Device encapsulated MSCs for adaptive secretome therapy to effectively target ischaemic heart injury

Abstract

Background: Effective long-term strategies to protect the ischaemic heart remain a significant challenge. Mesenchymal stromal cells (MSCs) offer therapeutic potential primarily through their secretome, a bioactive factor-rich milieu with broad beneficial effects. However, existing delivery methods have not demonstrated sustained cardioprotection. The objective of this study was to evaluate a clinically translatable approach for sustained MSC-secretome delivery to achieve long-term cardioprotection. Methods: Cymerus MSCs, derived from human induced pluripotent stem cells (iPSCs), were encapsulated in a Procyon immunoisolation device and implanted subcutaneously in adult Sprague Dawley rats with chronic myocardial ischaemia-reperfusion injury. A human iPSC-derived engineered cardiac microtissue model was used to simulate ischaemia-reperfusion injury and assess cardioprotective effects in a human context. Proteomic analysis was performed to characterize adaptive changes in MSCs and their secretome post-implantation. Results: The MSC-loaded Procyon device significantly improved cardiac function and reduced adverse left ventricular remodelling over 12 weeks in both young and middle-aged, male and female rats. The encapsulated MSCs remained viable and retained the ability to release therapeutic secretome at 12 weeks post-implantation. In vitro, the MSC secretome protected human engineered cardiac microtissues from simulated ischaemia-reperfusion injury by restoring contractile function, improving cell viability, and reducing oxidative stress. Proteomic profiling of encapsulated MSC identified 179 unique cellular proteins post-implantation, associated with adaptive immune and inflammatory responses as well as wound healing. MSC secretome profiling revealed increased protein diversity associated with tissue repair and immune regulation, suggesting MSCs undergo an adaptive response to ischaemic conditions.

1. Introduction

Ischaemic heart disease remains the leading cause of death globally, with acute myocardial infarction (AMI) as a key clinical manifestation [1]. A major complication following AMI is adverse left ventricular remodelling, which often progresses to heart failure. Although several therapies are available to protect and repair the heart post-AMI, their effectiveness diminishes as the disease advances and the extent of damage increases [2]. Consequently, there is a critical unmet need for more effective long-term cardioprotective interventions. Stem cell therapy presents a promising opportunity to address this critical unmet need.

Mesenchymal stromal cells (MSCs), including those derived from human induced pluripotent stem cells (iPSCs), have shown promising potential to enhance cardiac function and structure, primarily through the paracrine activity of their secretome [3–5]. This secretome significantly improves the myocardial microenvironment by activating endogenous repair mechanisms; these include enhancing cell survival, promoting angiogenesis, resolving inflammation, and mitigating adverse remodelling [6, 7]. These promising preclinical findings on the MSC secretome are further reinforced by the ongoing first-in-human Phase 1 clinical trial, SECRET-HF, which specifically evaluates the cardioprotective effect of an extracellular vesicle-enriched secretome derived from cardiovascular progenitor cells generated from human iPSCs. While the trial is still underway, a case study of a patient with non-ischaemic dilated cardiomyopathy who received three intravenous infusions of secretome at three-week intervals showed promising cardiac improvements with no signs of immunogenicity [8].

Despite these advancements, clinical studies using MSCs from various sources have only demonstrated modest improvements in cardiac function. The limited success of MSC therapies is p