Elsevier

Transplantation Proceedings

Volume 38, Issue 9, November 2006, Pages 3046-3051
Transplantation Proceedings

Experimental
Immunosuppression
Administration of Donor-Derived Mesenchymal Stem Cells Can Prolong the Survival of Rat Cardiac Allograft

https://doi.org/10.1016/j.transproceed.2006.10.002Get rights and content

Abstract

Background

Mesenchymal stem cells (MSCs) are multipotent adult elements that have recently been shown to have profound immunomodulatory effects both in vitro and in vivo. Herein we have examined the impact of intravenous infusion of donor MSCs on the survival of transplanted hearts in a rat allograft model.

Methods

Recipient Fisher344 rats were transplanted with hearts from inbred Wistar rats. Wistar rat MSCs were infused via the tail vein at designated intervals. In vitro mixed lymphocyte reaction (MLR) and cell-mediated lympholysis (CML) assays were performed to assess whether MSCs downregulated T-cell responses in vivo. Real-time polymerase chain reaction (PCR) was used to analyze the Th1/Th2 balance in MSC-treated and control groups.

Results

The MSCs cultured in vitro exhibited multipotential for differentiation. Survival of the allografts was markedly prolonged by administration of MSCs compared with the controls, namely mean survivals of 12.4 vs 6.4 days, respectively. Real-time PCR showed a shift in the Th1/Th2 balance toward Th2. By MLR and CML assays, untreated control rats showed greater alloreactivity than did MSC-treated rats.

Conclusion

Our results indicated that MSCs suppressed allogeneic T-cell responses both in vitro and in vivo. Intravenous administration of MSCs prolonged the survival of transplanted hearts, possibly by induction of allograft tolerance through changing the Th1/Th2 balance.

Section snippets

Experimental Animals

Inbred Wistar rats weighing 180 to 200 g and Fisher344(F344) rats weighing 160 to 180 g were used as donors and recipients in a cardiac allograft model, respectively. Animals were purchased from National Rodent Laboratory Animal Resources, Shanghai Branch (Shanghai, China) and humanely cared for in compliance with institutional guidelines.

Cell Isolation, Culture, and Characterization

Isolation and primary culture of MSCs were performed according to a protocol modified from a previously reported method.13 Briefly, after donor Wistar rats

Cell Culture of MSCs and Immunocytochemistry

The MSCs were isolated according to their ability to adhere to cell culture plastic. In vitro MSCs appeared as two distinct morphological phenotypes. Cells from passage 0 demonstrated a fibroblast-like, spindle-shaped morphology (Fig 1A). Later, MSCs began to display a broadened, flat morphology (Fig 1B). Immunocytochemical findings revealed that MSCs were negative for hematopoietic markers CD34, CD45, or endothelial cell marker CD31, but typically expressed the antigens CD29, CD106, and CD117 (

Discussion

Our study reported the implication for heart transplantation of the immunological properties of MSC. Infusion of MSCs appeared to shift the Th1/Th2 balance toward a Th2-type response. This shift of Th1/Th2 balance seemed to be closely associated with a significant prolongation of heart allograft survival.

Although there are several reports on the isolation of MSCs, we have selected the most efficient and clinically accessible method to obtain highly purified MSCs. The immunophenotype profile of

Acknowledgments

We thank P. Yuan, Department of Gynecology and Obstetrics, for his expert help with the real-time PCR study.

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