The Role of Autologous Mesenchymal Stem Cell Recellularization in Rescuing the Xenoreactive Immune Response

Abstract

Emerging evidence suggests that current xenograft valve replacements provoke an intense cell-mediated and humoral immune response that is a major regulator of time-dependent structural valve deterioration (SVD). Autologous recellularization may improve valvular durability by masking the xenograft scaffold from immune recognition. The purpose of this study was to directly address the role of autologous recellularization of xenograft scaffolds, in the regulation of the xenoreactive immune response in an in-vitro human model. To study the human xenoreactive immune response, we collected bone marrow, human pericardium and isolated peripheral blood mononuclear cells (PBMCs) from adult patients undergoing elective cardiac surgery. Decellularized bovine pericardium underwent recellularization with human mesenchymal stem cells (MSCs). Grafts were tested as either non-decellularized (fresh) bovine pericardium, decellularized bovine pericardium and recellularized bovine pericardium. We show that when decellularized bovine pericardium was recellularized with human MSCs and exposed to autologous human PBMCs in-vitro, there was a significant reduction in TNF-α and IFN-γ expression, along with a significant decrease in T-cell proliferation when compared to both wild-type and decellularized bovine pericardium (p<0.01). Importantly, recellularized bovine pericardium had an equivalent expression of TNF-α, IFN-γ and T-cell proliferation when compared to human pericardium exposed to autologous human PBMCs. Our data suggest that autologous MSC recellularization of xenogenic tissue abrogates the xenoreactive immune response with subsequent reduction in pro-inflammatory cytokine production and T-cell proliferation in an in-vitro human model. As such, autologous MSC recellularization of an acellular xenogenic scaffolds may be an effective approach to decrease the progression of bioprosthetic SVD.