Share This Article:

Engraftment of pre-differentiated stem cells into cardiomyocytes in an animal model of ischemic cardiopathy

DOI: 10.4236/scd.2014.41001    3,903 Downloads   6,978 Views   Citations

ABSTRACT

Stem cell therapy for cardiac infarct regeneration has been widely used in clinical research. Despite the fact that important advances in this field have been reached, the observed recovery does not demonstrate new cardiac muscle formation. Benefits have been observed due to an improvement in neovascularisation. The main objective of this study was to determine if pre-differentiated stem cells into cells of myocardic lineage are capable of engraftment in animal models with induced cardiac infarct and are capable of truly differentiating into myocardiocytes. Bone marrow rat stem cells were pre-differentiated with 5-AZ. After 4 weeks, pre-differentiated stem cells express muscarinic 1, 2 and β adrenergic 2 receptors. Also, proteins such as sarcomeric α-actin, cardiac myosin heavy chain, desmin and vimentin were detected by immunocytochemistry. Cells were transplanted intracardialy in an ischemic cardiac rat model. Pre-differentiated or non differentiated cells were transplanted after 4 weeks post infarct induction. Histopathology of the hearts was made 2 weeks after cell transplantation. Typical granulated tissue, scare formation and neovascularisation were observed in both groups. However, in those hearts from rats inoculated with pre-differentiated cells many appeared atypical and were α-actin sarcomeric positive. These events suggest that pre-differentiated cells conserve some muscle characteristic traits in situ that at least last for two weeks after transplantation.

Conflicts of Interest

The authors declare no conflicts of interest.

Cite this paper

Gonzalez-Garza, M. , Alcaraz, C. , Gonzalez-Jara, L. , Arcos, D. and Cuevas, J. (2014) Engraftment of pre-differentiated stem cells into cardiomyocytes in an animal model of ischemic cardiopathy. Stem Cell Discovery, 4, 1-7. doi: 10.4236/scd.2014.41001.

References

[1] Hamano, K., Nishida, M., Hirata, K., Mikamo, A., Li, T.S., Harada, M., et al. (2001) Local implantation of autologous bone marrow cells for therapeutic angiogenesis in patients with ischemic heart disease: Clinical trial and preliminary results. Japanese Circulation Journal, 65, 845-847. http://dx.doi.org/ 10.1253/jcj.65.845
[2] Strauer, B.E., Brehm, M., Zeus, T., K?stering, M., Hernandez, A., Sorg, R.V., et al. (2002) Repair of infarcted myocardium by autologous intracoronary mononuclear bone marrow cell transplantation in humans. Circulation, 106, 1913-1918.
[3] Tamm, C., Westphal, B., Kleine, H.D., Petzsch, M., Kittner, C., Klinge, H., et al. (2003) Autologous bone marrow stem cell transplantation for myocardial regeneration. Lancet, 361, 45-46.
http://dx.doi.org/10.1016/S0140-6736(03)12110-1
[4] Tse, H.F., Kwong, Y.L., Chan, J.K.F., Lo, G., Ho, C.L. and Lau, C.P. (2003) Angiogenesis in ischaemic myocardium by intramyocardial autologous bone marrow mononuclear cell implantation. Lancet, 361, 47-49. http://dx.doi.org/10.1016/S0140-6736(03)12111-3
[5] Wollert, K.C., Meyer, G.P., Lotz, J., Ringes-Lichtenberg, S., Lippolt, P., Breidenbach, C., et al. (2004) Intracoronary autologous bone marrow cell transfer after myocardial infarction: The BOOST randomised controlled clinical trial. Lancet, 364, 141-148. http://dx.doi.org/10.1016/S0140-6736 (04)16626-9
[6] Kang, H.J., Kim, H.S., Zhang, S.Y., Park, K.W., Cho, H.J., Koo, B.K., et al (2004) Effects of intracoronary infusion of peripheral blood stem cells mobilised with granulocyte-colony stimulating factor on left ventricular systolic function and restenosis after coronary stenting in myocardial infarction: The MAGIC cell randomised clinical trial. Lancet, 363, 751-756. http://dx.doi.org/10.1016/S0140-6736 (04)15689-4
[7] Fuchs, S., Satler, L.F., Kornowski, R., Okubagzi, P., Weisz, G., Baffour, R., et al. (2003) Catheter based autologous bone marrow myocardial injection in no-option patients with advanced coronary artery disease. Journal of the American College of Cardiology, 41, 1721-1724. http://dx.doi.org/ 10.1016/S0735-1097(03)00328-0
[8] Perin, E.C., Dohmann, H.F, , Borojevic, R., Silva, S.A., Sousa, A.L., et al. (2003) Transendocardial, autologous bone marrow cell transplantation for severe, chronic ischemic heart failure. Circulation, 107, 2294-2302. http://dx.doi.org/10.1161/01.CIR.0000070596.30552.8B
[9] Assmus, B., Schachinger, V., Teupe, C., Britten, M., Lehmann, R., Dobert, N., et al. (2002) Transplantation of progenitor cells and regeneration enhancement in acute myocardial infarction (TOPCARE-AMI) Circulation, 106, 3009-3017. http://dx.doi.org/10.1161/01.CIR.0000043246.74879. CD
[10] Avilés, F.F., San Román, J.A., García Frade, J, , Valdés. M., Sánchez, A., de la Fuente, L., et al. (2004) Intracoronary stem cell transplantation in acute myocardial infarction. Revista Espa?ola de Cardiologia, 57, 201-208. http://dx.doi.org/10.1016/S1885-5857(06)60137-0
[11] Fischer-Rasokat, U., Assmus, B., Seeger, F.H, , Honold, J., Leistner, D., Fichtlscherer, S., et al. (2009) A pilot trial to assess potential effects of selective intracoronary bone marrow-derived progenitor cell infusion in patients with nonischemic dilated cardiomyopathy: Final 1-year results of the transplantation of progenitor cells and functional regeneration enhancement pilot trial in patients with nonischemic dilated cardiomyopathy. Circulation Heart Failure, 2, 417-423.
http://dx.doi.org/10.1161/CIRCHEARTFAILURE.109.855023
[12] Balsam, L.B., Wagers, A.J., Christensen, J.L., Kofidis. T., Weissman, I.L. and Robbins, R.C. (2004) Haematopoietic stem cells adopt mature haematopoietic fates in ischaemic myocardium. Nature, 428, 668-673. http://dx.doi.org/10.1038/nature02460
[13] Murry, C.E., Soonpaa, M.H., Reinecke, H., Nakajima, H., Nakajima, H.O., Rubart, M., et al. (2004) Haematopoietic stem cells do not transdifferentiate into cardiac myocytes in myocardial infarcts. Nature, 428, 664-668. http://dx.doi.org/10.1038/nature02446
[14] van der Bogt, K.E., Sheikh, A.Y., Schrepfer, S., Hoyt, G., Cao, F., Ransohoff, K.J., et al. (2008) Comparison of different adult stem cell types for treatment of myocardialischemia. Circulation. 118, S121-S129. http://dx.doi.org/10.1161/CIRCULATIONAHA.107.759480
[15] Ma, N., Ladilov, Y., Moebius, J.M., Ong, L., Piechaczek, C., Dávid, A., et al. (2006) Intramyocardial delivery of human CD133+ cells in a SCID mouse cryoinjury model: Bone marrow vs. cord blood-derived cells. Cardiovascular Research, 71, 158-169. http://dx.doi.org/10.1016/j.cardiores.2006.03. 020
[16] Davy, P., Brienne Walker, B., Wong, L. and Allsopp, R. (2013) Hematopoietic stem cells are a critical sub-population of whole bone marrow in the treatment of myocardial infarction. Stem Cell Discovery, 3, 117-126. http://dx.doi.org/10.4236/scd.2013.32016
[17] Ahmadi, H., Baharvand, H., Ashtiani, S.K., Soleimani, M., Sadeghian, H., Ardekani, J.M., et al. (2007) Safety analysis and improved cardiac function following local autologous transplantation of CD133(+) enriched bone marrow cells after myocardial infarction. Current Neurovascular Research, 4, 153-160. http://dx.doi.org/10.2174/156720207781387141
[18] Kovacic, J.C., Macdonald, P., Feneley, M.P., Muller, D.W., Freund, J., Dodds, A., et al. (2008) Safety and efficacy of consecutive cycles of granulocyte-colony stimulating factor, and an intracoronary CD133+ cell infusion in patients with chronic refractory ischemic heart disease: The G-CSF in angina patients with IHD to stimulate neovascularization (GAIN I) trial. American Heart Journal, 156, 954-963. http://dx.doi.org/10.1016/j.ahj.2008.04.034
[19] Flores-Ramírez, R., Uribe-Longoria, A., Rangel-Fuentes, M.M., Gutiérrez-Fajardo, P., Salazar-Riojas, R., Cervantes-García, D., et al. (2010) Intracoronary infusion of CD133+ endothelial progenitor cells improves heart function and quality of life in patients with chronic post-infarct heart insufficiency. Cardiovascular Revascularization Medicine, 11, 72-78. http://dx.doi.org/10.1016/j.carrev.2009.04. 001
[20] Yerebakan, C., Kaminski, A., Westphal, B., Donndorf, P., Glass, A., et al. (2011) Impact of preoperative left ventricular function and time from infarction on the long-term benefits after intramyocardial CD133(+) bone marrow stem cell transplant. Journal of Thoracic and Cardiovascular Surgery, 142, 1530-1539. http://dx.doi.org/10.1016/j.jtcvs.2011.05.002
[21] Babin-Ebell, J., Sievers, H.H., Charitos, E.I., Klein, H.M., Jung, F., Hellberg, A.K., et al. (2010) Transmyocardial laser revascularization combined with intramyocardial endothelial progenitor cell transplantation in patients with intractable ischemic heart disease ineligible for conventional revascularization: Preliminary results in a highly selected small patient cohort. Journal of Thoracic and Cardiovascular Surgery, 58, 11-16. http://dx.doi.org/10.1016/j.jtcvs.2011.05.002
[22] Goussetis, E., Manginas, A., Koutelou, M., Peristeri, I., Theodosaki, M., Kollaros, N., et al. (2006) Intracoronary infusion of CD133+ and CD133-CD34+ selected autologous bone marrow progenitor cells in patients with chronic ischemic cardiomyopathy: Cell isolation, adherence to the infarcted area, and body distribution. Stem Cells, 24, 2279-2283. http://dx.doi.org/10.1634/stemcells.2005-0589
[23] Makino, S., Fukuda, K., Miyoshi, S., Konishi, F., Kodama, H., Pan, J., Sano, M., et al. (1999) Cardiomyocytes can be generated from marrow stromal cells in vitro. The Journal of Clinical Investigation, 103, 697-705. http://dx.doi.org/10.1172/JCI5298
[24] Hakuno, D., Fukuda, K., Makino, S., Konishi, F., Tomita, Y., Manabe, T., et al. (2002) Bone marrow derived regenerated cardiomyocytes (CMG cells) express functional adrenergic and muscarinic receptors. Circulation, 105, 380-386. http://dx.doi.org/10.1161/hc0302.102593
[25] Xu, C., Police, S., Rao, N. and Carpenter, M.K. (2002) Characterization and enrichment of cardiomyocytes derived from human embryonic stem cells. Circulation Research, 91, 50-58.
http://dx.doi.org/10.1161/01.RES.0000035254.80718.91
[26] Rangappa, S., Fen, C., Lee, E.H., Bongso, A. and Wei, E.S. (2003) Transformation of adult mesenchymal stem cells isolated from the fatty tissue into cardiomyocytes. The Annals of Thoracic Surgery, 75, 775-779. http://dx.doi.org/10.1016/S0003-4975(02)04568-X
[27] Choi, S.C., Yoon, J., Shim, W.J., Ro, Y.M. and Lim, D.S. (2004) 5-azacytidine induces cardiac differentiation of P19 embryonic stem cells. Experimental and Molecular Medicine, 36, 515-523. http://dx.doi.org/10.1038/emm.2004.66
[28] Woodbury, D., Schwarz, E.J., Prockop, D.J. and Black, I.B. (2000) Adult rat and human bone marrow stromal cells differentiate into neurons. Journal of Neuroscience Research, 61, 364-370.
[29] Chen, L.B. Jiang, X.B. and Yang L. (2004) Differentiation of rat marrow mesenchymal stem cells into pancreatic islet beta-cells. World Journal of Gastroenterology, 10, 3016-3020.
[30] Alexanian, A.R., Maiman, D.J., Kurpad, S.N. and Gennarelli, T.A. (2008) In vitro and in vivo characterization of neurally modified mesenchymal stem cells induced by epigenetic modifiers and neural stem cell environment. Stem Cells and Development, 17, 1123-1130. http://dx.doi.org/10. 1089/scd.2007.0212
[31] Chugh, A.R., Beache, G.M., Loughran, J.H., Mewton, N., Elmore, J.B., Kajstura, J., et al. (2012) Administration of cardiac stem cells in patients with ischemic cardiomyopathy: The SCIPIO trial: Surgical aspects and interim analysis of myocardial function and viability by magnetic resonance. Circulation, 126, S54-S64. http://dx.doi.org/10.1161/CIRCULATIONAHA.112.092627
[32] Makkar, R.R., Smith, R.R., Cheng, K., Malliaras, K., Thomson, L.E., Berman, D., et al. (2012) Intracoronary cardiosphere-derived cells for heart regeneration after myocardial infarction (CADUCEUS): A prospective, randomised phase 1 trial. Lancet, 379, 895-904.
http://dx.doi.org/10.1016/S0140-6736(12)60195-0
[33] Malliaras, K., Makkar, R.R., Smith, R.R., Cheng, K., Wu, E., Bonow, R.O., et al. (2013) Intracoronary cardiosphere-derived cells after myocardial infarction: Evidence for therapeutic regeneration in the final 1-year results of the CADUCEUS trial. Journal of American College of Cardiology, in Press. http://dx.doi.org/10.1016/j.jacc.2013.08.724

  
comments powered by Disqus

Copyright © 2019 by authors and Scientific Research Publishing Inc.

Creative Commons License

This work and the related PDF file are licensed under a Creative Commons Attribution 4.0 International License.