Cell-based therapy has been widely applied in bioengineering, as well as to facilitate tissue repair and regeneration. Neovascularization represents an important process involved in tissue regeneration , because a sufficient blood supply is required to ensure the availability of nutrients during tissue repair. The promotion of neovascularization during tissue repair is therefore the focus of intense effort in the field of regenerative medicine.
EPCs which reside in the bone marrow, adult peripheral blood, and human umbilical cord blood differentiate into mature ECs that not only participate in angiogenesis during embryonic development, but also play an important role in microvascular neovascularization and vascular endothelial repair following differentiation . MSCs, which represent important members of the stem cell family, possess the ability to self-renew, differentiate, and participate in angiogenesis . Numerous clinical trials have confirmed that MSCs may be used in the treatment of diseases such as chronic heart infarction, acute myocardial infarction, and hematological malignancies . MSCs and EPCs, which promote vascularization and tissue repair via different pathways, have both been used as seed cells for tissue engineering [26, 27]. Most previous studies have utilized single-cell transplantation, which suffers from several limitations. For several studies, it was reported that strategies involving the combined transplantation of multiple cell types are more effective than single-cell transplantation . This meta-analysis was conducted to access the efficacy of combined cell transplantation therapy in promoting angiogenesis and tissue repair.
Results showed that there was no difference in angiogenesis between the EPC and MSC cotransplantation group and the EPC single-transplantation group; the heterogeneity of the data was 88 %. This heterogeneity resulted from various factors, such as differences in the organization source, injection dose, and measurement time (Table 1). Because of the small amount of available data, we were unable to perform sensitivity analysis. Our findings indicated that the transplantation of EPCs alone achieved the same effect on angiogenesis as combined transplantation; however, MSCs were able to induce differentiation into EPCs under specific conditions . Several studies have reported that inducing the differentiation of EPCs into other cell types is no easier than inducing the differentiation of MSCs [12, 13, 28]. Numerous studies have demonstrated that these cells are capable of differentiating into ECs, thereby contributing to the formation of vascular networks [2, 10–15, 21]. These findings confirmed that EPCs may be utilized to achieve a significant enhancement in angiogenesis and revascularization. EPCs are considered capable of ensuring the availability of sufficient blood supply, thereby ensuring a source of nutrients during tissue repair. However, the present results showed that cell therapies using a combination of MSCs and EPCs may be applied to achieve improved tissue regeneration and repair, relative to the transplantation of either cell type alone. The results revealed that the combined transplantation of MSCs and EPCs achieved an improvement in cardiac function in cardiac diseases, in ALP activity and bone volume in damaged bone tissue, and in cerebral function in cerebrovascular diseases by increasing BDNF and reducing neurologic impairment. However, these results may be affected by the injection dose or organ source, and can also be associated with the injured tissue needing more new vessels to repair, the extent of tissue damage, or the ability of the tissue to regenerate. Our findings confirmed that combination therapy using both MSCs or EPCs is more effective than therapy using MSCs or EPCs alone, under some conditions. MSCs are capable of differentiating into various cell types, thereby providing a source of cells for the repair of damaged tissues; therefore, combination therapy involving the transplantation of these cells achieves improved tissue repair. However, compared with the transplantation of MSCs alone, the effect of combined transplantation on left ventricular function was not clear; the + dp/dt or –dp/dt value represented a significant difference, but no difference was observed in LVSP and LVEDP. We speculate that this heterogeneity may be attributed to the varying injection times of EPCs and MSCs reported in the studies: one study reported that EPCs were injected for 3 days (0.5 × 107 EPCs/day) at 7 days post MSC injection . In other studies, both cell types were injected at the same time. These findings suggested that EPCs play a more important role in the early stages of vascularization than MSCs and that MSCs promote EPC proliferation and provide a stable microenvironment for these cells. The observed heterogeneity may also be attributed the reduced capacity of the myocardium to regenerate, or variations in factors such as instrument sensitivity.
To our knowledge, the present meta-analysis is the first to evaluate the effectiveness of combined cell-transplantation therapy. Because this form of cell therapy has not been widely applied in clinical trials to date, most of the included studies reported the efficacy of combination cell therapies from animal studies. Our results are expected to guide preclinical and clinical trials in investigating the efficacy of combination cell therapies. Further investigation is required to determine the optimal cotransplantation dose, therapeutic method, and time of treatment.
Our meta-analysis has several limitations. Since the data were complex and insufficient, we could not assess the heterogeneity or perform sensitivity analyses of studies related to vessel density. However, the main factors that may affect the end evaluation are listed and divided into various groups (Table 1) or presented descriptively.