CGMP Expanded First Trimester Human Umbilical Cord Perivascular Cells (FTM HUCPVC) Induce Significant Angiogenesis, Myocardial Regeneration and Sustained Functional Recovery Exceeding Older MSC Sources in the Rat Myocardial Infarction (MI) Model

Introduction: FTM HUCPVC are a novel source of young, immunoprivileged mesenchymal stromal cells (MSC). FTM HUCPVC demonstrate significant homing, angiogenic and tissue remodelling capacities in vitro . We aimed to explore the therapeutic potential of cGMP compliant FTM HUCPVC for myocardial infarction (MI). Methods: FTM HUCPVC and term HUCPVC were expanded in cGMP compliant xeno-free (5% HPL) multilayer cultures (Corning) and Quantum Bioreactor (Terumo). One week post-MI Fox rnu rats (n=6) were intramyocardially injected with 3 million FTM HUCPVC, term HUCPVC, bone marrow MSC (BMSC) or basal media. Cardiac function (echocardiography, pressure/volume catheter and ECG telemetry), infarct scar (Trichrome), ECM remodelling activity (DQ collagenase substrate) vascular density (IB4) and contractile proteins (SarcA) were quantified 4 weeks and 6 months after cell implantation. Myocardial apoptosis (caspase-3) and macrophage infiltration (eNOS, CD68, CD80) were assessed at 5 days after cell treatment. Results: FTM HUCPVC significantly reduced apoptosis at 5 days and infarct size at 4 weeks (5.3±1.1, p<0.05) compared to other treatment groups. Histological analysis showed that the infarcted region of FTM HUCPVC treated hearts displayed significantly higher: M2 macrophage ratio, perivascular gelatinase activity, capillary density (543.4±118.6 vs. 276.5±42.69; p<0.05), abundance of contractile sarcomeric actinin (48.9±6.1 vs. 19.5±7.0; p<0.05), and Ca 2+ pump SERCA (69.9±5.9 vs. 49.8±3.7) over other experimental groups. FTM HUCPVCs induced significant and superior improvements in all measures of contractile function (ESV, EF, dPdt, tau) relative to cell-free media (p<0.001), BMSC (p<0.001) and term HUCPVC (p<0.001). Improvements in inotropy and lusitropy were maintained to 6 months (δ dPdt max 3.8±6.0; δ dPdt min 3.2±8.78) and resulted in near complete abolishment of premature ventricular contractions (<1/min). Conclusion: FTM HUCPVC treatment after MI induces superior structural and functional recovery compared to older MSC sources; characteristics that were maintained during xeno-free upscaling and for up to 6 months post injection. FTM HUCPVC are a promising option as a novel cell therapy for optimal cardiovascular regeneration.