c-kit+ Cardiac Stem Cells Alleviate Post-Myocardial Infarction Left Ventricular Dysfunction Despite Poor Engraftment and Negligible Retention in the Recipient Heart

Abstract

Although transplantation of c-kit+ cardiac stem cells (CSCs) has been shown to alleviate left ventricular (LV) dysfunction induced by myocardial infarction (MI), the number of exogenous CSCs remaining in the recipient heart following transplantation and their mechanism of action remain unclear. We have previously developed a highly sensitive and accurate method to quantify the absolute number of male murine CSCs in female recipient organs after transplantation. In the present study, we used this method to monitor the number of donor CSCs in the recipient heart after intracoronary infusion. Female mice underwent a 60-min coronary occlusion followed by reperfusion; 2 days later, 100,000 c-kit+/lin- syngeneic male mouse CSCs were infused intracoronarily. Only 12.7% of the male CSCs present in the heart immediately (5 min) after infusion were still present in the heart at 24 h, and their number declined rapidly thereafter. By 35 days after infusion, only ∼1,000 male CSCs were found in the heart. Significant numbers of male CSCs were found in the lungs and kidneys, but only in the first 24 h. The number of CSCs in the lungs increased between 5 min and 24 h after infusion, indicating recirculation of CSCs initially retained in other organs. Despite the low retention and rapid disappearance of CSCs from the recipient heart, intracoronary delivery of CSCs significantly improved LV function at 35 days (Millar catheter). These results suggest that direct differentiation of CSCs alone cannot account for the beneficial effects of CSCs on LV function; therefore, paracrine effects must be the major mechanism. The demonstration that functional improvement is dissociated from survival of transplanted cells has major implications for our understanding of cell therapy. In addition, this new quantitative method of stem cell measurement will be useful in testing approaches of enhancing CSC engraftment and survival after transplantation.

Repeated Administrations of Cardiac Progenitor Cells Are Superior to a Single Administration of an Equivalent Cumulative Dose

“…Clearly, given the lack of significant new myocyte formation (Figure 7C), CPCs exerted their salubrious actions via paracrine mechanisms, as previously reported 3, 8. Such paracrine actions may have been exerted not only by CPCs residing in the myocardium, but also by CPCs retained in other organs such as the lungs, since a large number of CPCs delivered intracoronally are found outside of the heart, primarily in the lungs 5, 6. Regardless of the exact source (cardiac versus extracardiac) of paracrine factors, our data indicate that the duration of myocardial exposure to paracrine factors may be more important than the intensity of the exposure.…”

Promoting differentiation and survival of human c-kit+ cardiac progenitor cells ex vivo.

“…For instance, our group has previously shown that ~99% of transplanted CPCs were undetected in the heart at 35 days post implantation [21,22]. Thus, strategies that can enhance CPC survival after adoptive transfer are needed.…”

“…Despite all the previous data that show the therapeutic potential of CPC for heart repair after MI, some studies have shown multiple shortcomings with the use of CPCs, including poor survival of the transplanted cells as well as lack of differentiation into mature cardiomyocytes [11,17,21,22] (See below for more details). Addressing these issues may enhance the beneficial effects of CPCs for heart repair.…”

“…Poor survival of cells engrafted in the heart is one of the major hurdles that slow the progress of heart cell-based therapies [21,22]. That rapid cell loss does not allow implanted cells to remain long in the diseased cardiac tissue, and may thus limit their therapeutic benefit.…”

Cell-based therapies for ischemic cardiomyopathy : investigations of intramyocardial retention and safety of high dose intracoronary delivery of c-kit positive cardiac progenitor cells, and therapeutic utility of a novel population of cardiac mesenchymal stem cells expressing stage-specific embryonic antigen-3 (SSEA-3).

“…The overall retention of cells observed at 24 h (~4-5%) was 51 comparable to that observed in previous preclinical and clinical investigations using a variety of cell types. 26,52,141,160,162,163,[165][166][167] Therefore, intracardiac retention may be more related to route of administration rather than cell type whether intrinsically native heart or from extra-cardiac organs. We found a relatively high level of radioactivity in the apical portions of the right ventricular wall (Fig.…”