Neuroprotection by GDNF-secreting stem cells in a Huntington's disease model: optical neuroimage tracking of brain-grafted cells

Abstract

The use of stem cells for reconstructive or neuroprotective strategies can benefit from new advances in neuroimaging techniques to track grafted cells. In the present work, we analyze the potential of a neural stem cell (NSC) line, which stably expresses the glial cell line-derived neurotrophic factor (GDNF) and the firefly luciferase gene (GDNF/Luc-NSC), for cell therapy in a Huntington's disease mouse model. Our results show that detection of light photons is an effective method to quantify the proliferation rate and to characterize the migration pathways of transplanted NSCs. Intravenous administration of luciferine, the luciferase substract, into the grafted animals allowed the detection of implanted cells in real time by an optical neuroimaging methodology, overpassing the limits of serial histological analyses. We observed that transplanted GDNF/Luc-NSCs survive after grafting and expand more when transplanted in quinolinatelesioned nude mouse striata than when transplanted in nonlesioned mice. We also demonstrate that GDNF/Luc-NSCs prevent the degeneration of striatal neurons in the excitotoxic mouse model of Huntington's disease and reduce the amphetamine-induced rotational behavior in mice bearing unilateral lesions.

Migration of Neurotrophic Factors-Secreting Mesenchymal Stem Cells Toward a Quinolinic Acid Lesion as Viewed by Magnetic Resonance Imaging

“…In the imaging field, it is difficult to delineate implanted cells from host tissue without contrast agents or markers. In a recent study, optical imaging with luciferase expression has been used to prove the migration of neural stem cells in the QA model of HD [1,44].…”

“…The objective is to fight the common pathway of the neurodegenerative processes exhibited in many of these diseases, such as excitotoxicity, oxidative stress, and so forth. The trophic effect in the impaired tissue may be provided by cells that secrete neurotrophic factors (NTFs) [1].…”

The R6 lines of transgenic mice: A model for screening new therapies for Huntington's disease

“…However, as discussed above, several other therapeutic strategies have been shown to be protective, even when started in older animals. Furthermore, grafting of neural stem cells stably expressing GDNF and the firefly luciferase gene prevented the degeneration of striatal neurons and reduced the amphetamine-induced rotational behavior in an excitotoxic HD mouse model (Pineda et al, 2007). Nevertheless, the study by Popovic et al (2005) proves that overexpression of neurotrophic factors using lentiviral vectors is doable in the R6 mouse model, and therefore, the same techniques may be used to evaluate the effects of overexpression of other neurotrophic factors.…”

Cell therapy in Huntington disease

“…93,105 Neurons and astrocytes are responsive to GDNF, especially after injury, 105 and GDNF protects striatal medium spiny GABAergic neurons from excitotoxic injury in rodent models of HD. 66,107,122 Neural stem cells and fibroblasts genetically modified to deliver GDNF and transplanted into sites of excitotoxic lesions protect striatal neurons from degeneration, 7,122,127 an effect similar to that observed in PD models. 1 Glial cell line-derived neurotrophic factor-secreting NSCs also partially restore functional deficits in neurotoxic lesioned mice.…”

“…1 Glial cell line-derived neurotrophic factor-secreting NSCs also partially restore functional deficits in neurotoxic lesioned mice. 127 Viral GDNF delivery into the striatum of presymptomatic transgenic mice with HD preserves striatal neuronal cells from degeneration, decreases the percentage of neuronal cells with mutant htt inclusions, and ameliorates behavioral deficits (hand clasping and accelerating rotarod). 107,108 The use of growth factors, administered virally or through transplanted engineered cells, has the potential to protect vulnerable neuronal cells in the degenerative HDaffected brain.…”