Intracoronary Transplantation of Mesenchymal Stem Cells with Overexpressed Integrin-Linked Kinase Improves Cardiac Function in Porcine Myocardial Infarction

Abstract

The effect of mesenchymal stem cell (MSCs)-based therapy on treating acute myocardial infarction (MI) is limited due to poor engraftment and limited regenerative potential. Here we engineered MSCs with integrin-linked kinase (ILK), a pleiotropic protein critically regulating cell survival, proliferation, differentiation, and angiogenesis. We firstly combined ferumoxytol with poly-L-lysine (PLL), and found this combination promisingly enabled MRI visualization of MSCs in vitro and in vivo with good safety. We provided visually direct evidence that intracoronary ILK-MSCs had substantially enhanced homing capacity to infarct myocardium in porcine following cardiac catheterization induced MI. Intracoronary transplantation of allogeneic ILK-MSCs, but not vector-MSCs, significantly enhanced global left ventricular ejection fraction (LVEF) by 7.8% compared with baseline, by 10.3% compared with vehicles, and inhibited myocardial remodeling compared with vehicles at 15-day follow-up. Compared with vector-MSCs, ILK-MSCs significantly improved regional LV contractile function, reduced scar size, fibrosis, cell apoptosis, and increased regional myocardial perfusion and cell proliferation. This preclinical study indicates that ILK-engineered MSCs might promote the clinical translation of MSC-based therapy in post-MI patients, and provides evidence that ferumoxytol labeling of cells combined with PLL is feasible in in vivo cell tracking.

Integrin-Linked Kinase Controls Choroidal Neovascularization by Recruitment of Endothelial Progenitor Cells

“…Several studies have indicated the importance of ILK in vasculogenesis, such as hindlimb ischemia 12 and myocardial infarction. 19 In our experiment, we also found that the expression of ILK was dramatically increased in the CNV area, especially during the early stage of CNV. Intravitreal injection of ILK siRNA significantly impaired the growth of CNV, and ILK downstream inhibitors (LY294002, PD98059, and HIF-1a short hairpin RNA) were able to decrease the number of EPC within CNV (data not shown).…”

Unmodified, autologous adipose-derived regenerative cells improve cardiac function, structure and revascularization in a porcine model of chronic myocardial infarction

“…2. Unlike in the present study Mu et al (2016) did not identify hyperenhancement as areas of signal intensity ≥ 5 standard deviations greater than normal myocardium. Table 2 Mean and standard error of the mean of functional (CO, SV, LVEF, EDV, ESV and HR) and structural alterations (MLV and ScVol) of the porcine heart at ten weeks (i.e., at time point T2) after experimental occlusion of the left anterior descending (LAD) artery for three hours at time point T0, followed by the delivery of respectively 18 × 10 6 unmodified, autologous adipose-derived regenerative cells (UA-ADRCs) (n=9) or saline (Control) (n=8) into the balloon-blocked LAD vein (matching the initial LAD artery occlusion site) at four weeks after T0 (i.e., at time point T1).…”

“…Furthermore, porcine models allow the opportunity to evaluate the therapeutic outcome with MRI, which is considered to provide the most accurate, comprehensive and reproducible measurements of cardiac chamber dimensions, volumes, function and infarct size compared with other techniques 8 . Unfortunately, in those studies on porcine and sheep models in which treatment success of cell-based therapies for (experimentally induced) MI was assessed using MRI, temporary occlusion of the left anterior descending (LAD) artery was (except of one study that showed no success 26 ) restricted to 60 min 27,28 or 90 min 29,30 . As a result, in most of these studies 27,28,30 the left ventricular ejection fraction (LVEF) after MI was between 42% and 54%, which may in clinical settings not represent the correct target population with moderate to severe left ventricular dysfunction 8 .…”

“…Unfortunately, in those studies on porcine and sheep models in which treatment success of cell-based therapies for (experimentally induced) MI was assessed using MRI, temporary occlusion of the left anterior descending (LAD) artery was (except of one study that showed no success 26 ) restricted to 60 min 27,28 or 90 min 29,30 . As a result, in most of these studies 27,28,30 the left ventricular ejection fraction (LVEF) after MI was between 42% and 54%, which may in clinical settings not represent the correct target population with moderate to severe left ventricular dysfunction 8 . Furthermore, cells were delivered immediately after experimental induction of MI in twelve out of the 16 preclinical studies on cell-based therapy for MI using porcine and sheep animal models summarized in Supplementary Table 1.…”

Intracoronary Administration of Allogeneic Adipose Tissue–Derived Mesenchymal Stem Cells Improves Myocardial Perfusion But Not Left Ventricle Function, in a Translational Model of Acute Myocardial Infarction

“…Intracoronary administration is one of the least invasive delivery methods, although infusion of large‐size adult mesenchymal stem cells (MSCs) (up to 20 μm in diameter) could potentially obstruct capillaries (from 6 to 10 μm in diameter), leading to permanent no‐reflow phenomena after cell administration. In this sense, clinical and preclinical studies have found that intracoronary injection of a significant number (up to 50 million) of large‐size stem cells (≈20–50 μm in diameter) can be safe when administered a few days after AMI. However, microvascular injury is higher during the first 24 hours post‐AMI, and therefore the probability of capillary plugging and MVO increases when administering large cells directly into the culprit artery.…”