Intravenous Followed by X-ray Fused with MRI-Guided Transendocardial Mesenchymal Stem Cell Injection Improves Contractility Reserve in a Swine Model of Myocardial Infarction

Abstract

The aim of this study is to determine the effects of early intravenous (IV) infusion later followed by transendocardial (TE) injection of allogeneic mesenchymal stem cells (MSCs) following myocardial infarction (MI). Twenty-four swine underwent balloon occlusion reperfusion MI and were randomized into 4 groups: IV MSC (or placebo) infusion (post-MI day 2) and TE MSC (or placebo) injection targeting the infarct border with 2D X-ray fluoroscopy fused to 3D magnetic resonance (XFM) co-registration (post-MI day 14). Continuous ECG recording, MRI, and invasive pressure-volume analyses were performed. IV MSC plus TE MSC treated group was superior to other groups for contractility reserve (p=0.02) and freedom from VT (p=0.03) but had more lymphocytic foci localized to the peri-infarct region (p= 0.002). No differences were observed in post-MI remodeling parameters. IV followed by XFM targeted TE MSC therapy improves contractility reserve and suppresses VT but does not affect post-MI remodeling and may cause an immune response.

Biodistribution and Clearance of Human Mesenchymal Stem Cells by Quantitative Three-Dimensional Cryo-Imaging After Intravenous Infusion in a Rat Lung Injury Model

“…Although several studies suggest that MSCs are immunoprivileged because of the relatively low expression of MHC class II and other and costimulatory proteins [43–47], there is the potential that an immune response could still be elicited. This is especially true when administering multiple MSCs doses, which could result in priming the immune system to target the second cell dose for clearance [48, 49]. We did not observe significant reductions in hMSCs between 60 and 240 minutes postinfusion, which would suggest that no significant immune system priming occurs in that short period of time.…”

Human MuStem Cell Grafting into Infarcted Rat Heart Attenuates Adverse Tissue Remodeling and Preserves Cardiac Function

“…These include myoblasts, 4 , 5 , 6 bone marrow (BM) mononuclear cells, 7 , 8 mesenchymal stem cells (MSCs), 9 , 10 and endogenous cardiac progenitors, such as c-kit + cardiac progenitor cells (CPCs), 11 sca1 + CPCs, 12 and cardiosphere-derived cells, 13 as well as embryonic stem cells (ESCs) 14 , 15 and induced pluripotent stem cell (iPSC)-induced cardiomyocytes (CMs). 16 , 17 Decreased myocardial fibrosis, neovascularization, prevention of left-ventricle (LV) dilation, and enhancement of local cardiac contractility have been successively described for stem cells of different origins, 18 , 19 , 20 leading to rapid progression to clinical trials for a subset of these cell types. To date, however, these encouraging preclinical findings have not been replicated in a clinical setting, and randomized clinical trials for MI have shown only modest long-term efficacy, 21 mainly due to poor survival and engraftment of injected cells in the harsh cardiac environment and negligible direct differentiation of stem cells into CMs and/or vascular cells.…”

Point of care, bone marrow mononuclear cell therapy in ischemic heart failure patients personalized for cell potency: 12-month feasibility results from CardiAMP heart failure roll-in cohort

“…The symptom and ambulatory functional improvement trends in the CardiAMP HF roll-in cohort are consistent with the observations from the TAC-HFT 17 and the TABMMI [36,37] chronic ischemic heart failure trials that used a similar bone marrow harvest and delivery method. Potential mechanisms underlying these symptom and functional improvements could include increased contractile and vascular reserve, which has been observed in animal ischemic heart disease models [5,38], but requires clinical confirmation.…”

“…Bone marrow harbors a heterogeneous mononuclear cell population that includes committed cell populations comprising endothelial progenitor cells, as well as uncommitted hematopoietic progenitor and stem cells, mesenchymal stromal/stem cells and lymphoblasts. Bone marrow mononuclear cell (BM MNC) injections have been linked to favorable functional and structural heart recovery in small [1] and large [2][3][4][5][6] animal models of cardiac ischemia/infarction. This response has presumably been via paracrine factors with the potential to facilitate angiogenesis, reduce local inflammation, oxidative stress, apoptosis, and limit reactive fibrosis [5,7] and adverse remodeling [8].…”