PD‐L1 overexpression conveys tolerance of mesenchymal stem cell‐derived cardiomyocyte‐like cells in an allogeneic mouse model

Abstract

Although the autologously transplanted cells are immunologically durable, allogeneic cell transplantation is inevitable in a series of cases. Mesenchymal stem cells (MSCs) are one of the suitable candidates for cardiac tissue regeneration that have been shown to acquire immunogenicity concurrent with cardiomyogenic differentiation. The present study aimed to exploit PD-L1, as a key immunomodulatory checkpoint ligand to protect the MSCs-derived cardiomyocyte-like cells (CLCs) against the detrimental alloimmunity. Mouse bone marrow-derived MSCs were stably transduced to overexpress PD-L1. MSCs were in vitro differentiated into CLCs and the expressions of immunologic molecules were compared between MSCs and CLCs. The in vitro and in vivo allogeneic immune responses were also examined. The differentiated CLCs had higher expressions of MHC-I and CD80. Upon in vitro coculture with allogeneic splenocytes, CLCs caused more CD4 + and CD8 + T cell activation, lymphocyte proliferation, and interferon-γ (IFN-γ) release in comparison to MSCs. PD-L1 overexpression on CLCs decreased the activation of CD8 + T cells, proliferation of lymphocytes, and release of IFN-γ. The PD-L1-overexpressing CLCs elicited lower in vivo CD4 + and CD8 + T cell activation and reduced the anti-donor antibody response accompanied by increased durability and reduced T cell infiltration. The present study verified the potential of PD-L1 overexpression as a preparative strategy for the protection of allogeneic MSCs-derived CLCs against the detrimental alloreaction.

Transplanted allogeneic cardiac progenitor cells secrete GDF-15 and stimulate an active immune remodeling process in the ischemic myocardium

“…Allogeneic cell therapy circumvents these limitations of autologous cell preparations. The immunosuppressive properties and low immunogenicity of certain allogenic cells contribute to a reduced or weakened immune response compared with other cell types [3].…”

The Role of Stem Cells in the Treatment of Cardiovascular Diseases

“…The modified stem cells reduced infarct size and promoted CD25+ cells, which play a cardioprotective role during MI [212,213]. In addition, overexpression of PD-L1 has been suggested to improve the viability and survival of stem cell-derived cardiomyocytes by reducing their immunogenicity [214].…”