Intracardiac allogeneic mesenchymal stem cell (MSC) transplantation. Can we translate the 'in vitro' immune properties of MSC into an 'in vivo' inflammatory model without immunosuppression ?
(2011)
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- Authors
- Supervisors
- Gianello, Pierre
- Abstract
- (en) This research work investigates the immune reaction which occurs after allogeneic mesenchymal stem cells transplantation in a swine model of subacute ischemic cardiomyopathy. The degree of MHC disparity selected in this experimental model is a one-haplotype MHC Class I and Class II mismatch that mimics an allogeneic transplantation from F1generation into parents. Prior to a series of in vivo experiments, the authors analyzed in vitro the MHC expression of swine mesenchymal stem cells in the context of inflammation, the T-cell proliferative responses to naïve and stimulated allogeneic mesenchymal stem cells. The immuno-modulatory properties of MSCs on T cell proliferation are described and potential mechanisms of action are studied. In vitro experiments revealed that in a pro-inflammatory cytokine environment, naïve swine mesenchymal stem cells up-regulate MCH Class I and Class II molecules on their cell surface, but failed to trigger recipient T cell proliferation. MSC can efficiently down-modulate T cell proliferation and this effect is not dependent on a Th2-type immune deviation, and is not mediated by the production of immuno-modulatory cytokines such as TGF-beta. It is dose-dependent and does not require cell-to-cell contact. In Vivo experiments revealed that immune B- and T-cell responses to allogeneic mesenchymal stem cells transplantation were triggered in the absence of immunosuppression. The design of the work allowed for investigate the role of the site of transplantation as well as the number of episode of cell transplantation. A single episode of allogeneic MSC transplantation into an injured myocardium elicited the production of cytotoxic and donor-specific antibodies as well as a donor-specific T-cell response. In order to avoid rejection, this research work further explores in vitro the interaction between MSCs and immunosuppressive drugs. Based on proliferation and viability assays as well as on their synergistic effect on down-modulating recipient T-cell proliferation, the authors showed that important differences existed between drugs used. In the second set of In Vivo experiments, this work demonstrates that a 12-day course of tacrolimus at the time of allogeneic MSC intracardiac transplantation can efficiently down-modulate recipient B- and T-cell responses. At one month, no significant CD3(+) T-Cell infiltration was present after cell transplantation in the injured myocardium, though an increase in macrophages was noticed, likely related to a tissue clearing process of apoptotic stem cells. Finally, the authors explored the neo-angiogenic effect of allogeneic mesenchymal stem cell transplantation. A four-fold increase in the density of neo-capillaries in the remote zone of myocardium adjacent to the fibrotic scarred tissue was demonstrated one month after MSC transplantation, suggesting that one of the mechanisms of action of MSC transplantation was recruitment of hibernating myocardium. In the last chapter, the authors elaborate on the future directions opened to cardiac regenerative medicine. Both the bio-engineering fields as well as the cellular xenotransplantation field are briefly covered.
- Affiliations
Citations
Poncelet, A. (2011). Intracardiac allogeneic mesenchymal stem cell (MSC) transplantation. Can we translate the ‘in vitro’ immune properties of MSC into an ‘in vivo’ inflammatory model without immunosuppression ? https://hdl.handle.net/2078.5/154363