Cardiopoietic Stem Cell Therapy in Heart Failure Bartunek, Jozef, MD, PhD; Behfar, Atta, MD, PhD; Dolatabadi, Dariouch, MD ...
Journal of the American College of Cardiology,
06/2013, Letnik:
61, Številka:
23
Journal Article
Recenzirano
Odprti dostop
Objectives This study sought to evaluate the feasibility and safety of autologous bone marrow–derived and cardiogenically oriented mesenchymal stem cell therapy and to probe for signs of efficacy in ...patients with chronic heart failure. Background In pre-clinical heart failure models, cardiopoietic stem cell therapy improves left ventricular function and blunts pathological remodeling. Methods The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial, a prospective, multicenter, randomized trial, was conducted in patients with heart failure of ischemic origin who received standard of care or standard of care plus lineage-specified stem cells. In the cell therapy arm, bone marrow was harvested and isolated mesenchymal stem cells were exposed to a cardiogenic cocktail. Derived cardiopoietic stem cells, meeting release criteria under Good Manufacturing Practice, were delivered by endomyocardial injections guided by left ventricular electromechanical mapping. Data acquisition and analysis were performed in blinded fashion. The primary endpoint was feasibility/safety at 2-year follow-up. Secondary endpoints included cardiac structure/function and measures of global clinical performance 6 months post-therapy. Results Mesenchymal stem cell cocktail–based priming was achieved for each patient with the dose attained in 75% and delivery without complications in 100% of cases. There was no evidence of increased cardiac or systemic toxicity induced by cardiopoietic cell therapy. Left ventricular ejection fraction was improved by cell therapy (from 27.5 ± 1.0% to 34.5 ± 1.1%) versus standard of care alone (from 27.8 ± 2.0% to 28.0 ± 1.8%, p < 0.0001) and was associated with a reduction in left ventricular end-systolic volume (−24.8 ± 3.0 ml vs. −8.8 ± 3.9 ml, p < 0.001). Cell therapy also improved the 6-min walk distance (+62 ± 18 m vs. −15 ± 20 m, p < 0.01) and provided a superior composite clinical score encompassing cardiac parameters in tandem with New York Heart Association functional class, quality of life, physical performance, hospitalization, and event-free survival. Conclusions The C-CURE trial implements the paradigm of lineage guidance in cell therapy. Cardiopoietic stem cell therapy was found feasible and safe with signs of benefit in chronic heart failure, meriting definitive clinical evaluation. (C-Cure Clinical Trial; NCT00810238 ).
Objectives The goal of this study was to guide bone marrow-derived human mesenchymal stem cells (hMSCs) 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. Pre-emptive lineage pre-specification may optimize therapeutic outcome. Methods hMSC were harvested from a coronary artery disease patient cohort. A recombinant cocktail consisting of transforming growth factor-beta1 , bone morphogenetic protein-4, activin A, retinoic acid, insulin-like growth factor-1, fibroblast growth factor-2, alpha-thrombin, and interleukin-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 Although 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 homeobox transcription factor Nkx-2.5, T-box transcription factor TBX5, helix–loop–helix transcription factor MESP1, and myocyte enhancer factor MEF2C, markers of cardiopoiesis. Recombinant cardiogenic cocktail guidance secured the cardiopoietic phenotype across the patient cohort. Compared with 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 hMSC in chronic ischemic cardiomyopathy.
Cardiac Cell Repair Therapy: A Clinical Perspective Gersh, Bernard J., MBChB, DPhil, FRCP; Simari, Robert D., MD, PhD; Behfar, Atta, MD, PhD ...
Mayo Clinic proceedings,
10/2009, Letnik:
84, Številka:
10
Journal Article
Recenzirano
Odprti dostop
From bone marrow transplants 5 decades ago to the most recent stem cell—derived organ transplants, regenerative medicine is increasingly recognized as an emerging core component of modern practice. ...In cardiovascular medicine, innovation in stem cell biology has created curative solutions for the treatment of both ischemic and nonischemic cardiomyopathy. Multiple cell-based platforms have been developed, harnessing the regenerative potential of various natural and bioengineered sources. Clinical experience from the first 1000 patients (approximately) who have received stem cell therapy worldwide indicates a favorable safety profile with modest improvement in cardiac function and structural remodeling in the setting of acute myocardial infarction or chronic heart failure. Further investigation is required before early adoption and is ongoing. Broader application in practice will require continuous scientific advances to match each patient with the most effective reparative phenotype, while ensuring optimal cell delivery, dosing, and timing of intervention. An interdisciplinary effort across the scientific and clinical community within academia, biotechnology, and government will drive the successful realization of this next generation of therapeutic agents for the “broken” heart.
Patient-derived stem cells enable promising regenerative strategies but display heterogenous cardiac reparative proficiency, leading to unpredictable therapeutic outcomes impeding practice adoption. ...Means to establish and certify the regenerative potency of emerging biotherapies are thus warranted. In this era of clinomics, deconvolution of variant cytoreparative performance in clinical trials offers an unprecedented opportunity to map pathways that segregate regenerative from non-regenerative states informing the evolution of cardioregenerative quality systems. A maiden example of this approach is cardiopoiesis-mediated lineage-specification developed to ensure regenerative performance. Successfully tested in pre-clinical and early clinical studies, the safety and efficacy of the cardiopoietic stem cell phenotype is undergoing validation in pivotal trials for chronic ischemic cardiomyopathy offering the prospect of a next-generation regenerative solution for heart failure.
Abstract Background Osteonecrosis (ON) of the femoral head occurs when cells of trabecular bone spontaneously die. Mesenchymal stem cells (MSCs) have been introduced into the femoral head in an ...attempt to halt progression of the disease. The purpose of this study was to functionally compare MSCs in patients with ON of the femoral head with patients without. Methods Mesenchymal stem cells were isolated from 20 patients with corticosteroid-induced ON and 10 controls without. Colony-forming unit and proliferation assays were used to assess MSC proliferation. Mesenchymal stem cells were differentiated into bone, fat, and cartilage. Functional assays were used to quantify the differentiation capacity. Results Control MSCs demonstrated greater cellular growth potential and improved ability to differentiate into bone. Conclusion The decreased ability to differentiate into bone may be a reason why patients treated with autologous MSC infusion fail regenerative treatment strategies and progress to collapse.
Stem Cells Versus Senescence Behfar, Atta, MD, PhD; Terzic, Andre, MD, PhD
Journal of the American College of Cardiology,
2015, Letnik:
65, Številka:
2
Journal Article
Recenzirano
Odprti dostop
...use of regenerative therapies in the elderly prompts investigation into the effectiveness of stem cell therapy in senescence. (11) (Figure 1), stem cells endowed with an enhanced regenerative ...function may accommodate rescue of myocardial function without exposing patients to allogeneic therapies (20). ...identifying nucleostemin as a molecular mediator underpinning stem cell health may provide a novel means of assessing progenitor vitality and, by extension, regenerative potency in heart disease (12).
Regenerative Medicine: On the Vanguard of Health Care Terzic, Andre, MD, PhD; Folmes, Clifford D., PhD; Martinez-Fernandez, Almudena, PhD ...
Mayo Clinic proceedings,
07/2011, Letnik:
86, Številka:
7
Journal Article
Merkel cell carcinoma (MCC) is a rare, rapidly proliferating skin cancer that commonly metastasizes to regional lymph nodes. We present the case of a 73-year-old woman with a history of MCC and ...non-Hodgkin B-cell lymphoma who presented with second-degree heart block (Mobitz type II) caused by an interatrial mass. Temporary pacing was required before biopsy, which revealed metastatic MCC. Treatment included permanent pacing, anti–programmed cell death ligand 1 immunotherapy, and radiation to the heart resulting in notable decrease in tumor size and normalized cardiac rhythm.
PDF
