J Reconstr Microsurg 2020; 36(06): 397-402
DOI: 10.1055/s-0040-1702150
Original Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

Robustness Testing of Mesenchymal Stem Cell Monotherapy Following Vascularized Composite Allotransplantation

Zvi Steinberger*
1   Department of Orthopedics Surgery, Penn Medicine University City, Philadelphia, Pennsylvania
2   Department of Orthopedic Surgery, Sheba Medical Center, Tel Hashomer, Ramat Gan, Israel
,
Heng Xu*
1   Department of Orthopedics Surgery, Penn Medicine University City, Philadelphia, Pennsylvania
3   Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai, China
,
Nikolas H. Kazmers
4   Department of Orthopaedic Surgery, University of Utah, Salt Lake City, Utah
,
Chi-Der Chen
5   Department of Anatomy and Cell Biology, School of Dental Medicine, University of Pennsylvania, Philadelphia, Pennsylvania
,
Robert J. Caron
6   Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania
,
Ling Qin
6   Department of Orthopaedic Surgery, University of Pennsylvania, Philadelphia, Pennsylvania
,
Yixin Zhang
3   Department of Plastic and Reconstructive Surgery, Shanghai Ninth People's Hospital, Shanghai, China
,
Lawrence Scott Levin
1   Department of Orthopedics Surgery, Penn Medicine University City, Philadelphia, Pennsylvania
7   Division of Plastic Surgery, Perelman Center for Advanced Medicine, Philadelphia, Pennsylvania
› Author Affiliations
Further Information

Publication History

14 May 2019

04 January 2020

Publication Date:
10 February 2020 (online)

Abstract

Background Immunosuppression risks are a major concern with vascularized composite allotransplantation (VCA). As an emerging strategy, the antirejection role played by mesenchymal stem cells (MSCs) is receiving attention. However, the current literature reports are inconclusive regarding the robustness of the MSC monotherapy. Using a rat forelimb VCA model, this study tested the robustness of the immunomodulation efficacy of gingival-derived MSCs (GMSCs) and bone marrow–derived MSCs (BMMSCs).

Methods Forelimbs were transplanted on pairs of major histocompatibility complex–incompatible rats (Wistar-Kyoto donor, Lewis [LEW] recipient). Twenty-four LEW rats were randomly divided into four groups, including control (no treatment) and three treatment groups: rapamycin (2 mg/kg/day for 28 days, postoperatively), BMMSC and GMSC, both of which received donor-derived stem cells administered intravenously on postoperative days (PODs) 0, 3, 7, and 14. Rejection was considered as 80% skin necrosis of the allograft. Microcomputed tomography (µCT) was performed to evaluate healing at osteosynthesis site. On POD 14, limbs from each group underwent histological analysis and rejection grading using the Banff system.

Results Both BMMSC (15.0 days) and GMSC (14.7 days) treatment failed to prolong VCA survival in comparison with the control group (13.8 days; p > 0.050), while the rapamycin significantly delayed acute VCA rejection (24.5 days; p = 0.003). Micro-CT imaging revealed no gross visual difference across all groups. Histology revealed that the control group was most severely affected (grades III and IV) followed by MSC (grade II) and rapamycin (grade I).

Conclusion MSC monotherapy, both BMMSC and GMSC, did not inhibit rejection in our VCA model. Skin immunogenicity is an important issue in promoting rejection, and a concomitant immunosuppression regimen should be considered to prolong allograft survival.

* These authors contributed equally to this work.


 
  • References

  • 1 Gander B, Brown CS, Vasilic D. , et al. Composite tissue allotransplantation of the hand and face: a new frontier in transplant and reconstructive surgery. Transpl Int 2006; 19 (11) 868-880
  • 2 Petruzzo P, Dubernard JM, Lanzetta M. International Registry on Hand and Composite Tissue Transplantation. Available at: https://www.handregistry.com/index.php . Updated 2017
  • 3 Gupta A, Kumer S, Kaplan B. Novel immunosuppressive strategies for composite tissue allografts. Curr Opin Organ Transplant 2014; 19 (06) 552-557
  • 4 Siemionow M, Gharb BB, Rampazzo A. Successes and lessons learned after more than a decade of upper extremity and face transplantation. Curr Opin Organ Transplant 2013; 18 (06) 633-639
  • 5 Le Blanc K, Rasmusson I, Sundberg B. , et al. Treatment of severe acute graft-versus-host disease with third party haploidentical mesenchymal stem cells. Lancet 2004; 363 (9419): 1439-1441
  • 6 Augello A, Tasso R, Negrini SM, Cancedda R, Pennesi G. Cell therapy using allogeneic bone marrow mesenchymal stem cells prevents tissue damage in collagen-induced arthritis. Arthritis Rheum 2007; 56 (04) 1175-1186
  • 7 Liang J, Zhang H, Hua B. , et al. Allogeneic mesenchymal stem cells transplantation in treatment of multiple sclerosis. Mult Scler 2009; 15 (05) 644-646
  • 8 Sun L, Akiyama K, Zhang H. , et al. Mesenchymal stem cell transplantation reverses multiorgan dysfunction in systemic lupus erythematosus mice and humans. Stem Cells 2009; 27 (06) 1421-1432
  • 9 Akiyama K, Chen C, Wang D. , et al. Mesenchymal-stem-cell-induced immunoregulation involves FAS-ligand-/FAS-mediated T cell apoptosis. Cell Stem Cell 2012; 10 (05) 544-555
  • 10 Hoogduijn MJ, Popp FC, Grohnert A. , et al; MISOT Study Group. Advancement of mesenchymal stem cell therapy in solid organ transplantation (MISOT). Transplantation 2010; 90 (02) 124-126
  • 11 Le Blanc K, Frassoni F, Ball L. , et al; Developmental Committee of the European Group for Blood and Marrow Transplantation. Mesenchymal stem cells for treatment of steroid-resistant, severe, acute graft-versus-host disease: a phase II study. Lancet 2008; 371 (9624): 1579-1586
  • 12 Hare JM, Traverse JH, Henry TD. , et al. A randomized, double-blind, placebo-controlled, dose-escalation study of intravenous adult human mesenchymal stem cells (Prochymal) after acute myocardial infarction. J Am Coll Cardiol 2009; 54 (24) 2277-2286
  • 13 Lu D, Chen B, Liang Z. , et al. Comparison of bone marrow mesenchymal stem cells with bone marrow-derived mononuclear cells for treatment of diabetic critical limb ischemia and foot ulcer: a double-blind, randomized, controlled trial. Diabetes Res Clin Pract 2011; 92 (01) 26-36
  • 14 Peng L, Xie DY, Lin BL. , et al. Autologous bone marrow mesenchymal stem cell transplantation in liver failure patients caused by hepatitis B: short-term and long-term outcomes. Hepatology 2011; 54 (03) 820-828
  • 15 Wang D, Zhang H, Liang J. , et al. Allogeneic mesenchymal stem cell transplantation in severe and refractory systemic lupus erythematosus: 4 years of experience. Cell Transplant 2013; 22 (12) 2267-2277
  • 16 Tan J, Wu W, Xu X. , et al. Induction therapy with autologous mesenchymal stem cells in living-related kidney transplants: a randomized controlled trial. JAMA 2012; 307 (11) 1169-1177
  • 17 Jeong SH, Ji YH, Yoon ES. Immunosuppressive activity of adipose tissue-derived mesenchymal stem cells in a rat model of hind limb allotransplantation. Transplant Proc 2014; 46 (05) 1606-1614
  • 18 Plock JA, Schnider JT, Zhang W. , et al. Adipose and bone marrow derived mesenchymal stem cells prolong graft survival in vascularized composite allotransplantation. Transplantation 2015; 99 (09) 1765-1773
  • 19 Kuo YR, Chen CC, Goto S. , et al. Modulation of immune response and T-cell regulation by donor adipose-derived stem cells in a rodent hind-limb allotransplant model. Plast Reconstr Surg 2011; 128 (06) 661e-672e
  • 20 Zhang Q, Shi S, Liu Y. , et al. Mesenchymal stem cells derived from human gingiva are capable of immunomodulatory functions and ameliorate inflammation-related tissue destruction in experimental colitis. J Immunol 2009; 183 (12) 7787-7798
  • 21 Tang L, Li N, Xie H, Jin Y. Characterization of mesenchymal stem cells from human normal and hyperplastic gingiva. J Cell Physiol 2011; 226 (03) 832-842
  • 22 Battaglia M, Stabilini A, Roncarolo MG. Rapamycin selectively expands CD4+CD25+FoxP3+ regulatory T cells. Blood 2005; 105 (12) 4743-4748
  • 23 Zhu H, Xie F, Luo X. , et al. Orthotopic forelimb allotransplantation in the rat model. Microsurgery 2016; 36 (08) 672-675
  • 24 Zhu H, Guo ZK, Jiang XX. , et al. A protocol for isolation and culture of mesenchymal stem cells from mouse compact bone. Nat Protoc 2010; 5 (03) 550-560
  • 25 Soleimani M, Nadri S. A protocol for isolation and culture of mesenchymal stem cells from mouse bone marrow. Nat Protoc 2009; 4 (01) 102-106
  • 26 Xu X, Chen C, Akiyama K. , et al. Gingivae contain neural-crest- and mesoderm-derived mesenchymal stem cells. J Dent Res 2013; 92 (09) 825-832
  • 27 Xu H, Dahiya S, Wang L. , et al. Utility of IL-2 complexes in promoting the survival of murine orthotopic forelimb vascularized composite allografts. Transplantation 2018; 102 (01) 70-78
  • 28 Cendales LC, Kanitakis J, Schneeberger S. , et al. The Banff 2007 working classification of skin-containing composite tissue allograft pathology. Am J Transplant 2008; 8 (07) 1396-1400
  • 29 Francois CG, Breidenbach WC, Maldonado C. , et al. Hand transplantation: comparisons and observations of the first four clinical cases. Microsurgery 2000; 20 (08) 360-371
  • 30 Casiraghi F, Azzollini N, Cassis P. , et al. Pretransplant infusion of mesenchymal stem cells prolongs the survival of a semiallogeneic heart transplant through the generation of regulatory T cells. J Immunol 2008; 181 (06) 3933-3946
  • 31 Franquesa M, Herrero E, Torras J. , et al. Mesenchymal stem cell therapy prevents interstitial fibrosis and tubular atrophy in a rat kidney allograft model. Stem Cells Dev 2012; 21 (17) 3125-3135
  • 32 Kuo YR, Chen CC, Shih HS. , et al. Prolongation of composite tissue allotransplant survival by treatment with bone marrow mesenchymal stem cells is correlated with T-cell regulation in a swine hind-limb model. Plast Reconstr Surg 2011; 127 (02) 569-579
  • 33 Dominici M, Le Blanc K, Mueller I. , et al. Minimal criteria for defining multipotent mesenchymal stromal cells. The International Society for Cellular Therapy position statement. Cytotherapy 2006; 8 (04) 315-317
  • 34 Webster KE, Walters S, Kohler RE. , et al. In vivo expansion of T reg cells with IL-2-mAb complexes: induction of resistance to EAE and long-term acceptance of islet allografts without immunosuppression. J Exp Med 2009; 206 (04) 751-760
  • 35 Boyman O, Krieg C, Letourneau S, Webster K, Surh CD, Sprent J. Selectively expanding subsets of T cells in mice by injection of interleukin-2/antibody complexes: implications for transplantation tolerance. Transplant Proc 2012; 44 (04) 1032-1034
  • 36 Battaglia M, Stabilini A, Migliavacca B, Horejs-Hoeck J, Kaupper T, Roncarolo MG. Rapamycin promotes expansion of functional CD4+CD25+FOXP3+ regulatory T cells of both healthy subjects and type 1 diabetic patients. J Immunol 2006; 177 (12) 8338-8347
  • 37 Akimova T, Kamath BM, Goebel JW. , et al. Differing effects of rapamycin or calcineurin inhibitor on T-regulatory cells in pediatric liver and kidney transplant recipients. Am J Transplant 2012; 12 (12) 3449-3461
  • 38 Strauss L, Czystowska M, Szajnik M, Mandapathil M, Whiteside TL. Differential responses of human regulatory T cells (Treg) and effector T cells to rapamycin. PLoS One 2009; 4 (06) e5994