Immunomodulation by mesenchymal stem cells for myocardial regeneration: cellular mechanisms and extracellular vesicles

Student thesis: Doctoral thesis

Abstract

Exacerbated immune responses hamper regeneration of injured tissues and organ transplantation, and lead to allergies and autoimmune disorders causing morbidity and mortality. One of these scenarios is the ischaemia-reperfusion injury (IRI) occurring upon myocardial infarction (MI). IRI triggers an intense inflammatory response that is initially necessary for dead cell clearance and the induction of cardiac repair, but its timely suppression is critical to minimize post-MI tissue damage, cardiac remodelling and ultimately, heart failure. In this context, mesenchymal stem cells (MSCs) are promising as a therapeutic strategy to counteract such unwanted immune responses, as MSC administration has a beneficial effect for the treatment of immune-related disorders and promote cardiac repair in preclinical models of MI, albeit their short lifespan after in vivo infusion. The aim of this thesis is to decipher the cellular and paracrine mechanisms that would help explain MSCs’ long-lasting immunosuppressive and regenerative effects. The working hypothesis is that these could be mediated by the modulation of the host’s immune cells for the generation of regulatory environments and enduring effect, in addition to the secretion of paracrine factors for a delocalized action that would also foster endogenous repair. With this in mind, we first studied MSC’s influence on monocytes as part of the innate immune response. We confirmed MSCs’ modulation of monocytes towards a wound-healing M2-like polarization, but with the added functionality of an active extracellular adenosinergic enzymatic activity. MSC-conditioned monocytes maintained CD39 and induced CD73 expression, which are responsible of the sequential hydrolysis of ATP/ADP to AMP and to Adenosine, respectively, to shift the pro-inflammatory milieu induced by extracellular ATP to the anti-inflammatory regulation by Adenosine. On the other side, MSCs also modulate the adaptive immune response, as we observed the immunosuppression of allogeneic lymphocyte polyclonal proliferation and inflammatory cytokine release. Regarding the paracrine activity of MSCs, we could identify extracellular vesicles (EVs) as one of the active components of MSC’s immunosuppressive secreted factors. Specifically, we demonstrated the importance of accurate isolation of MSC-EVs to unravel their immunosuppressive functionality, which can be efficiently performed by size-exclusion chromatography (SEC). Finally, this knowledge made us design a novel construct composed of MSC-EVs embedded in a biocompatible three-dimensional engineered cardiac scaffold, envisioned for the local treatment of MI to foster cardiac repair. Its in vitro validation reinforced EV secretion as an important mechanism of MSCs to both modulate the immune system and foster endogenous repair, as they could actively recruit pro-regenerative cells. Our findings unravel new mechanisms for the engineering of innovative, targeted and off-the-shelf therapeutic products.
Date of Award26 Oct 2018
Original languageEnglish
Awarding Institution
  • Universitat Autònoma de Barcelona (UAB)
SupervisorFrancisco Enrique Borras Serres (Director) & Maria Dolores Jaraquemada Perez de Guzman (Director)

Keywords

  • CD73
  • Extracellular vesicles
  • Myocardial infarction

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