Table 1 Mesenchymal stem-cell-based treatment of HD in preclinical rodent models Animal model Transplanted cells Histology Lesion volume Functional outcome Rat, QA Rat, QA Mice, QA R6/2-J2 mice Rat, QA R6/2 mouse Rat, 3NP Rat, QA Rat BM-MSCs Reduced striatal atrophy Human adipose MSCs Reduced striatal atrophy Reduced apoptosis Human BM-MSCs Increased cell proliferation in striatum Human BM-MSCs Improved cell differentiation Human BM-MSCs Reduced striatal atrophy Human adipose MSCs Reduced HTT aggregates Attenuated loss of striatal neuron Rat BM-MSCs ND Rat BM-MSCs Improved MSC migration to lesion Im et al., [77] YAC 128 mice Human adipose MSCs Reduced striatal atrophy Edalatmanesh et al., Rat, QA [76] Rat BM-MSCs ND Dey et al., [93] YAC 128 mice BM-MSCs engineered Reduced striatal atrophy to produce BDNF Mol Neurobiol (2012) 45:87–98 Improved striatal volume ND Decreased lesion volume Reduced Apo-M induced rotations Decreased lesion volume Improved rotarod performance Extended survival time ND Improved survival Decreased lesion volume Reduced motor dysfunction Improved striatal volume Improved rotarod Reduced clasping Improved survival Prevented 3NP-mediated Improved rotarod ventricle enlargement Improved paw placement Decreased lesion volume Regenerated striatal network Reduced Apo-M induced rotations Improved striatal volume Improved rotarod performance/motor function ND Reduced Apo-M induced rotations Improved beam walk Improved hang wire time Improved striatal volume Improved rotarod performance Reduced hindlimb clasping 92 References Amin et al., [73] Lee et al., [79] Lin et al., [80] Lin et al., [80] Jiang et al, [78] Lee et al., [79] Rossignol et al., [81] Sadan et al., [82] distance along the internal capsule toward the QA-induced lesion in the striatum. They were shown to have regen- erated the damaged striatal dopaminergic nerve terminal network in this animal model for HD [82, 84]. A human cellular therapy trial has already demonstrated progress in the treatment of HD by intracerebral implanta- tion. Bachoud-Levi and colleagues [85, 86] transplanted human fetal neurons into the brains of five patients with HD. Three out of five patients with HD produced motor and cognitive improvements 2 years after the fetal neural graft. The authors obtained convincing evidence that these human fetal striatal grafts were capable of reconnection and activation of the frontal lobes. Clinical improvement plateaued after 2 years and then faded off variably 4– 6 years after the implantation [85, 86]. These and other studies demonstrate that fetal striatal neurons can be safely implanted into the brain without adverse events. The group is currently conducting phase II clinical trials. Since fetal striatal tissue could be a limiting factor, an alternative might be derivation of striatal neurons from human embryonic stem cells. However, a major challenge yet to be robustly achieved from embryonic stem cell- derived neurons is to coerce the new neurons make bona fide synaptic connections, as the Bachoud-Levi group had seen from the fetal neurons. Co-transplantation of fetal or embryonic stem cell-derived neural grafts with MSC to enhance neuritogenesis and to guide axonal pathfinding through areas of damage could be considered [26]. A confounding factor for the treatment of HD by cellular therapy is the continued presence of the mutant HTT mRNA and protein in neighboring cells causing chronic damage, even if new, healthy neurons are implanted. Efforts to specifically knock down the expression of this mutant HTT mRNA and protein prior to or simultaneously with the MSC-based therapies must be considered [68–70]. Neural Growth Factor Delivery by MSC An interesting development candidate that we and others are characterizing is allogeneic human MSC engineered to secrete BDNF (Fig. 1). This candidate therapy could provide a potential strategy to enhance striatal neuron survival and regeneration in HD. BDNF levels are very low in mice and humans with HD. In rodent models, BDNF has been shown to ameliorate symptoms and to extend survival, making BDNF therapy a leading candidate for use in treating HD. Striatal neurons depend on BDNF for function and survival [87, 88]. In the later stages of HD, available BDNF levels plummet since the mutant protein prevents production at the mRNA level [61]. This reduction in BDNF affects the onset and severity of the disease in HD