilzarbe, O Agbulut, B Pelacho, C Ciorba, E San JoseEneriz, M Desnos, AA Hagege, P Aranda, EJ Andreu, P Menasche and F Prosper. Characterization of the paracrine effects of human skeletal myoblasts transplanted in infarcted myocardium. Eur J Heart Fail 2008;10:1065-1072.
  8. J Kajstura, M Rota, B Whang, S Cascapera, T Hosoda, C Bearzi, D Nurzynska, H Kasahara, E Zias, et al. Bone marrow cells differentiate in cardiac cell lineages after infarction independently of cell fusion. Circ Res 2005;96:127-137.
  9. R Uemura, M Xu, N Ahmad and M Ashraf. Bone marrow stem cells prevent left ventricular remodeling of ischemic heart through paracrine signaling. Circ Res 2006;98: 1414-1421.
  10. K Jujo, M Ii and DW Losordo. EPC in neovascularization of infarcted myocardium. J Mol Cell Cardiol 2008;45: 530-544.
  11. B Dawn, AB Stein, K Urbanek, M Rota, B Whang, R Rastaldo, D Torella, XL Tang, A Rezazadeh, et al. Cardiac stem cells delivered intravascularly traverse the vessel barrier, regenerate infarcted myocardium, and improve cardiac function. Proc Natl Acad Sci USA 2005;102:3766-3771.
  12. M Rota, ME Padin-Iruegas, Y Misao, A De Angelis, S Maestroni, J Ferreira-Martins, E Fiumana, R Rastaldo, ML Arcarese, et al. Local activation or implantation of cardiac progenitor cells rescues scarred infarcted myocardium improving cardiac function. Circ Res 2008;103:107-116.
  13. A Banfi, ML Springer ,HM Blau. Myoblast- mediated gene transfer for therapeutic angiogenesis. Methods Enzymol 2002;346:145-157.
  14. MI Niagara, H Haider, S Jiang, M Ashraf. Pharmacologically preconditioned skeletal myoblasts are resistant to oxidative stress and promote angiomyogenesis via release of paracrine factors in the infarcted heart. Circ Res 2007;100:545-555.
  15. M Konoplyannikov, Haider KH, Lai VK, Ahmed RP, Jiang S, Ashraf M. Activation of diverse signaling pathways by ex-vivo delivery of multiple cytokines for myocardial repair. Stem Cells Dev 2013. Jan 15; 22(2): 204-15.
  16. MA Stagg, SR Coppen, K Suzuki, A Varela-Carver, J Lee, NJ Brand, S Fukushima, MH Yacoub, CM Terracciano. Evaluation of frequency, type, and function of gap junctions between skeletal myoblasts overexpressing connexin43 and cardiomyocytes: relevance to cell transplantation. Faseb J 2006; 20:744-746.
  17. Jiang S, H Haider, NM Idris, A Salim, M Ashraf. Supportive interaction between cell survival signaling and angiocompetent factors enhances donor cell survival and promotes angiomyogenesis for cardiac repair. Circ Res 2006; 99:776-784.
  18. G Lu, HK Haider, S Jiang and M Ashraf. Sca-1+ stem cell survival and engraftment in the infarcted heart: dual role for preconditioning-induced connexin. Circulation 2009;119: 2587-96.
  19. HW Kim, HK Haider, S Jiang and M Ashraf. Ischemic preconditioning augments survival of stem cells via miR-210 expression by targeting caspase-8-associated protein 2. J Biol Chem 2009; 284: 33161-168.
  20. JY Hahn, HJ Cho, HJ Kang, TS Kim, MH Kim, JH Chung, JW Bae, BH Oh, YB Park and HS Kim. Pre-treatment of mesenchymal stem cells with a combination of growth factors enhances gap-junction formation, cytoprotective effect on cardiomyocytes, and therapeutic efficacy for myocardial infarction. J Am Coll Cardiol 2008; 51: 933-43.
  21. KM Sutton, S Hayat, NM Chau, S Cook, J Pouyssegur, A Ahmed, N Perusinghe, et al. Selective inhibition of MEK1/2 reveals a differential requirement for ERK1/2 signalling in the regulation of HIF-1 in response to hypoxia and IGF-1. Oncogene 2007; 26: 3920-29.
  22. M Pedersen, T Lofstedt, J Sun, L Holmquist- Mengelbier, S Pahlman, L Ronnstrand. Stem cell factor induces HIF-1α at normoxia in hematopoietic cells. Biochem Biophys Res Commun 2008; 377: 98-103.
  23. N Ferrara, HP Gerber, J LeCouter. The biology of VEGF and its receptors. Nat Med 2003; 9: 669-76.
  24. HP Gerber, AK Malik, GP Solar, D Sherman, XH Xiang, G Meng, K Hong, JC Marsters, N Ferrara. VEGF regulates haematopoietic stem cell survival by an internal autocrine loop mechanism. Nature 2002; 417: 954-58.
  25. RJ Lee, ML Springer, WE Blanco-Bose, R Shaw, PC Ursell, HM Blau. VEGF gene delivery to myocardium: deleterious effects of unregulated expression. Circulation 2000;102: 898-901.
  26. A Linke, P Muller, D Nurzynska, C Casarsa, D Torella, A Nascimbene, et al. Stem cells in the dog heart are self-renewing, clonogenic, and multipotent and regenerate infarcted myocardium, improving cardiac function. Proc Natl Acad Sci USA 2005; 102: 8966-71.
  27. R Madonna, G Rokosh, R De Caterina, R Bolli. Hepatocyte growth factor/Met gene transfer in cardiac stem cells-potential for cardiac repair. Basic Res Cardiol 2010; 105: 443-52.
  28. K Tambara, GU Premaratne, G Sakaguchi, N Kanemitsu, X Lin, H Nakajima, et al. Administration of control-released hepatocyte growth factor enhances the efficacy of skeletal myoblast transplantation in rat infarcted hearts by greatly increasing both quantity and quality of the graft. Circulation 2005;112: I129-34.
  29. M Iwasaki, Y Adachi, T Nishiue, K Minamino, Y Suzuki, Y Zhang, et al. Hepatocyte growth factor delivered by ultrasound-mediated destruction of microbubbles induces proliferation of cardiomyocytes and amelioration of left ventricular contractile function in Doxorubicin-induced cardiomyopathy. Stem Cells 2005; 23: 1589-97.
  30. A Poppe, P Golsong, B Blumenthal, R von Wattenwyl, P Blanke, F Beyersdorf, C Schlensak, M Siepe. Hepatocyte growth factor-transfected skeletal myoblasts to limit the development of post-infarction heart failure. Artif Organs 2011; 36: 238-46.
  31. AT Askari, S Unzek, ZB Popovic, CK Goldman, F Forudi, M Kiedrowski, A Rovner, SG Ellis, et al. Effect of stromal-cell-derived factor 1 on stem-cell homing and tissue regeneration in ischaemic cardiomyopathy. Lancet 2003; 362: 697-703.
  32. M Grunewald, I Avraham, Y Dor, E Bachar-Lustig, A Itin, S Jung, S Chimenti, et al. VEGF-induced adult neovascularization: recruitment, retention, and role of accessory cells. Cell 2006; 124:175-189.
  33. S Aharinejad, D Abraham, P Paulus, K Zins, M Hofmann, W Michlits, et al. Colony-stimulating factor-1 transfection of myoblasts improves the repair of failing myocardium following autologous myoblast transplantation. Cardiovasc Res 2008; 79: 395-404.
  34. M Bialas, Krupka M ,Janeczek A, Rozwadowska N, et al. Transient and stable transfections of mouse myoblasts with genes coding for pro-angiogenic factors. J Physiol Pharmacol 2011; 6: 219-28.
  35. B Blumenthal, P Golsong, A Poppe, C Heilmann, C Schlensak, F Beyersdorf, M Siepe. Polyurethane scaf-folds seeded with genetically engineered skeletal myoblasts: a promising tool to regenerate myocardial function. Artif Organs 2011; 34: E46-E54.
  36. B Heissig, K Hattori, S Dias, M Friedrich, B Ferris, NR Hackett, RG Crystal, et al. Recruitment of stem and progenitor cells from the bone marrow niche requires MMP-9 mediated release of kit-ligand. Cell 2002; 109: 625-37.
  37. Sang QX. Complex role of matrix metalloproteinases in angiogenesis. Cell Res 1998; 8: 171-77.
  38. Steve E, Jones CJ. Secreted frizzled-related proteins: searching for relationships and patterns. Bio Essays 2002; 24: 811-20.
  39. M Mirotsou, Z Zhang, A Deb, L Zhang, M Gnecchi, N Noiseux, H Mu, A Pachori, V Dzau. Secreted frizzled related protein 2 (Sfrp2) is the key Akt-mesenchymal stem cell-released paracrine factor mediating myocardial survival and repair. Proc Natl Acad Sci USA 2007; 104: 1643-48.
  40. Z Zhang, A Deb, A Pachori, W He, J Guo, et al. Secreted frizzled related protein 2 protects cells from apoptosis by blocking the effect of canonical Wnt3a. J Mol Cell Cardiol 2009; 46: 370-77.
  41. W He, L Zhang, A Ni, Z Zhang, M Mirotsou, et al. Exogenously administered secreted frizzled related protein 2 (Sfrp2) reduces fibrosis and improves cardiac function in a rat model of myocardial infarction. Proc Natl Acad Sci USA 2010; 107: 21110-15.
  42. H Laeremans, TM Hackeng, MA van Zandvoort, VL Thijssen, BJ Janssen, HC Ottenheijm, et al. Blocking of frizzled signaling with a homologous peptide fragment of Wnt3a/Wnt5a reduces infarct expansion and prevents the development of heart failure after myocardial infarction. Circulation 2011;124:1626-35.
  43. L Formigli, F Francini, A Tani, R Squecco, D Nosi, L Polidori, S Nistri, L Chiappini, V Cesati, et al. Morphofunctional integration between skeletal myoblasts and adult cardiomyocytes in coculture is favored by direct cell-cell contacts and relaxin treatment. Am J Physiol Cell Physiol 2005; 288: C795-C804.
  44. H Reinecke, E Minami, V Poppa and CE Murry. Evidence for fusion between cardiac and skeletal muscle cells. Circ Res 2004; 94: e56-e60.

Supplementary files

Supplementary Files
Action
1. JATS XML
Download

Copyright (c) 2013 Konoplyannikov M.A., Haider K.K., Ashraf M.

Creative Commons License
This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License.
СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77 - 38032 от 11 ноября 2009 года.


This website uses cookies

You consent to our cookies if you continue to use our website.

About Cookies