Analysis of Allogeneic and Syngeneic Bone Marrow Stromal Cell Graft Survival in the Spinal Cord

Abstract

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. INTRODUCTIONaxonal regeneration and survival of host neurons and glia (12,13,22,45,49,51). MSC are multipotent adult stem cells derived from Cell transplantation has emerged as a promising therapeutic approach for CNS disorders, including spinal bone marrow, with the capacity to differentiate along various mesenchymal lineages (37). They have also been cord and traumatic brain injury. Specialized cell types and a variety of stem cells have been transplanted into shown to promote functional recovery in animal models of spinal cord injury (SCI) (2,14,19,35,36,49), as well experimental models of spinal cord and brain injury, including Schwann cells [for review see (8)], olfactory enas brain disorders and injury [for review see (13)]. In addition, some studies showed that a small number of sheathing glia [for review see (5,41)], neural stem cells [for review see (9,43)], and bone marrow stromal cells MSC transplanted into the adult CNS may differen...

Innate Allorecognition Results in Rapid Accumulation of Monocyte-Derived Dendritic Cells

“…As such, it has been proposed that danger signals induced by surgical, ischemic, and other iatrogenic damage to host and graft tissue could contribute to the immunological response (11). In support of this, even syngeneic grafts can induce an initial immune response at graft sites (9,12). However, this conjecture does not easily explain several observations.…”

Adult Spinal Cord Stem/Progenitor Cells Transplanted as Neurospheres Preferentially Differentiate into Oligodendrocytes in the Adult Rat Spinal Cord

“…It is encouraging that with embryonic stem cell transplants (6,10), where there may be the potential for tumor formation. transplanted marrow stromal cells (39) and NSPCs, as shown in the current study, are not apoptotic at later…”

“…tected at any of the time points examined from 1 to 8 weeks posttransplantation (39). It is encouraging that with embryonic stem cell transplants (6,10), where there may be the potential for tumor formation.…”

Dedifferentiation-Reprogrammed Mesenchymal Stem Cells with Improved Therapeutic Potential

“…However, despite many transplantation studies showing beneficial effects, most studies report low levels of cell persistence and neuronal differentiation in vivo. In particular, when MSCs are injected directly into the lesion tissues, massive death of transplanted cells has been observed [20,23,24]. This greatly limits their overall effectiveness and clinical use.…”