Effects of intramuscular injection of heterogeneous umbilical cord mesenchymal stem cells on myocardial cardiac troponin and serum-related factors in rats

doi:10.3969/j.issn.2095-4344.2014.10.014

Abstract

Abstract:

BACKGROUND: Current researches on whether the intramuscular injection of heterogeneous umbilical cord mesenchymal stem cells (UC-MSCs) is safe or not lack theoretical basis.
OBJECTIVE: To explore the effects of intramuscular injection of heterogeneous UC-MSCs on expression of myocardial vascular endothelial growth factor (VEGF), cardiac troponin I (cTnI) and serum VEGF, hepatocyte growth factor (HGF), insulin-like growth factor 1 (IGF-1) and granulocyte macrophage colony stimulating factor (GM-CSF) in normal Wistar rats.
METHODS: A total of 60 Wistar rats were divided into six groups randomly. Rats in the six groups were respectively administrated with intramuscular injection of PBS, Dulbecco’s modified Eagle’s medium, hUC-MSC supernatant, 0.25×10⁵, 1.0×10⁵, 4.0×10⁵hUC-MSCs. Rats received a second intramuscular injection 4 weeks after first injection. Eight weeks later, the blood sample and myocardial tissue were taken. The serum concentration of VEGF, HGF, IGF-1 and GM-CSF were measured with enzyme-linked immunosorbent assay kit. The myocardial VEGF and cTnI expression were detected by immunohistochemical technique.
RESULTS AND CONCLUSION: There was no significant difference in the serum concentration of the VEGF, HGF, IGF-1 and GM-CSF among the groups before and after injection (P > 0.05). In the same group, no statistical significant changes in the serum concentration of the VEGF, HGF, IGF-1 and GM-CSF were found among the rats before and after injection (P > 0.05). Eight weeks after injection, weak positive expression of the VEGF in the cytoplasm of cardiocytes in the six groups was observed, and strong positive expression of the cTnI in the cytoplasm of cardiocytes in the six groups was observed. There was no significant difference in the VEGF and cTnI content in the myocardium among the groups (P > 0.05). Intramuscular injection of hUC-MSCs or the supernatant of hUC-MSCs had no effects on the serum concentration of the VEGF, HGF, IGF-1, GM-CSF and the myocardial VEGF and cTnI expression in normal Wistar rats.

中国组织工程研究杂志出版内容重点：干细胞；骨髓干细胞；造血干细胞；脂肪干细胞；肿瘤干细胞；胚胎干细胞；脐带脐血干细胞；干细胞诱导；干细胞分化；组织工程

全文链接：

Key words: stem cells, umbilical cord, mesenchymal stem cells, troponin I, vascular endothelial growth factors, hepatocyte growth factor

CLC Number:

R394.2

Wang Si-ping, Nie Na-na, Wang Li, Li Zi-pu. Effects of intramuscular injection of heterogeneous umbilical cord mesenchymal stem cells on myocardial cardiac troponin and serum-related factors in rats[J]. Chinese Journal of Tissue Engineering Research, 2014, 18(10): 1566-1572.

Figures/Tables 5

References

[1]Mollova M, Bersell K, Walsh S, et al. Cardiomyocyte proliferation contributes to heart growth in young humans. Proc Nat Acad Sci USA. 2013;110: 1446-1451.
[2]Laflamme MA, Murry CE. Heart regeneration. Nature. 2011; 473:326-335.
[3]Jacobs SA, Roobrouck VD, Verfaillie CM, et al. Immunological characteristics of human mesenchymal stem cells and multipotent adult progenitor cells. Immunol Cell Biol. 2013;91(1): 32-39.
[4]林晓波,何红燕,罗敏杰,等.人脐带间充质干细胞向心肌样细胞分化的研究[J].实用儿科临床杂志,2007,22(13):971-973.
[5]Liu P,Lin JH,Zhang B,et al.Differential regulation of cadherin expression by osteotropic hormones and growth factors in vitro in human osteoprogenitor cells .Acta Pharmacol Sin. 2005;26(6):705-713.
[6]Kim DW, Staples M, Shinozuka K, et al.Wharton's Jelly-Derived Mesenchymal Stem Cells: Phenotypic Characterization and Optimizing Their Therapeutic Potential for Clinical Applications.Int J Mol Sci. 2013;14(6):11692-11712.
[7]Hsieh JY, Wang HW, Chang SJ, et al.Mesenchymal stem cells from human umbilical cord express preferentially secreted factors related to neuroprotection, neurogenesis, and angiogenesis.PLoS One. 2013;8(8):e72604.
[8]Nartprayut K, U-Pratya Y, Kheolamai P, et al.Cardiomyocyte differentiation of perinatally-derived mesenchymal stem cells. Mol Med Rep. 2013;7(5):1465-1469.
[9]Maureira P, Marie PY, Yu F, et al.Repairing chronic myocardial infarction with autologous mesenchymal stem cells engineered tissue in rat promotes angiogenesis and limits ventricular remodeling.J Biomed Sci.2012;12:19-93.
[10]Wang Y, Han ZB, Ma J,et al.A toxicity study of multiple-administration human umbilical cord mesenchymal stem cells in cynomolgus monkeys.Stem Cells Dev. 2012; 10;21(9):1401-1408.
[11]Ma N, Stamm C, Kaminski A, et al. Human cord blood cells induce angiogenesis following myocardial infarction in NOD/scid mice. Cardiovasc Res. 2005;66(1):45-54.
[12]Breitbach M, Bostani T, Roell W, et al. Potential risks of bone marrow cell transplantation into infarcted hearts. Blood. 2007; 110(4): 1362-1369.
[13]Widimsky P,Penicka M. Complications after intracoronary stem cell transplantation in idiopathic dilated cardiomyopathy. Int J Cardiol. 2006;111(1):178-179.
[14]Yoon YS, Park JS, Tkebuchava T, et al.Unexpected severe calci?cation after transplantation of bone marrow cells in acute myocardial infarction. Circulation. 2004;109(25): 3154-3157.
[15]Shabbir A, Zisa D, Leiker M, et al. Muscular dystrophy therapy by nonautologous mesenchymal stem cells: muscle regeneration without immunosuppression and inflammation. Transplantation. 2009;87(9):1275-1282.
[16]Shabbir A, Zisa D, Suzuki G, et al. Heart failure therapy mediated by the trophic activities of bone marrow mesenchymal stem cells: a noninvasive therapeutic regimen. Am J Physiol. 2009;296(6):H1888-1897.
[17]张美荣,张学峰,胡建霞,等.大鼠肌肉注射移植人脐带间充质干细胞的安全性[J].中国组织工程研究与临床康复,2010,14(27): 4997-5000.
[18]Gnecchi M, Danieli P, Cervio E.Mesenchymal stem cell therapy for heart disease.Vascul Pharmacol. 2012;19;57(1):48-55.
[19]van den Akker F, Deddens JC, Doevendans PA, et al. Cardiac stem cell therapy to modulate inflammation upon myocardial infarction.Biochim Biophys Acta.2013;1830(2):2449-2458.
[20]Mohammadi Gorji S, Karimpor Malekshah AA, Hashemi-Soteh MB, et al .Effect of mesenchymal stem cells on Doxorubicin-induced fibrosis. Cell J. 2012;14(2):142-151.
[21]Suzuki MI,Haider H,Jiang S,et al. 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 (4):545-555.
[22]Huang J, Zhang Z, Guo J,et al. Genetic modify of mesenchymal stem cells overexpressing CCR1 increases cell viability, migration, engraftment, and capillary density in the injured myocardium. Circ Res. 2010;106 (11): 1753-1762.
[23]Hatzistergos KE, Quevedo H, Oskouei BN, et al. Bone marrow mesenchymal stem cells stimulate cardiac stem cell proliferation and differentiation. Circ Res. 2010;107(7):913-922.
[24]Zisa D,Shabbir A,Suzuki G,et al. Vascular endothelial growth factor (VEGF) as a key therapeutic tropic factor in bone marrow mesenchymal stem cell-mediated cardiac repair. Biochem Biophys Res Commun. 2009;390(3):834-838.
[25]Mazhari R,Hare JM.Mechanisms of action of mesenchymal stem cells in cardiac repair: potential in?uences on the cardiac stem cell niche. Nat Clin Pract Cardiovasc Med.2007; 4(Suppl 1):S21-26.
[26]Gnecchi M, He H,Liang OD,et al. Paracrine action accounts for marked protection of ischemic heart by Akt-modi?ed mesenchymal stem cells. Nat Med. 2005;11(4):367-368.
[27]Lee RH, Pulin AA., Seo MJ, et al .Intravenous hMSCs improvemyocardial infarction inmice because cells embolized in lung are activated to secrete the anti-in?ammatory protein TSG-6.Cell Stem Cell. 2009;5(1): 54-63.
[28]Yancopoulos GD, Davis S, Gale NW,et al.Vascular-specific growth factors and blood vessel formation. Nature. 2000;407: 242-248.
[29]Fang J, Chen L, Fan L, et al .Enhanced therapeutic effects of mesenchymal stem cells on myocardial infarction by ischemic postconditioning through paracrine mechanisms in rats.J Mol Cell Cardiol. 2011;51(5):839-847.
[30]Tiwari RP, Jain A, Khan Z, et al.Cardiac troponins I and T: molecular markers for early diagnosis, prognosis, and accurate triaging of patients with acute myocardial infarction. Mol Diagn Ther.2012;16(6):371-381.
[31]Iwasaki H, Kawamoto A, Willwerth C,et al.Therapeutic potential of unrestricted somatic stem cells isolated from placental cord blood for cardiac repair post myocardial infarction. Arterioscler Thromb Vasc Biol. 2009;29(11): 1830-1835.
[32]Wen Z, Zheng S, Zhou C, et al.Repair mechanisms of bone marrow mesenchymal stem cells in myocardial infarction.J Cell Mol Med. 2011;15(5):1032-1043.
[33]Kamdar F, Jameel MN, Score P, et al.Cellular therapy promotes endogenous stem cell repair.Can J Physiol Pharmacol. 2012;90(10):1335-1344.
[34]Laflamme MA, Zbinden S, Epstein SE,et al. Cell-based therapy for myocardial ischemia and infarction: pathophysiological mechanism.Annu Rev Pathol. 2007;2:307-309.
[35]Taniyama Y, Morishita R, Aoki M,et al.Angiogenesis and antifibrotic action by hepatocyte growth factor in cardiomyopathy.Hypertension. 2002;40(1):47-53.
[36]Kinnaird T, Stabile E, Burnett MS,et al.Marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in-vitro and in-vivo arteriogenesis through paracrine mechanisms.Circ Res. 2004;94(5):678-685.
[37]Lamblin N, Bauters A, Fertin M, et al.Circulating levels of hepatocyte growth factor and left ventricular remodelling after acute myocardial infarction (from the REVE-2 study).Eur J Heart Fail. 2011;13(12):1314-1322.
[38]Liu TB, Fedak PW, Weisel RD,et al.Enhanced IGF-1 expression improves smooth muscle cell Engraftment after cell transplantation. Am J Physiol Heart Circ Physiol. 2004; 287(6):H2840-2849.
[39]Zhao QB,Sun CF,Xu X,et al.CD34+ cell mobilization and upregulation of myocardial cytokines in a rabbit model of myocardial ischemia.Int J Cardiol. 2011;152(1):18-23.
[40]Fishbein MC, Wang T, Matijasevic M,et al.Myocardial tissue troponins T and I. An immunohistochemical study in experimental models of myocardial ischemia. Cardiovasc Pathol. 2003;12(2):65-71.
[41]Gu JW, Adair TH.Hypoxia-induced expression of VEGF is reversible in myocardial vascular smooth muscle cells. Am J Physiol. 1997;273:H628-633.
[42]Welch S, Plank D, Witt S, et al. Cardiac-specific IGF-1 expression attenuates dilated cardiomyopathy in tropomodulin-overexpressing transgenic mice. Circ Res. 2002;90(6):641-648.
[43]陶则伟,李隆贵,耿召华,等.自体间充质干细胞植入促进大鼠衰竭心肌生长因子表达、改善心室重构和心功能[J].中华心血管病杂志,2009,37(6):495-500.
[44]Yamaguchi H, Komamura K, Choraku M, et al.Impact of serum insulin-like growth factor-1 on early prognosis in acute myocardial infarction. Intern Med. 2008;47(9):819-825.
[45]Nagaya N, Fujii T, Iwase T, et al. Intravenous administration of mesenchymal stem cells improves cardiac function in rats with acute myocardial infarction through angiogenesis and myogenesis. Am J Physiol Heart Circ Physiol. 2004;287(6): H2670-2676.
[46]Cho HJ,Lee N,Lee JY,et al. Role of host tissues for sustained humoral effects after endothelial progenitor cell transplantation into the ischemic heart.J Exp Med. 2007;204(13):3257-3269.