Christian Homsy

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

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-beta(1), 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.

Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART-1) trial design.

Cardiopoiesis is a conditioning programme that aims to upgrade the cardioregenerative aptitude of patient‐derived stem cells through lineage specification. Cardiopoietic stem cells tested initially for feasibility and safety exhibited signs of clinical benefit in patients with ischaemic heart failure (HF) warranting definitive evaluation. Accordingly, CHART‐1 is designed as a large randomized, sham‐controlled multicentre study aimed to validate cardiopoietic stem cell therapy.

Optimized Delivery System Achieves Enhanced Endomyocardial Stem Cell Retention

Background—Regenerative cell-based therapies are associated with limited myocardial retention of delivered stem cells. The objective of this study is to develop an endocardial delivery system for enhanced cell retention. Methods and Results—Stem cell retention was simulated in silico using 1- and 3-dimensional models of tissue distortion and compliance associated with delivery. Needle designs, predicted to be optimal, were accordingly engineered using nitinol, a nickel and titanium alloy displaying shape memory and superelasticity. Biocompatibility was tested with human mesenchymal stem cells. Experimental validation was performed with species-matched cells directly delivered into Langendorff-perfused porcine hearts or administered percutaneously into the endocardium of infarcted pigs. Cell retention was quantified by flow cytometry and real-time quantitative polymerase chain reaction methodology. Models, computing optimal distribution of distortion calibrated to favor tissue compliance, predicted that a 75°-curved needle featuring small-to-large graded side holes would ensure the highest cell retention profile. In isolated hearts, the nitinol curved needle catheter (C-Cath) design ensured 3-fold superior stem cell retention compared with a standard needle. In the setting of chronic infarction, percutaneous delivery of stem cells with C-Cath yielded a 37.7±7.1% versus 10.0±2.8% retention achieved with a traditional needle without effect on biocompatibility or safety. Conclusions—Modeling-guided development of a nitinol-based curved needle delivery system with incremental side holes achieved enhanced myocardial stem cell retention.

Reply: The C-CURE Randomized Clinical Trial (Cardiopoietic stem Cell therapy in heart failURE).

We appreciate the interest of Dr. Mielewczik and colleagues in the C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial. As outlined in our paper [(1)][1], feasibility and safety were the primary endpoints in this first-in-man study that assessed cardiogenically-oriented, autologous bone

Benefit of cardiopoietic mesenchymal stem cell therapy on left ventricular remodelling: results from the Congestive Heart Failure Cardiopoietic Regenerative Therapy (CHART‐1) study

Left ventricular (LV) reverse remodelling is an important marker of improved outcomes in patients with advanced heart failure (HF). We examined the impact of the intramyocardial administration of bone‐marrow‐derived, lineage‐directed, autologous cardiopoietic mesenchymal stem cells (C3BS‐CQR‐1) on LV remodelling in patients with advanced HF enrolled in the CHART‐1 study.

The effect of intracoronary infusion of bone marrow-derived mononuclear cells on all-cause mortality in acute myocardial infarction: rationale and design of the BAMI trial

Over the past 13 years bone marrow‐derived mononuclear cells (BM‐MNCs) have been widely investigated for clinical efficacy in patients following acute myocardial infarction (AMI). These early phase II trials have used various surrogate markers to judge efficacy and, although promising, the results have been inconsistent. The phase III BAMI trial has therefore been designed to demonstrate that intracoronary infusion of BM‐MNCs is safe and will significantly reduce the time to first occurrence of all‐cause death in patients with reduced left ventricular ejection fraction after successful reperfusion for ST‐elevation AMI (powered with the aim of detecting a 25% reduction in all‐cause mortality). This is a multinational, multicentre, randomized, open‐label, controlled, parallel‐group phase III study aiming to enrol approximately 3000 patients in 11 European countries with at least 17 sites. Eligible patients who have impaired left ventricular ejection (≤45%) following successful reperfusion for AMI will be randomized to treatment or control group in a 1:1 ratio. The treatment group will receive intracoronary infusion of BM‐MNCs 2–8 days after successful reperfusion for AMI added on top of optimal standard of care. The control group will receive optimal standard of care. The primary endpoint is time from randomization to all‐cause death. The BAMI trial is pivotal and the largest trial to date of BM‐MNCs in patients with impaired left ventricular function following AMI. The aim of the trial is to provide a definitive answer as to whether BM‐MNCs reduce all‐cause mortality in this group of patients.