Significant Prolongation Of Animal Survival By Therapy Of Mesenchymal Stem Cells And Cyclosporine A In Rat Renal Allografts

Background: Mesenchymal stem cells (MSC) are pluripotent progenitorsfor a variety of cell types, including fibroblasts and muscle cells. Theirinvolvement in the tissue repair of allografts during the development ofrejection has been hypothesized, but not yet substantiated, byexperimental evidence. Cyclosporine A (CsA) has improved short-termresults in renal transplantation. However, its toxicities have been seriousproblems in clinical patients undergoing long-term administration. We tryto find if using MSC can develop a new way that allows replacing of CsAand prolong animal survival. Methods: The authors tested the effect ofMSC intravenously transplanted, using a rat renal acute rejection model(Sprague-Dawley to Wistar). MSC were isolated from bone marrow of male Sprague-Dawley(SD) rats and purified by density centrifuge andadhered to the culture plate in vitro. Female Wistar rats bearing femaleSD renal allografts were divided randomly into three groups, CsA, MSCand no therapy respectively. The rats were engrafted with MSC byintravenous injection (1×10~7 cells resuspended in 1 mL sterile lactatedD-hank solution every time). The first dose was given at 1 week beforeand the second dose was immediately before renal transplantation,followed by 2 additional doses at weekly intervals Posttransplantation.The other two groups were given 1mL D-hank solution in the same time.CsA was hypodermically injected with 15mg/kg to the group of CsA perday after the transplantation. The other two groups were not injected. Weassessed graft function by measuring serial serum creatinine (S-Cr) levelsusing the Jaffe reaction method, Graft histology harvested on day 5 aftertransplantation and observed the survival days. Results: Therapy of MSC(13.50±6.351 days) and therapy of CsA (18.50±5.972days) prolongedanimal survival (vs. 6.50±3.109in controls). S-Cr levels demonstrated thesignificantly protection by the treatment of MSC and CsA as comparedwith the other group. Graft histology harvested on day 5. Allografts ofcontrol animals exhibited findings typical of severe acute rejection,including widespread interstitial infiltrates with tubulitis and patchynecrosis with hemorrhage, severe glomerulitis with extensive capillaryocclusion caused by endothelial swelling, and intimal arteritis in the cortex. In the medullary part, tubules had severe tubulitis, with numerousinfiltrates and hemorrhage. Allografts of recipients with MSCmonotherapy or CsA monotherapy showed findings of acute rejectionwith considerably milder severity. Interstitial infiltrates were significantlydecreased throughout the graft tissue. But most glomeruli and arteriesappeared normal. Tubular structures remained mostly normal, with noapparent tubulitis or protein deposition. Conclusions: This data suggeststhat MSC transfusion is an effective way to prolong animal survival in ratrenal transplantation and MSC may be a promising candidate for a newregimen that potentially replaces CsA.