In this study, we have demonstrated that extracts derived from human BMC and MNC preserve cardiac function and decrease scar size post-MI when compared to the control group. Mouse and human bone marrow cells have several differences, which would potentially result in different outcomes as therapeutic agents [17
]. Therefore, our results expand our previous report with the mouse BMC extract to human cells reinforcing that intact cells do not appear to be necessary to obtain cardiac benefit post-MI.
We and others have reported that mouse BMCs can aid in tissue preservation post-MI via a paracrine mechanism [12
]. In our previous report, we demonstrated an early increase in vascularity at day 6 but at day 28 after injection of extracts derived from mouse BMC, this increase in vascularity had equilibrated back to the expected level in normal tissue, while the overall cardiac functional benefits appear to have lasted for a longer time period. We hypothesized that increased vascularity early after MI rescued ischemic cardiomyocytes from apoptosis, thereby salvaging myocardium. These results are consistent with prior studies by Schuleri et al.,
] who demonstrated that an early increase in myocardial perfusion resulted in longer term functional improvement. Indeed, these authors also show no increase in vessel number after 8 weeks.
In the current study, although only hBMC extract was noted to have more vessels in the border zone at day 28, both treatment groups resulted in improvement of cardiac function and led to a reduction in infarct size (Figs. -). Potential reasons for this difference should be highlighted. First, this could be due to a small sample size which may have affected statistical power. Second, several paracrine factors and cytokines might be differentially expressed within the whole BMCs vs MNCs extract. The detailed mechanism(s) and which paracrine factor(s) within each extract lead(s) to cardiac functional improvement following therapy are not yet fully understood, and this continues to be an important area of investigation within the field. Lastly, we only assessed the vessel count at day 28 post MI and not at an earlier timepoint. As discussed previously, we and others have shown that increased vascularity early after MI rescues ischemic cardiomyocytes from apoptosis, thereby salvaging myocardium, and that increased vascularity was not necessarily found at a later timepoint (12, 21).
The mechanisms underlying the beneficial effects of BMC implantation into post-MI hearts are complex and controversial. Identification of cellular factors present in the lysates with anti-apoptotic and cardio-protective properties are of key interest in the search for effective clinical therapies and gain insight into the possible mechanisms of cardiac functional improvement.
Additionally, there is controversy in the cardiology field as to whether human BMCs or MNCs are more optimal cells for human clinical trials, and here we report that the extract from either was beneficial and that neither intact cell is necessary to result in cardiac functional benefit post-MI. The use of the cell extract rather than cells themselves is an important strategy in the development of novel therapies post-MI. Use of the extract eliminates the issues of cell rejection for allogeneic cells and negates the need for invasive bone marrow harvesting for autologous cell transplantation. The extract as a whole, or factors within the extract, can be given at the time of an acute coronary syndrome as an “off the shelf” medication at the time of coronary reperfusion. Which factor(s) within the human extract results in cardiac functional improvement is a topic of intense investigation at the present time.
Our study has several limitations. First, we did not assess vessel counts at an early timepoint post-MI. In addition, having human cell control groups would potentially allow us to confirm the non-superiority of live cells compared with the cell extracts. However, the use of human cells in a mouse model would require changing the animal model including: use of immunocompromised animals (to avoid cell rejection) and antibiotic therapy. Use of cell lysate (even from human derived source) negates the need for the use of immunocompromised animals or antibiotic therapy. For these reasons, the whole cell group was not included in the current study to avoid these confounding factors which would then make our model not as clinically translatable and impact our ability to correlate the current data with our previous findings using mouse BMC.
In conclusion, our results show for the first time that hBMC and hMNC extracts improve cardiac function post-MI in a mouse model. Further studies should evaluate the benefits of the cellular extract and identify the cellular factors present within the extract with cardio-protective properties.