The main result of this analysis is that MSC therapy may only achieve better LVEF improvement within a specific hair transplant time window and when using an optimal MSC dose.

The efficacy of stem cellular therapy in patients with AMI has long been discussed. One of the candidate cell types, MSCs are suggested to achieve much better global LVEF, thus reducing infarct size and still left ventricular remodeling compared with other cell types, such as CD34 + /CD133 + and bone marrow mononuclear cells, in AMI [ 32 , 33 ]. Interestingly, researchers are often uncertain about the timing plus MSC dose that should be administered to achieve better LVEF within AMI patients. However , data addressing this issue are contrary: Liu et al. reported that various doses associated with stem cells (hybrid cells) did not influence LVEF enhancement in AMI [ 32 ], but other investigators possess suggested that beneficial effects might only be achieved whenever higher numbers (> 10 8 ) of stem cells are infused [ 34 , 35 ]. Hence, this meta-analysis addresses the optimal time window and dosage of MSCs administered to AMI patients for the first time. Simply no significant further LVEF increase was observed in the MSC group compared with the controls in all trials, and higher heterogeneity ( I 2   =  97%) was noted among the tests. The authors then explored whether the transplantation time and cell dose used explained the insignificant findings concerning LVEF.

Effect of timing and MSC dose on LVEF

In the subanalysis of hair transplant time, LVEF was increased by 3. 22% within the MSC group compared with the controls when the cells had been injected within 1  week after PCI. However , simply no benefit for LVEF over the controls was observed whenever MSCs were administered after more than 1  week. This particular finding is consistent with other randomized trials studying cellular administration time using bone marrow stem cells that will claimed that the best benefits for global LVEF were attained when administering cell therapy between 4 and 7  days after AMI [ 36 , 37 ]. Stem cells which are infused immediately after AMI might cause excessive obstruction and disorder in the microvascular bed, thereby creating a hostile environment because of inflammation of the myocardium potentially limiting cell retention plus engraftment [ 38 ]. However , preclinical trials in which originate cells were administered within 1  week but not instantly indicated that administering stem cells served to prevent cardiomyocyte loss by secreting anti-apoptotic and anti-inflammatory paracrine aspects or by inducing an angiogenic effect [ 39 41 ]. Moreover, the refusion time of MSCs was determined through PCI to cell administration, which is different from measuring time interval starting at AMI. Considering that PCI is performed as early as possible after AMI in clinical emergencies, the particular intracoronary or intravascular administration of stem cells might save viable myocardium after the reperfusion of infarcted myocardium. More clinical data and basic research are needed to address this problem.

Regarding the effects of cell dosage on LVEF improvement, the results found in this study demonstrated that an MSC dose of less than 10 seven can provide a significant beneficial effect on LVEF, whilst higher doses (more than 10 7 ) of MSCs exhibit no LVEF increase in contrast to the controls. However , several studies have reported that individuals administered with a higher number (more than 10 8 cells) of bone marrow come cells exhibit a greater LVEF benefit [ 42 , 43 ]. Nevertheless , those who advocate using the standard number of infused cells have got suggested that MSCs, which are larger (~22– 25  μ m in diameter) than capillaries (~8– 10  μ m in diameter), may be associated with a risk of impeding microvessels and might compromise blood flow when injected intracoronarily [ 36 , 44 ]. Gao et al. reported that one affected person suffered from a serious complication involving coronary artery occlusion plus subsequent lack of flow during the intracoronary procedure when treating a higher dose (3. 08  ×   10 6 ) of MSCs [ 28 ]. Vulliet et al. also reported the occurrence of coronary embolisms leading to acute myocardial ischemia and subacute myocardial microinfarctions after the intracoronary injection of MSCs in a canine model [ 45 ].

Whenever studying injection timing and dose in combination, a significant effect on LVEF (an increase of 3. 32%) was present in a subgroup combining a transplantation time within 1  week and an injected dose of less than ten 7 cells (95% CI one 14 to 5. 50); transplanting the cells within 1  week and injecting more than 10 7 cells resulted in a slight improvement of LVEF, while administering the cells at more than 1  week and treating more than 10 7 cells got the opposite effect on LVEF. However , these results should be carefully interpreted as only two trials were included in this research, and one used a small patient samples. Notably, the data through Gao et al. markedly demonstrated a similar result along with strong significance [ 27 ].

As we mentioned above, the preliminary results should be interpreted along with caution. The potential of stem cell therapy for cardiac restoration may be influenced not only by cell dosage but also simply by patient status, such as the level of basic ejection fraction (28. 7  ±   4. 33 to 51. 51  ±   0. 95 in the included studies). Furthermore, the inter-study differences in patient age and gender might affect therapeutic effectiveness indicating that aging patients who are prone to suffer from impaired endothelium might exhibit inadequate physiological angiogenesis responses to ischemia and females may benefit a lot more from stem cell therapy than males [ 46 ]. In addition , we suspect that the source and purity of MSCs can affect therapeutic response.

Mechanisms of the therapeutic a result of MSCs

It has been widely shown that the four main mechanisms of action for the cardioreparative effects of MSC therapy are as follows: (1) in vivo reduction of myocardial fibrosis; (2) stimulation of angiogenesis; (3) restoration of contractile function through engraftment difference; and (4) stimulation of endogenous cardiac stem tissue to proliferate and differentiate [ 47 ]. Accumulating proof has indicated that the paracrine mechanism is the predominant reason for the beneficial effects exerted by MSCs and is depending on a multitude of bioactive molecules, including cytokines, chemokines, and development factors [ 48 ]. These molecules contribute to reducing fibrosis through suppressing the proliferation of fibroblasts and advertising their metalloproteinase secretion, stimulating the angiogenesis, proliferation plus differentiation of host cells, and recruiting endogenous heart stem cells. In addition , MSCs can alter endothelial cell behaviour and differentiate into endothelial cells in vitro or even into cardiomyocytes in vivo. Moreover, implanted MSCs may regulate the proliferation and differentiation of endogenous heart stem cells and enhance myocyte cell cycling through cell– cell interaction, thereby homing to the injury web site to repair injured myocardium and boost angiogenesis for myocardial repair [ 49 ]. In addition , it has been reported that immediate cellular mechanisms involving exosomes, mitochondrial transfer, connexin43, and so forth, can convincingly explain the effects observed in preclinical and medical studies [ 47 ]. Moreover, studies also indicate the fact that mesenchymal– endothelial transition appears to have an important physiological part in cardiac repair due to possible neovascularization [ 50 ].

Limitations

This study provides several limitations. First, the scope of the results is restricted by the small number of trials included. Ideally, more observation guidelines regarding endpoints, such as LVESV, LVEDV, and the wall movement score index, could be included to evaluate cardiac structure plus function when more RCTs are conducted. Second, since the authors mentioned previously, the results describing the combination of cellular injection timing and dose were drawn from just two trials; this might reduce the power of the study in order to draw solid conclusions. However , a separately conducted meta-analysis on timing and dose including more trials is certainly expected to draw the same conclusions. Finally, a trial from Wang et al. applied MSCs in patients with seriously impaired LVEF (< 35%), and this might have affected the particular inhomogeneity of the meta-analyses. Detailed conclusions regarding baseline LVEF and LVEF changes during follow-up require support through more data.