AUTHOR=Wang Xicheng , Yang Chao , Ma Xiaoxue , Li Xiuhua , Qi Yiyao , Bai Zhihui , Xu Ying , Ma Keming , Luo Yi , Song Jiyang , Jia Wenwen , He Zhiying , Liu Zhongmin 

TITLE=A division-of-labor mode contributes to the cardioprotective potential of mesenchymal stem/stromal cells in heart failure post myocardial infarction

JOURNAL=Frontiers in Immunology

VOLUME=Volume 15 - 2024

YEAR=2024

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2024.1363517

DOI=10.3389/fimmu.2024.1363517

ISSN=1664-3224

ABSTRACT=Treatment of heart failure post myocardial infarction (post-MI HF) with mesenchymal stem/stromal cells (MSCs) holds great promise. Nevertheless, 2-dimensional (2D) GMP-grade MSCs from different labs and donor sources have different therapeutic efficacy and still in a low yield. Therefore, it is crucial to increase the production and find novel ways to assess the therapeutic efficacy of MSCs.hUC-MSCs were cultured in 3-dimensional (3D) expansion system for obtaining enough cells for clinical use, named as 3D MSCs. A post-MI HF mouse model was employed to conduct in vivo and in vitro experiments. Single-cell and bulk RNA-seq analyses were performed on 3D MSCs. A total of 125 combination algorithms were leveraged to screen for core ligand genes. Shinyapp and shinycell workflows were used for deploying web-server.3D GMP-grade MSCs can significantly and stably reduce the extent of post-MI HF.To understand the stable potential cardioprotective mechanism, scRNA-seq revealed the heterogeneity and division-of-labor mode of 3D MSCs at the cellular level. Specifically, scissor phenotypic analysis identified a reported wound-healing CD142 + MSCs subpopulation that is also associated with cardiac protection ability and CD142 -MSCs that is in proliferative state, contributing to the cardioprotective function and self-renewal, respectively. Differential expression analysis was conducted on CD142 + MSCs and CD142 -MSCs and the differentially expressed ligand-related model was achieved by employing 125 combination algorithms. The present study developed a machine learning predictive model based on 13 ligands.Further analysis using CellChat demonstrated that CD142 + MSCs have a stronger  secretion capacity compared to CD142 -MSCs and Flow cytometry sorting of the CD142 + MSCs and qRT-PCR validation confirmed the significant upregulation of these 13 ligand factors in CD142 + MSCs. Clinical GMP-grade 3D MSCs could serve as a stable cardioprotective cell product.Using scissor analysis on scRNA-seq data, we have clarified the potential functional and proliferative subpopulation, which cooperatively contributed to self-renewal and functional maintenance for 3D MSCs, named as "division of labor" mode of MSCs.Moreover, a ligand model was robustly developed for predicting the secretory efficacy of MSCs. A user-friendly web-server and a predictive model were constructed and available (https://wangxc.shinyapps.io/3D_MSCs/).