Mol Neurobiol (2012) 45:87–98 trophic factors to encourage repair and potentially new growth of neurons from endogenous neural progenitor cells. Proposed regenerative approaches include delivery via intra- cerebral or intrathecal injection or even infusion via an intra- nasal route [21]. Therapies will capitalize upon the innate trophic support from MSC or on additional augmented growth factor support. Genetically engineered MSC can serve as the vehicle to deliver brain-derived neuro- trophic factor (BDNF) or glial-derived neurotrophic factor (GDNF) into the brain to support injured neurons, as reviewed in this report. Upon transplantation, MSC in the brain promote endogenous neuronal growth, decrease apoptosis, and regu- late inflammation through the use of secreted factors. Rossignol et al. [22] demonstrated that after xenotransplanta- tion of human MSC into rat brain, there were higher levels of messenger RNAs (mRNAs) for the anti-inflammatory molecules IL-6 and TGF-β1 than for the pro-inflammatory cytokines IL-8 and IL-12. MSC can mediate modification of the damaged tissue microenvironment to enhance endoge- nous neural regeneration and protection. MSC transplanted at sites of nerve injury have been shown to promote functional recovery by producing trophic factors that induce survival and regeneration of host neurons [23]. Transplanta- tion of human bone marrow stem cells into the brains of immunodeficient mice markedly increased the proliferation of endogenous neural stem cells [24]. In an experimental allergic encephalomyelitis model of multiple sclerosis, rodents that received an intraventricular infusion of MSC were found to have almost twice the number of axons as control animals [25]. Busch et al. [26] demonstrated that human multipotent adult progenitor cells, a precursor of MSC, prevented axonal dieback and significantly enhanced neurite growth into the lesion core after a spinal cord injury. Although candidate molecules are under investigation, further detailed studies are needed to carefully define the factors responsible for the MSC-mediated induction of proliferation and enhancement of axonal extension and synaptic connection in resident neural stem cells, in order to best capitalize upon this type of therapy for the repair of neurodegenerative diseases. Several groups have shown that intraparenchymal delivery of human MSC is safe and can delay loss of motor neurons in rodents. Vercelli et al. [27] transplanted human MSC directly into the lumbar spinal cords of SOD1 ALS mice. The MSC migrated throughout the spinal cord and delayed loss of motor neurons, prolonging motor performance. Another study compared the efficacy of transplanting olfactory ensheathing cells (OEC) and rat MSC intrathecally through the fourth ventricle in the spinal cord. The OEC distributed widely, but significant changes in clinical outcomes were observed only with addition of MSC transplantation when female ALS mice 89 showed statistically longer lifespans than males and control mice [28]. Numerous clinical trials have demonstrated the low risk of systemic infusion of allogeneic MSC into patients with various diseases. Biosafety monitoring of MSC infusion has been performed throughout these trials, with no serious adverse events reported. For direct infusion of MSC into the brain or spinal cord, the biosafety aspects should be monitored extremely carefully. Possible risks include the development of cytogenetic abnormalities in cultured cells or ectopic differentiation to other tissue lineages. The development of cytogenetic abnormalities when MSC were cultured past the crisis point has been reported in rodent MSC [29]. In our lab, we have found that, in general, rodent MSC cultures are frequently contaminated with hematopoietic elements and do not well reflect human MSC biology. There has been only one report of a karyotypic abnormality happening in human MSC that were cultured in conditions that would never be allowed in a good manufacturing practice (GMP) or good laboratory practice (GLP) setting [30]. It was later found that the tumor arose due to cross-contamination of MSC cultures with fibrosar- coma and glioma cells [31]. When human MSC are cultured under GLP/GMP conditions, with appropriate release criteria, adverse events have not been observed throughout the field, both in vivo and in numerous human clinical trials [1, 2, 32–38]. We have published a decade- long biosafety study on the clinical biosafety profile of genetically engineered MSC [18]. A potential risk for infusion of MSC into the spinal cord or brain is that they have potent revascularization capacity and will home to the hypoxic region around a tumor bed [39, 40]. This tropism for the tumor or wound bed could result in enhanced revascularization and survival of a growing tumor. Therefore, in proposed cellular therapy trials, an important exclusion criterion is the lack of prior brain tumors or other cancers in the past 5 years. Magnetic resonance imaging (MRI) or other functional imaging modalities should be done prior to treatment in HD trials to establish the baseline striatal volume [41, 42] and would be also used to rule out existing brain tumors. Several groups have reported that MSC can be induced to express neural markers in vitro, in particular after co- cultivation with human or murine neurons or conditioned medium. However, although mature neurons with functional activity can be generated in culture from neural stem cells (NSC) [43, 44], it has not been shown conclusively that mature neurons with signaling capacity can be generated from MSC [45]. While attractive in theory, MSC do not appear to be a viable alternative to NSC as a neural tissue replacement strategy. It has been reported that undifferentiated MSC often express a number of proteins used as markers of neural differentiation [46].