Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, University of Navarra, Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain.
Instituto de Investigación Sanitaria de Navarra (IdiSNA), Pamplona, Spain; Program of Regenerative Medicine, CIMA, University of Navarra, Pamplona, Spain; Department of Animal Biology, Institute of Biomedicine of Málaga (IBIMA) Faculty of Science, University of Málaga, Málaga, Spain; Andalusian Centre for Nanomedicine and Biotechnology (BIONAND), Málaga, Spain.
Acta Biomater. 2021 May;126:394-407. doi: 10.1016/j.actbio.2021.03.017. Epub 2021 Mar 11.
Despite tremendous progress in cell-based therapies for heart repair, many challenges still exist. To enhance the therapeutic potential of cell therapy one approach is the combination of cells with biomaterial delivery vehicles. Here, we developed a biomimetic and biodegradable micro-platform based on polymeric microparticles (MPs) capable of maximizing the therapeutic potential of cardiac progenitor cells (CPCs) and explored its efficacy in a rat model of chronic myocardial infarction. The transplantation of CPCs adhered to MPs within the infarcted myocardial microenvironment improved the long-term engraftment of transplanted cells for up to one month. Furthermore, the enhancement of cardiac cellular retention correlated with an increase in functional recovery. In consonance, better tissue remodeling and vasculogenesis were observed in the animals treated with cells attached to MPs, which presented smaller infarct size, thicker right ventricular free wall, fewer deposition of periostin and greater density of vessels than animals treated with CPCs alone. Finally, we were able to show that part of this beneficial effect was mediated by CPC-derived extracellular vesicles (EVs). Taken together, these findings indicate that the biomimetic microcarriers support stem cell survival and increase cardiac function in chronic myocardial infarction through modulation of cardiac remodeling, vasculogenesis and CPCs-EVs mediated therapeutic effects. The biomimetic microcarriers provide a solution for biomaterial-assisted CPC delivery to the heart. STATEMENT OF SIGNIFICANCE: In this study, we evaluate the possibility of using a biomimetic and biodegradable micro-platform to improve cardiovascular progenitor therapy. The strategy reported herein serves as an injectable scaffold for adherent cells due to their excellent injectability through cardiac catheters, capacity for biomimetic three-dimensional stem cell support and controllable biodegradability. In a rat model of chronic myocardial infarction, the biomimetic microcarriers improved cardiac function, reduced chronic cardiac remodeling and increased vasculogenesis through the paracrine signaling of CPCs. We have also shown that extracellular vesicles derived from CPCs cultured on biomimetic substrates display antifibrotic effects, playing an important role in the therapeutic effects of our tissue-engineered approach. Therefore, biomimetic microcarriers represent a promising and effective strategy for biomaterial-assisted CPC delivery to the heart.
尽管细胞疗法在心脏修复方面取得了巨大进展，但仍存在许多挑战。为了提高细胞治疗的治疗潜力，一种方法是将细胞与生物材料输送载体结合。在这里，我们开发了一种基于聚合物微球 (MPs) 的仿生可生物降解微平台，该平台能够最大限度地提高心脏祖细胞 (CPCs) 的治疗潜力，并在慢性心肌梗死大鼠模型中探索其疗效。在梗死心肌微环境中，将粘附在 MPs 上的 CPC 移植可改善移植细胞的长期植入，最长可达 1 个月。此外，心脏细胞保留的增强与功能恢复的增加相关。一致地，在附着在 MPs 上的细胞处理的动物中观察到更好的组织重塑和血管生成，其表现为梗死面积较小，右心室游离壁较厚，骨膜蛋白沉积较少，血管密度较高，而单独用 CPC 处理的动物则较小。最后，我们能够表明，这种有益效果的一部分是由 CPC 衍生的细胞外囊泡 (EVs) 介导的。总之，这些发现表明，仿生微载体通过调节心脏重塑、血管生成和 CPCs-EVs 介导的治疗效果，支持干细胞存活并增加慢性心肌梗死中的心脏功能。仿生微载体为生物材料辅助 CPC 向心脏输送提供了一种解决方案。
