Short- and long-term maturation of human stem-cell derived striatal progenitors grafted into a rat model of Huntington disease

Huntington disease (HD) is an inherited adult-onset neurodegenerative disorder, characterized by progressive loss of medium spiny neurons (MSNs) and consequent degeneration of the striatum, resulting in motor and cognitive impairments. A cell replacement approach using human embryonic stem cells may represent a good strategy to repair the damaged tissues and significantly improve disease conditions. In this study, we transplanted in vitro-differentiated human striatal progenitors into the striatum of quinolinic acid (QA)-lesioned athymic rat model of HD; then we compared the maturation and the integration of the graft in host brain circuitry at short and long times after transplantation (two and six months, respectively). By immunohistochemistry we observed that transplanted cells progressively acquire a striatal mature phenotype and early extend projections at long distance to the proper striatal targets. We also evaluated animal recovery after transplantation performing different behavioral tests. Results showed that MSN engraftments early improve the sensorimotor performances, but long-time transplantation is able to rescue more complex motor deficits, supporting the increase in time of graft maturation and integration. In conclusion, our results highlight the feasibility of stem cells transplantation as a good therapeutic approach for the replacement of degenerated striatal neurons, in order to ameliorate HD pathological conditions.