Cord Lining-Mesenchymal Stem Cells Graft Supplemented with an Omental Flap Induces Myocardial Revascularization and Ameliorates Cardiac Dysfunction in a Rat Model of Chronic Ischemic Heart Failure

Abstract

Myocardial restoration using tissue-engineered grafts to regenerate the ischemic myocardium offers improved donor cell retention, yet a limited cell survival resulting from poor vascularization needs to be addressed. A cell type derived from the subamnion, namely, cord-lining mesenchymal stem cells (CL-MSC), has recently been identified. Here we present a restorative strategy that combines a fibrin graft containing human CL-MSC and omental flap providing, thereby, cell-, structural-, and angiogenic support to the injured myocardium. The graft consisted of a mixture of 2 · 10 6 CL-MSC-GFP-Fluc and fibrin. Myocardial infarction (MI) was induced in nude rats and following confirmation of ensued heart failure with echocardiography 2 weeks after injury, therapeutic intervention was performed as follows: untreated (MI, n = 7), CL-MSC graft (CL-MSCG, n = 8), CL-MSCG and omental flap (CL-MSCG + OM, n = 11), and omental flap (OM, n = 8). In vivo bioluminescence imaging at 1, 3, 7, and 14 days post-treatment indicated comparable early donor cell viability between the CL-MSCG and CL-MSCG + OM. Treatment with CL-MSCG + OM improved the myocardial function as assessed by the measurement of end-diastolic left ventricular (LV) pressure (3.53 -0.34 vs. 5.21 -0.54 mmHg, p < 0.05), contractility ( + dP/dt, 3383.8 -250.78 mmHg vs. 2464.9 -191.8 mmHg, p < 0.05), and the relaxation rate (-dP/ dt, -2707.2 -250.7 mmHg vs. 1948.7 -207.8 mmHg, p < 0.05), compared to MI control 6 weeks after ischemic injury. Furthermore, evidence of a 20.32% increase in the ejection fraction was observed in CL-MSCG + OM rats from week 2 to 6 after injury. Both CL-MSCG and CL-MSCG + OM led to an enhanced cardiac output (p < 0.05), and attenuated the infarct size (35.7% -4.2% and 34.7% -4.8%), as compared to MI (60.7% -3.1%; p < 0.01 and p < 0.001, respectively). All treated groups had a higher arteriole density than controls. Yet, a higher amount of functional blood vessels, and a 20-fold increase in arteriole numbers were found in CL-MSCG + OM. Altogether, CL-MSCGs supplemented with vascular supply have the potential to repair the failing, chronically ischemic heart by improving myocardial revascularization, attenuating remodeling, and ameliorating cardiac dysfunction.

Grafts Enriched with Subamnion-Cord-Lining Mesenchymal Stem Cell Angiogenic Spheroids Induce Post-Ischemic Myocardial Revascularization and Preserve Cardiac Function in Failing Rat Hearts

“…Yet, the possibility that differentiation might have occurred by cell fusion could not be excluded. These findings differ from our previous study, as we were not able to detect CL-MSC-derived vascular differentiation in the few engrafted cells found 1 month after implantation of monodispersed CL-MSC seeded within FGs in failing rat hearts [14]. Thus, self-assembly of CL-MSC into 3D spheroids might have favored vascular differentiation.…”

“…We have recently shown that monodispersed CL-MSC embedded within FGs prevented further deterioration of cardiac function in failing rat hearts. Yet, the combination of CL-MSC grafts with a vascular omental flap had a synergistic effect that promoted myocardial revascularization improving thereby cardiac function and adverse remodeling [14]. In the present study, CL-MSC were used to assemble angiogenic spheroids that were then coated with HUVEC.…”

“…Treatment with monodispersed CL-MSC embedded in a fibrin graft (FG) prevented further deterioration of cardiac function in a model of chronic heart failure in nude rats. However, when the CL-MSC grafts were supplemented with direct vascular supply through an omental flap, it improved myocardial revascularization, and ameliorated cardiac dysfunction through a synergistic effect [14]. In the present study, CL-MSC were used to generate angiogenic spheroids that were allowed to self-assemble in hanging drop cocultures with HUVEC.…”

Fibrin, the preferred scaffold for cell transplantation after myocardial infarction? An old molecule with a new life

“…Their results showed a general recovery of lost cardiac functions. Further studies in rat MI models have applied fibrin‐based scaffolds loaded with ESC‐derived cardiac progenitors (Menasché et al , ; Bellamy et al , ), neonatal rat cardiac cells (Wendel et al , ), MSCs from the subamnion (Lilyanna et al , ) or skeletal myoblasts (Christman et al , ). All those strategies provided sustained improvements in myocardial vessel density and cardiac function, and they attenuated post‐MI remodelling.…”

Creating the bioartificial myocardium for cardiac repair: challenges and clinical targets

“…Several experimental studies showed the benefits of engineered materials charged with stem cells for ischemic models. In addition, in some of these studies the cell transplantation was associated with epicardial grafting of scaffolds onto the ventricular surface [11][12][13][14]. Subsequently, our group coordinated the MAGNUM Clinical Trial (Myocardial Assistance by Grafting a New bioartificial Upgraded Myocardium).…”