Stimulation of autologous progenitorial and committed cells in ischemically damaged myocardium

Summary. Local progenitor cells are present in all tissues, including the myocardium. Stimulation of these cells can significantly improve the efficiency of the regeneration process. Biodegradation products of Alloplant biomaterials (ABM) are an inhibitor of fibrosis and serve as an inducer of stem cells in various body tissues including smooth and skeletal muscles, as well as connective tissue.

Aim. To determine the cell regenerative potential of progenitorial c-kit and committed GATA-4 cells in ischemic myocardium on the background of ABM application in chronic experiment.

Materials and methods. 100 Wistar rats weighing 180-200g were used, that underwent  ligation of coronary artery. In the experimental group (n = 50), 600 μl of a physiological solution containing 12 mg of ABM was administered simultaneously with coronary occlusion. General histological studies (hematoxylin and eosin staining, and staining as per Mallory), immunohistochemical (c-kit, GATA-4) and morphometric studies (determination of the index of the scar's area, counting of stained cells) were carried out. The statistical processing of the results was carried out using the rank methods - single factor dispersion analysis as per Kruskalou-Wallace and the comparison of uncorrelated data by the Mann-Whitney method.

Results. When using ABM during coronary occlusion, myocardium was characterized by a statistically significant (p <0.0001) prevalence of c-kit⁺ / GATA-4⁺ cells numbers throughout the follow-up period (3-45 days). These cells were localized mainly in the granulation tissue of the peri-cicatricial area, bordering on the preserved cardiac muscle tissue. In the peri-cicatricial area, cardiac cells had a different degree of maturity - from poorly differentiated forms (without clear ultrastructural signs of cardiomyogenic orientation) to young cardiomyocytes. In the presence of ABM, coronary occlusion was characterized by statistically significantly smaller values of the index of the scar's area (p <0,05 ÷ <0,0001).

Conclusion. ABM degradation products are chemoattractants for c-kit cells and promote their differentiation into cardiomyogenic GATA-4 cells, which contributes to more successful myocardium repair.

1. Anversa P, Kajstura J, Rota M et al. Regenerating new heart with stem cells. J Clin Invest. 2013;123(1): 62–70. doi: 10.1172/JCI63068.

2. Bergmann О. Stadies of myocardial regeneration. Stockholm. Published by Karolinska Institutet 2010: p 35. ISBN 978-91-7457-114-1.

3. Lebedev AI. spongiform biomaterial – inductor misallocation in damaged skeletal muscle. Uspechi sovremennoi biologii 2016; 3: 276-284.

4. Lebedevа A I. Spongiform biomaterial - inhibitor of fibrosis of damaged skeletal muscle. Russуiskyi biotherapeuticheskyi journal 2014; 4 (13): 37-44.

5. Guidance on laboratory animals and alternative models in biomedical research / NN Karkishchenko, SV Grachev.- M.: Profile-2C. 2010: р.358.

6. van Berlo JH, Kanisicak O, Maillet M et al. C-kit+ cells minimally contribute cardiomyocytes to the heart. Nature 2014; 509:337–341. doi:10.1038/nature13309.

7. Lu L, Li F, Lu J. Identification of functional tissue-resident cardiac stem/progenitor cells in adult mouse. Cell Biology International Reports 2012; l, Is.1:15–22. doi:10.1042/CBR20120001.

8. Kurchatova NN, Siberyaс SV, Khasanov RA et al. Migration of mesenchymal stem cells in biomaterials ALLOPLANT: preliminary data. Immunologiya Urala 2005;1,4: 17-18

9. Li L, Wu Sh, Liu Zh et al. Ultrasound-Targeted Microbubble Destruction Improves the Migration and Homing of Mesenchymal Stem Cells after Myocardial Infarction by Upregulating SDF-1/CXCR4: A Pilot Study. Stem Cells Int. 2015: 14p. 691310. doi: 10.1155/2015/691310 PMCID: PMC4436519.

10. Shahov VP, Popov SV. Stem cells and cardiomyogenesis in norm and pathology. Tomsk 2004: 4-38 (Шахов В.П., Попов С.В. Стволовые клетки и кардиомиогенез в норме и патологии. Томск 2004: 4-38.)

11. Oka T, Maillet M, Watt A et al. Cardiac-specific deletion of Gata4 reveals its requirement for hypertrophy, compensation, and myocyte viability. Circ Res. 2006; 98:837–845. DOI:10.1161/01.RES.0000215985.18538.c4

12. TianY, Liu Y, Wang T et al. A microRNA-Hippo pathway that promotes cardiomyocyte proliferation and cardiac regeneration in mice. Science Translational Medicine 2015; 7, 279: 279-338. DOI: 10.1126/scitranslmed.3010841.

13. Lebedevа AI. Regulation of parenchymal-stromal relationship for the correction of defects of skeletal muscle allogenic biomaterial. Experimental and clinical dermatocosmetology 2014; 1: 51-56.

14. Serov VV, Shehter AB. Connective tissue. M.: Medicina 1981:p 312 (Серов В.В., Шехтер А.Б. Соединительная ткань. М.: Медицина 1981:с. 312.)

15. Lebedevа AI., Muslimov SA., Gareev EM. et al. Morphological features of macrophages and their cytokine profile in the regeneration of skeletal muscle plastic surgery allogenic spongy biomaterial. Cytokines and inflammation 2015; 14(1): 27-33.