Extracellular Vesicles Released by Allogeneic Human Cardiac Stem/Progenitor Cells as Part of Their Therapeutic Benefit

Stem Cells Translational Medicine

Yann J. Ferrat¹  Nabila Jabrane‐Ferrat²  Qian Chen²  Olga de laRosa³  Mabel Jouve San Roman⁴  Dominique Charron⁵  Simon Brunel⁵  Armand Bensussan⁵  Jerome Giustiniani⁵  Hocine Rachid Hocine⁵  Reem Al‐Daccak⁵  Eleuterio Lombardo⁶  Itziar Palacios⁶ 

[1]CERAG Laboratory University of Grenoble Alpes Grenoble France

[2]Centre of Pathophysiology Toulouse Purpan INSERM U1043, CNRS UMR5282, Toulouse III University Toulouse France

[3]Cortherapix SLU Tigenix Group Tres Cantos Madrid Spain

[4]Institut Curie UMR3215 Paris France

[5]Institut National de la Santé et de la Recherche Médicale (INSERM) UMRS‐976 Université Paris‐Diderot, Hôpital Saint‐Louis Paris France

[6]Tigenix Tres Cantos Madrid Spain

关键词: Human cardiac stem/progenitor cells;    Extracellular vesicles;    Exosomes;    Allogeneic stem cell‐based therapy;    Paracrine effect;    Cardiac repair/regeneration;   

DOI  :  10.1002/sctm.18-0256

来源: DOAJ

【 摘 要 】

Abstract The positive effects of therapeutic human allogeneic cardiac stem/progenitor cells (hCPC) in terms of cardiac repair/regeneration are very likely mediated by paracrine effects. Our previous studies revealed the advantageous immune interactions of allogeneic hCPC and proposed them as part of the positive paracrine effects occurring upon their application postmyocardial infarction (MI). Currently, extracellular vesicles/exosomes (EV/Exs) released by stem/progenitor cells are also proposed as major mediators of paracrine effects of therapeutic cells. Along this line, we evaluated contribution of EV/Exs released by therapeutic hCPC to the benefit of their successful allogeneic clinical application. Through tailored allogeneic in vitro human assay models mimicking the clinical setting, we demonstrate that hCPC‐released EV/Exs were rapidly and efficiently up‐taken by chief cellular actors of cardiac repair/regeneration. This promoted MAPK/Erk1/2 activation, migration, and proliferation of human leukocyte antigens (HLA)‐mismatched hCPC, mimicking endogenous progenitor cells and cardiomyocytes, and enhanced endothelial cell migration, growth, and organization into tube‐like structures through activation of several signaling pathways. EV/Exs also acted as pro‐survival stimuli for HLA‐mismatched monocytes tuning their phenotype toward an intermediate anti‐inflammatory pro‐angiogenic phenotype. Thus, while positively impacting the intrinsic regenerative and angiogenic programs, EV/Exs released by therapeutic allogeneic hCPC can also actively contribute to shaping MI‐inflammatory environment, which could strengthen the benefits of hCPC allogeneic interactions. Collectively, our data might forecast the application of allogeneic hCPC followed by their cell‐free EV/Exs as a strategy that will not only elicit the cell‐contact mediated reparative/regenerative immune response but also have the desired long‐lasting effects through the EV/Exs. Stem Cells Translational Medicine 2019;8:911&924

【 授权许可】

Unknown