Guided Cardiopoiesis Enhances Therapeutic Benefit of Bone Marrow Human Mesenchymal Stem Cells in Chronic Myocardial Infarction

Abstract

Objective The goal of this study was to guide bone marrow-derived human mesenchymal stem cells (hMSC) into a cardiac progenitor phenotype, and assess therapeutic benefit in chronic myocardial infarction. Background Adult stem cells, delivered in their naïve state, demonstrate a limited benefit in patients with ischemic heart disease. Preemptive lineage pre-specification may optimize therapeutic outcome. Methods hMSC were harvested from a coronary artery disease patient cohort. A recombinant cocktail consisting of TGFβ1, BMP-4, Activin-A, retinoic acid, IGF-1, FGF-2, α-thrombin and IL-6 was formulated to engage hMSC into cardiopoiesis. Derived hMSC were injected into the myocardium of a nude infarcted murine model, and followed over 1-year for functional and structural end-points. Results While the majority of patient-derived hMSC in their native state demonstrated limited effect on ejection fraction, stem cells from rare individuals harbored a spontaneous capacity to improve contractile performance. This reparative cytotype was characterized by high expression of Nkx2.5, Tbx5, Mesp-1 and Mef2C, markers of cardiopoiesis. Recombinant cardiogenic cocktail guidance secured the cardiopoietic phenotype across the patient cohort. Compared to unguided counterparts, cardiopoietic hMSC delivered into infarcted myocardium achieved superior functional and structural benefit without adverse side effects. Engraftment into murine hearts was associated with increased human-specific nuclear, sarcomeric and gap junction content along with induction of myocardial cell cycle activity. Conclusions Guided cardiopoiesis thus enhances the therapeutic benefit of bone marrow-derived human mesenchymal stem cells in chronic ischemic cardiomyopathy.

Primed 3D injectable microniches enabling low-dosage cell therapy for critical limb ischemia

“…N.F.I., normalized fluorescence intensity. mixture of growth factors also led to cardiopoietic phenotype and improved their therapeutic benefit in chronic ischemic cardiomyopathy (26). In our study, effect of cell priming on hMSCs differentiation was preliminarily investigated, because up-regulated expression of ECM components was realized in the primed GMs (Fig.…”

Hematopoietic stem cells are a critical sub-population of whole bone marrow in the treatment of myocardial infarction

“…However, the search for the most therapeutically effective stem cell population within the bone marrow has led many researchers to hypothesize that the MSC, being more plastic and having the capacity to differentiate into myocytes [45,46], are principally responsible for regeneration of the myocardium. Hence, considerable research has been dedicated to the study of BM MSC [45][46][47][48][49][50] based on the assumption that their multi-lineage potential make them more likely candidates for enhancing cardiogenic repair than HSC. We have assessed the relative contribution of HSC within the context of the whole BM aspirate, and our data from mice receiving BM samples depleted of HSC (Figures 3-5) suggest that human bone marrow HSC are largely responsible for the recovery reported in cell-based MI therapy.…”

Menstrual Stem cells

“…The prospect of using mesenchymal stem cells in heart failure uses the ability of these cells to directly differentiate into cardiomyocytes [4] and also to secrete certain angiogeneic and trophic factors [5][6][7]. That assist in regeneration and activation of endogenous cardiac stem cells [8].…”