Analysis of allogeneic and syngeneic bone marrow stromal cell graft survival in the spinal cord.
Bone marrow stromal cells (MSC) are attractive candidates for developing cell therapies for central nervous system (CNS) disorders. They can be easily obtained, expanded in culture, and promote modest functional recovery following transplantation into animal models of injured or degenerative CNS. While syngeneic MSC grafts can be used efficiently, achieving long-term survival of allogeneic MSC grafts has been a challenge. We hypothesize that improved graft survival will enhance the functional recovery promoted by MSC. To improve MSC graft survival, we tested two dosages of the immune suppressant cyclosporin A (CsA) in an allogeneic model. Syngeneic transplantation of MSC where cells survive well without immune suppression was used as a control. Sprague-Dawley rats treated with standard dose (n = 12) or high-dose (n = 12) CsA served as allogeneic hosts; Fisher 344 rats (n = 12) served as syngeneic hosts. MSC were derived from transgenic Fisher 344 rats expressing human placental alkaline phosphatase and were grafted into cervical spinal cord. Animals treated with standard dose CsA showed significant decreases in allograft size 4 weeks posttransplantation; high CsA doses yielded significantly better graft survival 4 and 8 weeks posttransplantation compared to standard CsA. As expected, syngeneic MSC transplants showed good graft survival after 4 and 8 weeks. To investigate MSC graft elimination, we analyzed immune cell infiltration and cell death. Macrophage infiltration was high after 1 week in all groups. After 4 weeks, high-dose CsA and syngeneic animals showed significant reductions in macrophages at the graft site. Few T lymphocytes were detected in any group at each time point. Cell death occurred throughout the study; however, little apoptotic activity was detected. Histochemical analysis revealed no evidence of neural differentiation. These results indicate that allogeneic transplantation with appropriate immune suppression permits long-term survival of MSC; thus, both allogeneic and syngeneic strategies could be utilized in devising novel therapies for CNS injury.
Swanger
Sharon A
SA
Department of Neurobiology and Anatomy, Drexel University College of Medicine, Philadelphia, Pennsylvania 19129, USA.
Neuhuber
Birgit
B
Himes
B Timothy
BT
Bakshi
Ajay
A
Fischer
Itzhak
I
D000818:Animals; D016026:Bone Marrow Transplantation; D016923:Cell Death; D002454:Cell Differentiation; D002465:Cell Movement; D002493:Central Nervous System Diseases / Q000601:surgery; D016572:Cyclosporine / Q000627:therapeutic use; D005260:Female; D006085:Graft Survival / Q000276:immunology; D007150:Immunohistochemistry; D007165:Immunosuppression Therapy / Q000379:methods; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008264:Macrophages / Q000166:cytology / Q000276:immunology; D010641:Phenotype; D051381:Rats; D011916:Rats, Inbred F344; D017207:Rats, Sprague-Dawley; D013116:Spinal Cord / Q000166:cytology / Q000502:physiology / Q000601:surgery*; D017154:Stromal Cells / Q000276:immunology / Q000502:physiology / Q000637:transplantation*; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology; D014184:Transplantation, Homologous; D014185:Transplantation, Isogeneic
D007166:Immunosuppressive Agents; D016572:Cyclosporine