Stem cell therapy for heart failure: Ensuring regenerative proficiency

Abstract

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 cardio-regenerative 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.

Keywords: Cardiopoiesis; Cardiopoietic stem cell; Cardiovascular disease; Clinical trial; Clinomics; Epidemic; Health care; Myocardial infarction; Next generation; Quality; Regenerative medicine; System.

Fig. 1

The chronic heart failure epidemic in the context of advances in acute coronary care. Fifty year-long trends highlighting the impact of acute revascularization on myocardial infarction (MI) mortality (red line) and concomitant increase in heart failure hospitalizations (blue line). Data represented as incidence per 10,000 persons and normalized to US Census population figures. Vertical markers: Institution of coronary artery bypass grafting (CABG); percutaneous transluminal coronary angioplasty (PTCA); thrombolytics (streptokinase and tPA); bare metal stent (BMS); and drug eluting stent (DES). Dashed line: percutaneous coronary intervention (PCI).

Fig. 2

Heterogenous regenerative proficiency. Left column: Harvest of unselected stem cell populations, which when delivered as a singular intervention produce mixed results. Middle column: Only 5% of patients with heart failure harbor stem cells associated with clinically demonstrable benefit. Right column: Reparative cell populations are distinguished from non-reparative counterparts by a distinct molecular signature reflecting functional plasticity.

Fig. 3

Targeted (re)activation of latent plasticity in adult stem cells augments the repair quotient. Left: Cardiopoiesis, via cardiogenic cues, guides patient-derived stem cells into a state of active cellular plasticity and cardiovasculogenesis to augment repair aptitude. Right: Increase of cardiac repair propensity in stem cells following cardiopoietic guidance.

Fig. 4

Cardiopoiesis platform: Translating discovery into application. Deconvoluted molecular events underlying cardiogenesis guided translation and scale-up of lineage-specified stem cells manufactured for clinical application.

Fig. 5

Multitier release criteria offer a quality control system to ensure optimal regenerative proficiency. A quality system infrastructure conforming to Good Manufacturing Practice standards is needed for procurement, manufacture, and release of lineage-specified cellular product. A logistics-supervised distribution insures delivery of stable product for clinical use.

Fig. 6

Clinical implementation of the lineage-guidance paradigm in cell therapy. The C-CURE (Cardiopoietic stem Cell therapy in heart failURE) trial was conducted in patients with ischemic heart failure. Bone marrow was harvested (step 1) and isolated mesenchymal stem cells (step 2) lineage-specified by cardiogenic cocktail priming (step 3). Cardiopoietic stem cells meeting release criteria were delivered by endomyocardial injections (step 4). On follow-up, signs of efficacy were documented (step 5).

Fig. 7

Clinomics-based optimization algorithm informs next generation regenerative biotherapies. Mixed outcomes documented in cardiovascular clinical trials underscore a limitation of first generation stem cell regimens. High-throughput clinomics strategies provide the opportunity to delineate the molecular underpinnings of responders versus non-responders informing next generation strategies. Use of a priming platform to guide patient-derived stem cells into a pro-reparative phenotype exemplifies such an optimizing approach aimed to ensure benefit in heart failure patient populations.