PMU-Autor/inn/en
Rohde EvaAbstract
OBJECTIVES
We previously reported that combined transplantation of skeletal myoblasts and AC-133+ cells leads to improved left ventricular function, reduced infarct size and myocardial apoptosis in a model of chronic ischemia. The aim of this study is to elucidate on the possible mechanisms and to assess new implications in increasing cell therapy efficacy in chronic ischemia.
Heart failure was induced by LAD-ligation in nude rats. (a) Homologous skeletal myoblasts (SM), (b) human derived AC-133+ cells (SC), (c) combination of both cells (Comb) and (d) culture medium (CM) were injected in the infarct and peri-infarct area, respectively, four weeks after infarction. Cell engraftment was detected by fluorescence microscopy and confirmed by immunohistochemical techniques. Cardiac gene expression levels of VEFG-A, cardiac troponin, ACTA2, SDF-1, TGF-beta-1, were assessed by RT-PCR.
Both cell types were detected in the injection areas four weeks after cell transplantation. Double cell therapy led to increased cell engraftment (SM: 52+/-13/mm(2), SC: 45+/-8 in the combination group vs. SM: 31+/-9 and 23+/-7 in the monotherapy groups, P=0.007). This effect was confirmed using PCR. Apoptotic index among engrafted cells was significantly lower in the Comb group (Comb: 0.53+/-0.12 for myoblasts and 0.34+/-0.09 for SC, vs. SM: 0.76+/-0.19 and SC: 0.63+/-0.16, P=0.013). Expression of cardiac troponin was higher in the combination group in the peri-infarct area. Evaluation of capillary density revealed increased angiogenesis in the combination group (Comb: 12.3+/-2.3, SM: 5.2+/-1.2, SC: 8.3+/-1.8, P=0.002). Neoangiogenesis was associated with higher levels of VEGF-A and TGF-beta in the injection areas as detected by RT-PCR. The higher SDF-1 expression in the injected areas implies an increased secretion of chemoattractants by the injected cells, which suggests that the effect of combined cell transplantation is mainly associated with paracrine mechanisms.
The mechanism of functional improvement after combined transplantation of skeletal myoblasts and AC-133+ progenitors in ischemic heart failure is mainly associated with increased angiogenesis based on paracrine factors, which leads to improved survival and lower apoptosis rates of the injected cells.
Useful keywords (using NLM MeSH Indexing)
AC133 Antigen
Actinin/metabolism
Animals
Antigens, CD/analysis
Apoptosis*
Cell Survival
Cells, Cultured
Chemokine CXCL12/metabolism
Disease Models, Animal
Endothelial Cells/immunology
Endothelial Cells/transplantation*
Glycoproteins/analysis
Heart Failure/etiology
Heart Failure/pathology
Heart Failure/physiopathology
Heart Failure/surgery*
Humans
Male
Myoblasts, Skeletal/transplantation*
Myocardial Infarction/etiology
Myocardial Infarction/pathology
Myocardial Infarction/physiopathology
Myocardial Infarction/surgery*
Myocardial Ischemia/complications*
Myocardial Ischemia/pathology
Myocardial Ischemia/physiopathology
Myocardial Ischemia/surgery
Myocardium/metabolism
Myocardium/pathology*
Neovascularization, Physiologic*
Paracrine Communication
Peptides/analysis
RNA, Messenger/metabolism
Rats
Rats, Inbred F344
Rats, Nude
Stem Cell Transplantation*
Time Factors
Transforming Growth Factor beta1/metabolism
Troponin T/metabolism
Vascular Endothelial Growth Factor A/metabolism