Effect of Transplantation of Bone Marrow-Derived Mesenchymal Stem Cells on Mice Infected with Prions

Abstract

Bone marrow-derived mesenchymal stem cells (MSCs) have been reported to migrate to brain lesions in experimental models of ischemia, tumors, and neurodegenerative diseases and to ameliorate functional deficits. In this study, we attempted to evaluate the therapeutic potential of MSCs for treating prion diseases. Immortalized human MSCs (hMSCs) that express the LacZ gene were transplanted into the unilateral hippocampi or thalami of mice, and their distributions were monitored by the expression of ␤-galactosidase. In mice infected with prions, hMSCs transplanted at 120 days postinoculation (dpi) were detected on the contralateral side at 2 days after transplantation and existed there even at 3 weeks after transplantation. In contrast, few hMSCs were detected on the contralateral side for mock-infected mice. Interestingly, the migration of hMSCs appeared to correlate with the severity of neuropathological lesions, including disease-specific prion protein deposition. The hMSCs also migrated to a prion-specific lesion in the brain, even when intravenously injected. Although the effects were modest, intrahippocampal and intravenous transplantation of hMSCs prolonged the survival of mice infected with prions. A subpopulation of hMSCs in the brains of prion-infected mice produced various trophic factors and differentiated into cells of neuronal and glial lineages. These results suggest that MSCs have promise as a cellular vehicle for the delivery of therapeutic genes to brain lesions associated with prion diseases and, furthermore, that they may help to regenerate neuronal tissues damaged by prion propagation.

Identification of Chemoattractive Factors Involved in the Migration of Bone Marrow-Derived Mesenchymal Stem Cells to Brain Lesions Caused by Prions

“…The hMSCs were transplanted into the thalamus as described previously (51). Briefly, after anesthesia, mouse scalps were incised.…”

“…Human bone marrow-derived MSCs that were immortalized with the human telomerase catalytic subunit gene (26) and that stably expressed the LacZ gene (hMSCs [51]) were used. The hMSCs were cultured in Dulbecco modified Eagle medium (DMEM; Sigma Chemical Co., St. Louis, MO) containing 10% fetal bovine serum (FBS) in a humidified atmosphere under normoxic (21% O 2 and 5% CO 2 ) or hypoxic (2% O 2 and 5% CO 2 ) conditions at 37°C.…”

“…It is known that MSCs transplanted into the left hippocampus or thalamus migrate to the contralateral (right) hippocampus through the corpus callosum (3,19,51). Therefore, we hypoth- …”

“…We recently reported that human MSCs (hMSCs) migrate to CNS lesions and prolong the survival of mice infected with prions (51). In the present study, we investigated factors that are involved in the migration of hMSCs to brain lesions of prion diseases.…”

“…Therefore, despite their mesodermal origin, MSCs are considered to be a candidate for cell-mediated therapy for neurodegenerative diseases. One of the characteristics of MSCs is their migration to brain lesions caused by neurodegenerative diseases, including prion diseases (10,19,39,51). This feature may be of further use for cell-mediated therapy of neurodegenerative diseases, particularly for prion diseases, Multiple sclerosis and Alzheimer's disease, which have diffuse pathological lesions.…”