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To circumvent ethical and legal complications associated with embryonic cell sources, investigators have proposed the use of nonneural donor sources for use in neural transplantation strategies. Leading candidate sources include autologous marrow stromal cells (MSCs) and fibroblasts, which are mesodermal derivatives. However, we recently reported that MSCs transplanted to the adult brain are rapidly rejected by an inflammatory response. Whether extrinsic variables or intrinsic mesenchymal traits stimulated inflammation and rejection is unknown. To determine the future utility of these cells in neural transplantation, we have now performed a systematic analysis of MSC transplantation to the brain.To examine the effects of extrinsic variables on transplantation, green fluorescent protein (GFP)-expressing rat MSCs, cultured under distinct conditions, were transplanted stereotactically to the normal adult rat striatum, and donor survival and the host response was compared. To examine whether intrinsic donor traits promoted rejection, 50,000 GFP-expressing rat MSCs, fibroblasts, or astrocytes were transplanted stereotactically to the adult rat striatum and graft survival and the host response was compared.Irrespective of preoperative culture conditions, MSCs elicited an inflammatory response and were rejected by 14 days, indicating acute rejection was not mediated by culture conditions. Comparison of MSC, fibroblast, or astrocyte grafts revealed that mesenchymal derivatives, MSCs and fibroblasts, elicited an inflammatory response and were rapidly rejected, whereas neuroectodermal astrocytes demonstrated robust survival in the absence of inflammation.Our findings suggest that intrinsic characteristics of mesenchymal cells may stimulate host inflammation, and thus may not represent an ideal donor source for transplantation to the adult brain.