The Influence of Timing and Frequency of Adipose-Derived Mesenchymal Stem Cell Therapy on Immunomodulation Outcomes After Vascularized Composite Allotransplantation

Transplantation. 2017 Jan;101(1):e1-e11. doi: 10.1097/TP.0000000000001498.


Background: Cellular therapies for immunomodulation in vascularized composite allotransplantation (VCA) have gained importance due to their potential for minimization of immunosuppression. Adipose-derived (AD) mesenchymal stem cells (MSCs) especially have shown encouraging potential. We investigated the influence of timing and frequency of AD-MSC treatment on immunologic and graft survival as well as graft vasculopathy outcomes after VCA.

Methods: Lewis rats received full-mismatched Brown Norway rat hindlimb transplants. Recipient animals were assigned to groups receiving donor-derived AD-MSCs (10 cells/animal) either on postoperative day (POD) 1, POD 4, or repeatedly on POD 4, 8, and 15, and compared to untreated controls.

Results: Although AD-MSC administration on POD 1 or POD 4, 8, and 15 resulted in 50% long-term graft acceptance, recipients treated on POD 4, and controls rejected before POD 50. All treated animals revealed peripheral blood chimerism (4 weeks), most pronounced after repetitive cell administration (12.92% vs 5.03% [POD 1] vs 6.31% [POD 4]; P < 0.05; all P < 0.01 vs control 1.45%). Chimerism was associated with the generation of regulatory T cells (CD4CD25FoxP3). In vitro mixed lymphocyte reactions revealed modulation of the recipient immune response after AD-MSC treatment. Graft arteries at end point revealed significant differences of arterial intimal thickness between rejecting and AD-MSC-treated animals (P < 0.01).

Conclusions: Taken together, our results point to the potential for repetitive AD-MSC administration in improving outcomes after VCA. Future studies are warranted into optimization of the dosing and frequency of AD-MSC therapy, either alone or used in, combination with other cell therapies (such as hematopoietic stem cells or bone marrow-derived MSC or dendritic cells) for optimization of appropriate conditioning or maintenance regimens.

Publication types

  • Comparative Study

MeSH terms

  • Adipose Tissue / cytology*
  • Animals
  • Cell Proliferation
  • Cells, Cultured
  • Composite Tissue Allografts / blood supply*
  • Composite Tissue Allografts / immunology
  • Composite Tissue Allografts / transplantation*
  • Graft Rejection / immunology
  • Graft Rejection / prevention & control
  • Graft Survival*
  • Hindlimb / blood supply*
  • Hindlimb / immunology
  • Hindlimb / transplantation*
  • Immunotherapy / adverse effects
  • Immunotherapy / methods*
  • Lymphocyte Activation
  • Male
  • Mesenchymal Stem Cell Transplantation / adverse effects
  • Mesenchymal Stem Cell Transplantation / methods*
  • Mesenchymal Stem Cells / immunology*
  • Models, Animal
  • Rats, Inbred BN
  • Rats, Inbred Lew
  • T-Lymphocytes, Regulatory / immunology
  • Time Factors
  • Transplantation Chimera
  • Transplantation Tolerance
  • Vascular Diseases / immunology
  • Vascular Diseases / prevention & control
  • Vascularized Composite Allotransplantation / adverse effects
  • Vascularized Composite Allotransplantation / methods*