Extracellular vesicles from human cardiovascular progenitors trigger a reparative immune response in infarcted hearts

Cardiovasc Res. 2021 Jan 1;117(1):292-307. doi: 10.1093/cvr/cvaa028.

Abstract

Aims: The cardioprotective effects of human induced pluripotent stem cell-derived cardiovascular progenitor cells (CPC) are largely mediated by the paracrine release of extracellular vesicles (EV). We aimed to assess the immunological behaviour of EV-CPC, which is a prerequisite for their clinical translation.

Methods and results: Flow cytometry demonstrated that EV-CPC expressed very low levels of immune relevant molecules including HLA Class I, CD80, CD274 (PD-L1), and CD275 (ICOS-L); and moderate levels of ligands of the natural killer (NK) cell activating receptor, NKG2D. In mixed lymphocyte reactions, EV-CPC neither induced nor modulated adaptive allogeneic T cell immune responses. They also failed to induce NK cell degranulation, even at high concentrations. These in vitro effects were confirmed in vivo as repeated injections of EV-CPC did not stimulate production of immunoglobulins or affect the interferon (IFN)-γ responses from primed splenocytes. In a mouse model of chronic heart failure, intra-myocardial injections of EV-CPC, 3 weeks after myocardial infarction, decreased both the number of cardiac pro-inflammatory Ly6Chigh monocytes and circulating levels of pro-inflammatory cytokines (IL-1α, TNF-α, and IFN-γ). In a model of acute infarction, direct cardiac injection of EV-CPC 2 days after infarction reduced pro-inflammatory macrophages, Ly6Chigh monocytes, and neutrophils in heart tissue as compared to controls. EV-CPC also reduced levels of pro-inflammatory cytokines IL-1α, IL-2, and IL-6, and increased levels of the anti-inflammatory cytokine IL-10. These effects on human macrophages and monocytes were reproduced in vitro; EV-CPC reduced the number of pro-inflammatory monocytes and M1 macrophages, while increasing the number of anti-inflammatory M2 macrophages.

Conclusions: EV-CPC do not trigger an immune response either in in vitro human allogeneic models or in immunocompetent animal models. The capacity for orienting the response of monocyte/macrophages towards resolution of inflammation strengthens the clinical attractiveness of EV-CPC as an acellular therapy for cardiac repair.

Keywords: Acellular therapies; Extracellular vesicles; Heart failure; Immunomodulatory effects.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Cell Proliferation*
  • Coculture Techniques
  • Cytokines / metabolism
  • Disease Models, Animal
  • Extracellular Vesicles / immunology
  • Extracellular Vesicles / metabolism
  • Extracellular Vesicles / transplantation*
  • Heart Failure / immunology
  • Heart Failure / metabolism
  • Heart Failure / physiopathology
  • Heart Failure / surgery*
  • Humans
  • Induced Pluripotent Stem Cells / immunology
  • Induced Pluripotent Stem Cells / metabolism
  • Induced Pluripotent Stem Cells / transplantation*
  • Inflammation Mediators / metabolism
  • Macrophages / immunology
  • Macrophages / metabolism
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Monocytes / immunology
  • Monocytes / metabolism
  • Myocardial Infarction / immunology
  • Myocardial Infarction / metabolism
  • Myocardial Infarction / physiopathology
  • Myocardial Infarction / surgery*
  • Myocardium / immunology*
  • Myocardium / metabolism
  • Myocardium / pathology
  • Myocytes, Cardiac / immunology
  • Myocytes, Cardiac / metabolism
  • Myocytes, Cardiac / transplantation*
  • Neutrophils / immunology
  • Neutrophils / metabolism
  • Phenotype
  • Rats
  • Regeneration*

Substances

  • Cytokines
  • Inflammation Mediators