Intrastriatal transplantation of neurotrophic factor-secreting human mesenchymal stem cells improves motor function and extends survival in R6/2 transgenic mouse model for Huntington's disease

Abstract

Stem cell-based treatment for Huntington's disease (HD) is an expanding field of research. Although various stem cells have been shown to be beneficial in vivo, no long standing clinical effect has been demonstrated. To address this issue, we are developing a stem cell-based therapy designed to improve the microenvironment of the diseased tissue via delivery of neurotrophic factors (NTFs). Previously, we established that bone marrow derived human mesenchymal stem cells (MSCs) can be differentiated using medium based cues into NTF-secreting cells (NTF+ cells) that express astrocytic markers. NTF+ cells were shown to alleviate neurodegeneration symptoms in several disease models in vitro and in vivo, including the model for excitotoxicity. In the present study, we explored if the timing of intrastriatal transplantation of hNTF+ cells into the R6/2 transgenic mouse model for HD influences motor function and survival. One hundred thousand cells were transplanted bilaterally into the striatum of immune-suppressed mice at 4.5, 5.5 and 6.5 weeks of age. Contrary to our expectations, early transplantation of NTF+ cells did not improve motor function or overall survival. However, late (6.5 weeks) transplantation resulted in a temporary improvement in motor function and an extension of life span relative to that observed for PBS treated mice. We conclude that late transplantation of NTF+ cells induces a beneficial effect in this transgenic model for HD. Since no transplanted NTF+ cells could be detected in vivo, we suspect that the temporary nature of the beneficial effect is due to poor survival of transplanted cells. In general, we submit that NTF+ cells should be further evaluated for the therapy of HD.

The amount of BDNF and GDNF secreted by NTF+ cells is species specific.

(A) BDNF secretion. (B) GDNF secretion (n=3 per species).

Cell transplantation at different time point in R6/2 transgenic mice.

(A) Early (at 4th week) intrastriatal transplantation of hNTF+ cells does not influence motor function in the R6/2 mouse model of HD, (B) nor its survival. (C) Later (at 5th week) intrastriatal transplantation of hNTF+ cells does not alter motor function, (D) however it increases survival of R6/2 mice. (E) Late (6.5 weeks) transplantation of NTF+ cells induce a statistically significant but temporary improvement in motor function. (F) hMSC or hNTF+ cells transplantation increases life span, as compared to sham treated mice.