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Joo Youn Oh, Ryang Hwa Lee, Ji Min Yu, Darwin J. Prockop; Intravenously Infused Mesenchymal Stem/progenitor Cells (MSCs) Promote The Long-term Survival Of Corneal Allografts By Secreting TNF-α Stimulated Gene/protein 6 To Reduce The Early Surgery-induced Inflammation. Invest. Ophthalmol. Vis. Sci. 2012;53(14):3526.
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Mesenchymal stem/progenitor cells (MSCs) were reported to enhance the survival of cellular and organ transplants in animals and humans. However, their mode of action was not established. We performed the study to define how MSCs might improve the engraftment of organ transplants using a mouse model of allogeneic corneal transplantation.
We performed orthotropic corneal allotransplantation using C57BL/6 mice (H-2b) as donors and BALB/c (H-2d) as recipients. Recipient mice received 1 x 106 hMSCs IV either once immediately after surgery or twice at one day before surgery and again immediately after surgery. HBSS was injected IV as a positive control, and the syngeneic autografts (BALB/c-to-BALB/c) served as negative controls. Then, we examined the effects of hMSCs separately on the early surgically-induced inflammation and on the later immune response.
The peri-transplant intravenous (IV) infusion of human MSCs (hMSCs) decreased the early surgically-induced inflammation and reduced the activation of dendritic cells in the cornea. Subsequently, the immune rejection was decreased, and the long-term survival of allografts was prolonged. Quantitative assays for mRNA for human GAPDH revealed that <10 hMSCs out of 1x106 cells injected were recovered in the cornea 10 hours to 28 days after IV infusion. Most of hMSCs were trapped in lungs where they were activated to increase the expression of the gene for the anti-inflammatory protein TNF-α stimulated gene/protein 6 (TSG-6) upto 114-fold. The administration of hMSCs decreased the expression of chemokine (C-C motif) receptor 7 (CCR7) in the mouse cornea, a key molecule for migration of dendritic cells from the inflamed cornea to draining lymph nodes. IV hMSCs with a knockdown of TSG-6 did not suppress the early postoperative inflammation and failed to prolong the long-term survival of the allografts. Also, IV infusion of recombinant TSG-6 reproduced the effects of hMSCs in reducing the early postoperative inflammation in the allografts.
MSCs prolonged the survival of corneal allografts by suppressing the surgery-induced inflammation early after transplantation. The action of MSCs was exerted without significant engraftment of the cells in the cornea and primarily by secreting trophic factors including the anti-inflammatory molecule TSG-6. The observations may account for the favorable effects of MSCs seen previously in models of solid organ and cellular transplantation. Moreover, the data may provide a basis for using MSCs to improve the survival of transplants of the cornea and other tissues.
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