Autologous Mesenchymal Stem Cells Produce Concordant Improvements in Regional Function, Tissue Perfusion, and Fibrotic Burden When Administered to Patients Undergoing Coronary Artery Bypass Grafting

Karantalis, Vasileios; DiFede, Darcy L.; Gerstenblith, Gary; Pham, Si M.; Symes, James F.; Zambrano, Juan P.; Fishman, Joel E.; Pattany, Pradip M.; McNiece, Ian; Conte, John V.; Schulman, Steven P.; Wu, Kathérine C.; Shah, Ashish S.; Breton, Elayne; Davis-Sproul, Janice; Schwarz, Richard P.; Feigenbaum, Gary S.; Mushtaq, Muzammil; Suncion, Viky Y; Lardo, Albert C.; Borrello, Ivan; Mendizabal, Adam; Karas, Tomer Z.; Byrnes, John; Lowery, Maureen H.; Heldman, Alan W.; Hare, Joshua M.

doi:10.1161/circresaha.114.303180

Cited by 320 publications

(252 citation statements)

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“…Research from several laboratories, including ours, suggests that stem cells hold immense potential for cardiac repair and regeneration. [1][2][3][4] Clinical use of adult stem cells is a reality today and many stem cell types, including bone marrow-derived mesenchymal stem cells (MSCs), 5 bone marrow cells, 7,8 cardiac-derived cardiac progenitor, 6 and cardio-sphere derived cells 9 have been tested. The beneficial effects of tested cell therapies on cardiac structure and function have been modest and most studies to date have not been adequately powered to document efficacy.…”

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confidence: 99%

Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart

Mohsin

Troupes

Starosta

et al. 2015

Circulation Research

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Rationale: Adoptive transfer of multiple stem cell types has only had modest effects on the structure and function of failing human hearts. Despite increasing the use of stem cell therapies, consensus on the optimal stem cell type is not adequately defined. The modest cardiac repair and functional improvement in patients with cardiac disease warrants identification of a novel stem cell population that possesses properties that induce a more substantial improvement in patients with heart failure. Objective: To characterize and compare surface marker expression, proliferation, survival, migration, and differentiation capacity of cortical bone stem cells (CBSCs) relative to mesenchymal stem cells (MSCs) and cardiac-derived stem cells (CDCs), which have already been tested in early stage clinical trials. Methods and Results: CBSCs, MSCs, and CDCs were isolated from Gottingen miniswine or transgenic C57/BL6 mice expressing enhanced green fluorescent protein and were expanded in vitro. CBSCs possess a unique surface marker profile, including high expression of CD61 and integrin β4 versus CDCs and MSCs. In addition, CBSCs were morphologically distinct and showed enhanced proliferation capacity versus CDCs and MSCs. CBSCs had significantly better survival after exposure to an apoptotic stimuli when compared with MSCs. ATP and histamine induced a transient increase of intracellular Ca 2+ concentration in CBSCs versus CDCs and MSCs, which either respond to ATP or histamine only further documenting the differences between the 3 cell types. Conclusions: CBSCs are unique from CDCs and MSCs and possess enhanced proliferative, survival, and lineage commitment capacity that could account for the enhanced protective effects after cardiac injury.

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confidence: 99%

Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart

Mohsin

Troupes

Starosta

et al. 2015

Circulation Research

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“…The precise mechanism of action has yet to be defined, but it may involve secretion of paracrine factors and stimulation of endogenous mechanisms of myocardial repair (3). As a therapeutic for adults, MSCs have recently emerged as a leading stem cell candidate based on a series of early phase clinical trials that have shown a favorable safety profile, feasibility as an allogeneic cell therapy product, and preliminary efficacy to improve contractility, quality of life, and reduce myocardial scar formation (11,12,20). Additionally, MSCs have shown the capacity to recruit and activate resident c-kit ϩ cardiac stem cells (CSCs), a myocardial compartment of undifferentiated progenitor cells, to areas of myocardial injury (13).…”

Section: We Demonstrate For the First Time That Intramyocardial Injecmentioning

confidence: 99%

Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload

Wehman

Sharma

Pietris

et al. 2016

American Journal of Physiology-Heart and Circulatory Physiology

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(MSCs) have not been evaluated in a preclinical model of pressure overload, which simulates the pathophysiology relevant to many forms of CHD. A neonatal swine model of RV pressure overload was utilized to test the hypothesis that MSCs preserve RV function and attenuate ventricular remodeling. Immunosuppressed Yorkshire swine underwent pulmonary artery banding to induce RV dysfunction. After 30 min, human MSCs (1 million cells, n ϭ 5) or placebo (n ϭ 5) were injected intramyocardially into the RV free wall. Serial transthoracic echocardiography monitored RV functional indices including 2D myocardial strain analysis. Four weeks postinjection, the MSC-treated myocardium had a smaller increase in RV end-diastolic area, end-systolic area, and tricuspid vena contracta width (P Ͻ 0.01), increased RV fractional area of change, and improved myocardial strain mechanics relative to placebo (P Ͻ 0.01). The MSC-treated myocardium demonstrated enhanced neovessel formation (P Ͻ 0.0001), superior recruitment of endogenous c-kitϩ cardiac stem cells to the RV (P Ͻ 0.0001) and increased proliferation of cardiomyocytes (P ϭ 0.0009) and endothelial cells (P Ͻ 0.0001). Hypertrophic changes in the RV were more pronounced in the placebo group, as evidenced by greater wall thickness by echocardiography (P ϭ 0.008), increased cardiomyocyte cross-sectional area (P ϭ 0.001), and increased expression of hypertrophy-related genes, including brain natriuretic peptide, ␤-myosin heavy chain and myosin light chain. Additionally, MSC-treated myocardium demonstrated increased expression of the antihypertrophy secreted factor, growth differentiation factor 15 (GDF15), and its downstream effector, SMAD 2/3, in cultured neonatal rat cardiomyocytes and in the porcine RV myocardium. This is the first report of the use of MSCs as a therapeutic strategy to preserve RV function and attenuate remodeling in the setting of pressure overload. Mechanistically, transplanted MSCs possibly stimulated GDF15 and its downstream SMAD proteins to antagonize the hypertrophy response of pressure overload. These encouraging results have implications in congenital cardiac pressure overload lesions. stem cell therapy; congenital heart disease; right ventricle; pressure overload CONGENITAL HEART DISEASE (CHD) is the leading cause of morbidity and mortality in children with birth defects. While surgical interventions have dramatically improved outcomes and longevity in patients with CHD, many patients still progress to heart failure, a population that has grown significantly over the last decade (30). In contrast to adult patients, in whom ischemic heart disease is the predominant etiology of heart failure, children with CHD are frequently exposed to acute or chronic ventricular pressure and volume overload, which if untreated can progress to ventricular dysfunction and ultimately to heart failure. Further, patients with CHD who develop right ventricular (RV) dysfunction have the poorest outcomes (23, 26), particularly in those patients with univentricular heart disease i...

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“…The center of the scar on the endothelial border was noted, and scar thickness and wall thickness were measured at this point. Then, the same measurements were performed at half the distance between the center of the scar and the lateral edges of the scar, as previously described 6. Scar transmurality was calculated as the percentage of scar thickness over wall thickness.…”

Section: Methodsmentioning

confidence: 99%

Durable Benefits of Cellular Postconditioning: Long‐Term Effects of Allogeneic Cardiosphere‐Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction

Tseliou¹,

Couto²,

Gallet³

et al. 2016

JAHA

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BackgroundInfusion of allogeneic cardiosphere‐derived cells (allo‐CDCs) postreperfusion elicits cardioprotective cellular postconditioning in pigs with acute myocardial infarction. However, the long‐term effects of allo‐CDCs have not been assessed. We performed a placebo‐controlled pivotal study for long‐term evaluation, as well as shorter‐term mechanistic studies.Methods and ResultsMinipigs underwent 1.5‐hour mid‐left anterior descending balloon occlusion followed by reperfusion and were randomized to receive intracoronary allo‐CDCs or vehicle 30 minutes postreperfusion. Left ventriculography (LVG) demonstrated preserved ejection fraction (EF) and attenuation of LV remodeling in CDC‐treated pigs. Pigs underwent cardiac magnetic resonance imaging (MRI) and LVG 1 hour and 8 weeks after therapy to evaluate efficacy. MRI showed improvement of EF and attenuation of LV remodeling immediately after allo‐CDC infusion. In addition, allo‐CDCs improved regional function and decreased hypertrophy 2 months post‐treatment. Histological analysis revealed increased myocardial salvage index, enhanced vascularity, sustained reductions in infarct size/area at risk and scar transmurality, and attenuation of collagen deposition in the infarct zone of allo‐CDC‐treated pigs at 2 months. Allo‐CDCs did not evoke lymphohistiocytic infiltration or systemic humoral memory response. Short‐term experiments designed to probe mechanism revealed antiapoptotic effects of allo‐CDCs on cardiomyocytes and increases in cytoprotective macrophages, but no increase in overall inflammatory cell infiltration 2 hours after cell therapy.ConclusionsAllo‐CDC infusion postreperfusion is safe, improves cardiac function, and attenuates scar size and remodeling. The favorable effects persist for at least 2 months after therapy. Thus, cellular postconditioning confers not only acute cardioprotection, but also lasting structural and functional benefits.

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Autologous Mesenchymal Stem Cells Produce Concordant Improvements in Regional Function, Tissue Perfusion, and Fibrotic Burden When Administered to Patients Undergoing Coronary Artery Bypass Grafting

Cited by 320 publications

References 50 publications

Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart

Unique Features of Cortical Bone Stem Cells Associated With Repair of the Injured Heart

Mesenchymal stem cells preserve neonatal right ventricular function in a porcine model of pressure overload

Durable Benefits of Cellular Postconditioning: Long‐Term Effects of Allogeneic Cardiosphere‐Derived Cells Infused After Reperfusion in Pigs with Acute Myocardial Infarction

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