Immunomodulatory Effects of Bone Marrow-Derived Mesenchymal Stem Cells in a Swine Hemi-Facial Allotransplantation Model

Abstract

BackgroundIn this study, we investigated whether the infusion of bone marrow-derived mesenchymal stem cells (MSCs), combined with transient immunosuppressant treatment, could suppress allograft rejection and modulate T-cell regulation in a swine orthotopic hemi-facial composite tissue allotransplantation (CTA) model.Methodology/Principal FindingsOutbred miniature swine underwent hemi-facial allotransplantation (day 0). Group-I (n = 5) consisted of untreated control animals. Group-II (n = 3) animals received MSCs alone (given on days −1, +1, +3, +7, +14, and +21). Group-III (n = 3) animals received CsA (days 0 to +28). Group-IV (n = 5) animals received CsA (days 0 to +28) and MSCs (days −1, +1, +3, +7, +14, and +21). The transplanted face tissue was observed daily for signs of rejection. Biopsies of donor tissues and recipient blood sample were obtained at specified predetermined times (per 2 weeks post-transplant) or at the time of clinically evident rejection. Our results indicated that the MSC-CsA group had significantly prolonged allograft survival compared to the other groups (P<0.001). Histological examination of the MSC-CsA group displayed the lowest degree of rejection in alloskin and lymphoid gland tissues. TNF-α expression in circulating blood revealed significant suppression in the MSC and MSC-CsA treatment groups, as compared to that in controls. IHC staining showed CD45 and IL-6 expression were significantly decreased in MSC-CsA treatment groups compared to controls. The number of CD4+/CD25+ regulatory T-cells and IL-10 expressions in the circulating blood significantly increased in the MSC-CsA group compared to the other groups. IHC staining of alloskin tissue biopsies revealed a significant increase in the numbers of foxp3+T-cells and TGF-β1 positive cells in the MSC-CsA group compared to the other groups.ConclusionsThese results demonstrate that MSCs significantly prolong hemifacial CTA survival. Our data indicate the MSCs did not only suppress inflammation and acute rejection of CTA, but also modulate T-cell regulation and related cytokines expression.

Preclinical Models in Vascularized Composite Allotransplantation

“…It is also possible that the early management of rejection increases the long-term survival and outcomes of a skincontaining VCA. It has been reported that the bone marrow component of the VCA graft may confer immunogenic protection, and investigations including bone marrow infusions or bone marrow-derived mesenchymal stem cells have resulted in tolerance to VCA grafts, however, not without complications related to graft vs. host disease and post transplant lymphoproliferative disorders [40][41][42][43].…”

iPSC-MSCs Combined with Low-Dose Rapamycin Induced Islet Allograft Tolerance Through Suppressing Th1 and Enhancing Regulatory T-Cell Differentiation

“…The immunosuppressive effect and low immunogenicity of mesenchymal stem cells (MSCs) make them ideal candidates for immunosuppressive strategies [3,4]. Adult MSCs have been used widely in the allogeneic heart [5][6][7][8][9][10][11], liver [12], islet [13][14][15][16][17], kidney [18,19], and composite tissue transplants [20,21]. Bone marrow mesenchymal stem cells (BM-MSCs) alone prolong heart allograft survival [8].…”

Mesenchymal Stem Cells as Immune Modulators in VCA

“…Furthermore, the very nature of a skin-bearing allograft being visible to the patient allows for continuous monitoring for signs of rejection, which would likely be a benefit when undertaking clinical trials of MSC therapy or minimization protocols. While there are no active clinical trials using exclusively MSCs for VCA, several preclinical studies have demonstrated a marked immunosuppressive effect of systemically delivered MSCs following VCA on the incidence and severity of acute rejection, the peripheral blood T regulatory response, inflammatory cytokine expression profile, and ultimately allograft survival [2,59,61,63]. These promising findings serve as a foundation for eventual translation of MSC therapy to clinical cases.…”