The clinical translation dilemma of mesenchymal stem cell-based therapies for cardiac repair: What can tissue engineering do?

The inherently minimal self-renewal potential of cardiomyocytes (CMs) is insufficient to achieve comprehensive cardiac regeneration post myocardial infarction (MI). Mesenchymal stem cells (MSCs) and MSC-derived exosomes (MSC-Exos) exhibit distinguished paracrine effects, thereby presenting important prospects for cardiac repair. However, key challenges, including the hostile microenvironment within the infarcted myocardium, poor retention of MSC-derived therapeutic agents, and the risk of immune rejection, hinder the clinical application of MSC-based therapies. Advanced cardiac tissue engineering (CTE) strategies can optimize the therapeutic effects of MSC-based therapies by improving delivery targeting, enhancing the resistance of MSCs and MSC-Exos, prolonging cell retention, and facilitating the paracrine signaling pathways. By integrating CTE technology, MSC-derived therapeutic formulations are anticipated to evolve into therapeutic products that comply with good manufacturing practice (GMP) standards while also meeting the demand for “off-the-shelf " medications in clinical practice. Despite growing interest, a lack of systematic reviews remains, focusing on the integration of CTE technology to facilitate the clinical translation of MSC-based therapeutic strategies. In this review, we briefly outline the mechanisms underlying MSC-mediated cardioprotection and the challenges hindering their clinical application. We emphasize the critical role of CTE strategies, such as cell sheets, hydrogels, nanotechnology, and 3D bioprinting, in advancing the clinical translation of MSC-derived products. Moreover, innovative delivery approaches for minimally invasive administration and the future orientation of MSC-based therapies, combined with CTE in cardiac regeneration, are also summarized. Collectively, this review provides a latest paradigm that highlights the crucial role of CTE strategies in expediting the translation of MSC-based cardiac repair therapies into practical clinical applications.