Extracellular vesicles from dental pulp mesenchymal stem cells modulate macrophage phenotype during acute and chronic cardiac inflammation in athymic nude rats with myocardial infarction.

Autores de IIS La Fe

• Marta Gómez Ferrer

  Autor

• Imelda Ontoria Oviedo

  Autor

• Esteban Peiró Molina

  Autor

• 

  Pilar Sepúlveda Sanchis

  Autor

Participantes ajenos a IIS La Fe

• Amaro-Prellezo, Elena
• Hakobyan, Lusine
• Tarazona, Sonia
• Salguero, Pedro
• Ruiz-Sauri, Amparo
• Selva-Roldan, Marta
• Vives-Sanchez, Rosa

Grupos

• Regeneración y Trasplante Cardíaco

Abstract

BACKGROUND/AIMS: Extracellular vesicles (EVs) derived from dental pulp mesenchymal stem cells (DP-MSCs) are a promising therapeutic option for the treatment of myocardial ischemia. The aim of this study is to determine whether MSC-EVs could promote a pro-resolving environment in the heart by modulating macrophage populations. METHODS: EVs derived from three independent biopsies of DP-MSCs (MSC-EVs) were isolated by tangential flow-filtration and size exclusion chromatography and were characterized by omics analyses. Biological processes associated with these molecules were analyzed using String and GeneCodis platforms. The immunomodulatory capacity of MSC-EVs to polarize macrophages towards a pro-resolving or M2-like phenotype was assessed by evaluating surface markers, cytokine production, and efferocytosis. The therapeutic potential of MSC-EVs was evaluated in an acute myocardial infarction (AMI) model in nude rats. Infarct size and the distribution of macrophage populations in the infarct area were evaluated 7 and 21days after intramyocardial injection of MSC-EVs. RESULTS: Lipidomic, proteomic, and miRNA-seq analysis of MSC-EVs revealed their association with biological processes involved in tissue regeneration and regulation of the immune system, among others. MSC-EVs promoted the differentiation of pro-inflammatory macrophages towards a pro-resolving phenotype, as evidenced by increased expression of M2 markers and decreased secretion of pro-inflammatory cytokines. Administration of MSC-EVs in rats with AMI limited the extent of the infarcted area at 7 and 21days post-infarction. MSC-EV treatment also reduced the number of pro-inflammatory macrophages within the infarct area, promoting the resolution of inflammation. CONCLUSION: EVs derived from DP-MSCs exhibited similar characteristics at the omics level irrespective of the biopsy from which they were derived. All MSC-EVs exerted effective pro-resolving responses in a rat model of AMI, indicating their potential as therapeutic agents for the treatment of inflammation associated with AMI.

Keywords

• Extracellular vesicles; Mesenchymal stromal cells; Acute myocardial infarction; Inflammation; Macrophage