In Vivo Roles of a Patient-Derived Induced Pluripotent Stem Cell Line (HD72-iPSC) in the YAC128 Model of Huntington’s Disease

Abstract

Induced pluripotent stem cells (iPSCs) generated from somatic cells of patients can provide immense opportunities to model human diseases, which may lead to develop novel therapeutics. Huntington's disease (HD) is a devastating neurodegenerative genetic disease, with no available therapeutic options at the moment. We recently reported the characteristics of a HD patient-derived iPSC carrying 72 CAG repeats (HD72-iPSC). In this study, we investigated the in vivo roles of HD72-iPSC in the YAC128 transgenic mice, a commonly used HD mouse model carrying 128 CAG repeats. To do this, we transplanted HD72-iPSC-derived neural precursors into the striatum of YAC128 mice bilaterally and observed a significant behavioral improvement in the grafted mice. Interestingly, the transplanted HD72-iPSC-derived neural precursors formed GABAeric neurons efficiently, but no EM48-positive protein aggregates were detected at 12 weeks after transplantation. Taken together, these results indicate no HD pathology was developed from the grafted cells, or no transmission of HD pathology from the host to the graft occurred at 12 weeks post-transplantation.

Pluripotent Stem Cells to Model and Treat Huntington’s Disease

“…The beneficial effect of hiPSC, as well as hiPSC-derived NPCs has also been tested in HD animal models aiming to the future clinical application of these cells [69,70,78] Neurotrophic action was not evaluated in any of the studies. Table 3.…”

“…Using the ipsilateral ventricular route, these cells were transplanted into both chemical [69,78] and transgenic HD rodent models [70]. Similar to ESCs, the hiPSCs differentiate in vivo into neurons, including GABAergic specification neurons [69,70,78], and astrocytes [78].…”

“…The ability of these transplanted cells to reverse HD symptoms in animal models was assessed using several motor and memory tests, such as the using rotarod performance test, the staircase test, the stepping test and the Morris water maze spatial memory task. They showed that experimental animals receiving iPSC-derived NPCs showed short-and medium-term functional motor improvements in different Skills, exhibiting a significantly better performance than sham group animals [69,70,78]. However, the long-term (<12 months) stability of such behavioral improvements still needs to be demonstrated.…”

“…The majority of in vivo studies which transplant human PSCs into HD animal models used immunosuppressive drugs [69,70,79], making these studies hard to interpret, since these drugs may relieve HD symptoms [116].…”

“…Additionally, though behavior improvements have been achieved after transplantation of NPCs derived from hESC and hiPSC, these improvements were observed during short-and middle-term periods (until 12 weeks), whereas long-term studies are lacking and would be more useful in reproducing sort after effects for human treatment [69,70,72,81].…”