Enhancing myocardial repair with CardioClusters

• Published in: Nature communications Vol. 11; no. 1; p. 3955
• Main Authors: Monsanto, Megan M., Wang, Bingyan J., Ehrenberg, Zach R., Echeagaray, Oscar, White, Kevin S., Alvarez, Roberto, Fisher, Kristina, Sengphanith, Sharon, Muliono, Alvin, Gude, Natalie A., Sussman, Mark A.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 07-08-2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13; 13/106; 13/2; 13/31; 14; 14/1; 14/19; 14/35; 14/63; 38; 38/22; 38/39; 38/91; 631/61/2296; 64/60; 692/308/2171; 692/4019/592/2725; c-Kit protein; Cardiomyocytes; Cell size; Cellular structure; Combinatorial analysis; Congestive heart failure; Cytokines; Gene expression; Heart failure; Humanities and Social Sciences; Injectability; Interstitial cells; Mesenchyme; Microenvironments; multidisciplinary; Myocardial infarction; Optimization; Populations; Preservation; Progenitor cells; Recovery of function; Regeneration; Science; Science (multidisciplinary); Stem cell transplantation; Stem cells; Structure-function relationships; Synergistic effect
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-020-17742-z

Cellular therapy to treat heart failure is an ongoing focus of intense research, but progress toward structural and functional recovery remains modest. Engineered augmentation of established cellular effectors overcomes impediments to enhance reparative activity. Such ‘next generation’ implementation includes delivery of combinatorial cell populations exerting synergistic effects. Concurrent isolation and expansion of three distinct cardiac-derived interstitial cell types from human heart tissue, previously reported by our group, prompted design of a 3D structure that maximizes cellular interaction, allows for defined cell ratios, controls size, enables injectability, and minimizes cell loss. Herein, mesenchymal stem cells (MSCs), endothelial progenitor cells (EPCs) and c-Kit
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cardiac interstitial cells (cCICs) when cultured together spontaneously form scaffold-free 3D microenvironments termed CardioClusters. scRNA-Seq profiling reveals CardioCluster expression of stem cell-relevant factors, adhesion/extracellular-matrix molecules, and cytokines, while maintaining a more native transcriptome similar to endogenous cardiac cells. CardioCluster intramyocardial delivery improves cell retention and capillary density with preservation of cardiomyocyte size and long-term cardiac function in a murine infarction model followed 20 weeks. CardioCluster utilization in this preclinical setting establish fundamental insights, laying the framework for optimization in cell-based therapeutics intended to mitigate cardiomyopathic damage.
Despite recent progress to advance cardiac cell-based therapy for patients, heart failure mortality rivals most cancers. Here, the authors describe an approach to control and pattern 3 distinct human cardiac cell populations to promote superior repair and regeneration after myocardial infarction.