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.