Magnetic Enhancement of Cell Retention, Engraftment, and Functional Benefit after Intracoronary Delivery of Cardiac-Derived Stem Cells in a Rat Model of Ischemia/Reperfusion

Abstract

The efficiency of stem cell transplantation is limited by low cell retention. Intracoronary (IC) delivery is convenient and widely used but exhibits particularly low cell retention rates. We sought to improve IC cell retention by magnetic targeting. Rat cardiosphere-derived cells labeled with iron microspheres were injected into the left ventricular cavity of syngeneic rats during brief aortic clamping. Placement of a 1.3 Tesla magnet ~1 cm above the heart during and after cell injection enhanced cell retention at 24 h by 5.2–6.4-fold when 1, 3, or 5 × 105 cells were infused, without elevation of serum troponin I (sTnI) levels. Higher cell doses (1 or 2 × 106 cells) did raise sTnI levels, due to microvascular obstruction; in this range, magnetic enhancement did not improve cell retention. To assess efficacy, 5 × 105 iron-labeled, GFP-expressing cells were infused into rat hearts after 45 min ischemia/20 min reperfusion of the left anterior coronary artery, with and without a superimposed magnet. By quantitative PCR and optical imaging, magnetic targeting increased cardiac retention of transplanted cells at 24 h, and decreased migration into the lungs. The enhanced cell engraftment persisted for at least 3 weeks, at which time left ventricular remodeling was attenuated, and therapeutic benefit (ejection fraction) was higher, in the magnetic targeting group. Histology revealed more GFP+ cardiomyocytes, Ki67+ cardiomyocytes and GFP−/ckit+ cells, and fewer TUNEL+ cells, in hearts from the magnetic targeting group. In a rat model of ischemia/reperfusion injury, magnetically enhanced intracoronary cell delivery is safe and improves cell therapy outcomes.

Targeted repair of heart injury by stem cells fused with platelet nanovesicles

“…11). Consistent with our previous work 12,17 , 4 weeks after injection, very few injected cells still persisted in the recipient heart, with even fewer cells exhibiting a cardiac phenotype. Nevertheless, the number of DiI/α-SA (α-sarcometric actin) double-positive cells was greater in the PNV-CSC group than that in the control CSC group (Supplementary Fig.…”

The effect of encapsulation of cardiac stem cells within matrix-enriched hydrogel capsules on cell survival, post-ischemic cell retention and cardiac function

“…When compared to other biomaterial-based approaches, cell encapsulation avoids delivery of exogenous pro-thrombotic materials (e.g., delivery of excess exogenous collagen [8] or fibrin glue plugging of the injection site) [5], intrinsic modification of the CSCs (e.g., magnet-based retention of iron labeled CSCs) [7,28] or intracoronary implant of pro-thrombotic metal stents [29]. Importantly, cell encapsulation restricts the use of foreign materials resulting in a significantly lower biomaterial to cell ratio that is gelled prior to transplantation and remains gelled at physiological temperature for straightforward clearance following the integration of CSCs into the myocardium.…”

Is Cardioprotection Dead?

“…The results were promising in revealing evidence of therapeutic regeneration with CDCs, but the chronicity of the MI ruled out any contribution from cardioprotection in that study. Although heart-derived stem cells have been tested in both large animals and humans in chronic ischemic settings, 36,66 until recently, the only studies using an acute ischemia/reperfusion (I/R) model were in rats, 65,67 where structural and functional outcomes were improved dramatically by the intracoronary infusion of allogeneic CDCs 20 minutes post-AMI. However, the 3-week end point in those studies made it impossible to separate cardioprotection from regeneration.…”

“…60 Thus, the prevailing concept of stem cell efficacy has shifted toward the paracrine hypothesis, which proposes that transplanted cells produce soluble factors beneficial to the infarcted heart. 68 Potential cardioprotective effects of paracrine factors include antiapoptotic effects on resident myocytes, 67,69 upregulation of angiogenesis, 60,70 modulation of inflammatory processes resulting in better infarct healing, 71 promotion of cardiomyocyte cell cycle reentry, 31 and induction of secondary humoral effects in the host tissue. 72,73 Recent findings implicate exosomes as critical agents of the indirect effects of CDCs, likely attributable, at least in part, to the transfer of cardio-protective and regenerative microRNAs (eg, miR-146a) from CDCs to surrounding heart tissue.…”