Survival, Neuronal Differentiation, and Fiber Outgrowth of Propagated Human Neural Precursor Grafts in an Animal Model of Huntington's Disease

Abstract

Expanded neural precursor cells provide an attractive alternative to primary fetal tissue for cell replacement therapies in neurodegenerative diseases. In this study we transplanted epigenetically propagated human neural precursor cells into a rat model of Huntington's disease. Neural precursors survived transplantation and large numbers differentiated to express neuronal antigens, including some that expressed DARPP-32, indicating a mature striatal phenotype had been adopted. Neuronal fibers from the grafts projected diffusely throughout the host brain, although there was no evidence that outgrowth was specifically target directed. This study supports the contention that propagated human neural precursors may ultimately be of use in therapeutic neural transplantation paradigms for diseases such as Huntington's disease.

Transplanted human fetal neural stem cells survive, migrate, and differentiate in ischemic rat cerebral cortex

“…Human neural precursor cells did not migrate extensively in rodent models of PD or HD (14,15). PD and HD lesions are much smaller than the present ischemic infarcts, so migratory signals may be weaker.…”

“…Targeted migration toward the lesion was observed, and most migrating cells had a neuronal phenotype. Similar human neural progenitor cells have been used in animal models of PD (15,16) and HD (14), and delivered intravenously in animal models of stroke (20,26). Compared with a PD or HD brain, the massive cell death and inflammatory response in the ischemic brain creates a more hostile environment for transplanted cells, an assertion supported by our finding of a negative correlation between the inflammatory response and cell survival.…”

“…Studies in animal models of Parkinson's disease (PD) and Huntington's disease (HD) show that transplanted human neural precursor cells survive and differentiate into neurons and glia (14)(15)(16). Functional studies with such human cells have not been reported in these animal models, but primary fetal human tissue is known to ameliorate the symptoms of PD (17,18), findings that have been replicated to some extent in clinical trials (19).…”

Noninvasive method of immortalized neural stem-like cell transplantation in an experimental model of Huntington's disease

“…Intrastriatial lesions created using excitatory amino acid mimic the neurochemical and neuropathological characteristics of HD (DiFiglia, 1990), and anatomical and functional recovery induced by striatal grafts has been observed (Armstrong et al, 2000;Chen et al, 2002). However, the possibility of acute tissue reaction by quinolinic acid may enabled NSC to migrate into the striatum in the present study.…”

“…To modify disease progression, fetal tissue transplantation in the striatum has been tried in humans (Hauser et al, 2002;Gaura et al, 2004). The transplantation of neural tissue improves functional and morphological outcomes, restores electrophysiological sensitivity to dopamine (Chen et al, 2002), and neuronal differentiation and fiber outgrowth from grafts in an animal model of HD (Armstrong et al, 2000).…”