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of QA adjacent to the implant site. Separate groups of animals served as controls and
received QA alone. In controls, QA lesions produced a significant loss of body weight
and impaired function of the contralateral forelimb. In contrast, implants of CP were
potently neuroprotective, as rats receiving CP transplants did not lose body weight
and were not significantly impaired when tested for motor function. These benefits
were independent of the length of time that the cells were held
in vitro.
A second set of studies determined whether age-related impairments occur in the
neuroprotective capacity of CP. Choroid plexus was isolated from either young (3-4
months) or aged (24 months) rats
[42]
.
In vitro,
young CP epithelial cells secreted
more vascular endothelial growth factor (VEGF) and were metabolically more active
than aged CP epithelial cells. Additionally, conditioned medium from cultured aged
CP was less potent than young CP at enhancing the survival of serum-deprived neu-
rons. Finally, encapsulated CP was tested in the QA model of HD as described in
Section 4.10. Animals were tested for motor function 28 days after CP implantation
(21 days post-QA administration). In the control group, QA lesions severely impaired
function of the contralateral forelimb. Implants of young CP again prevented the
impairments in motor function. In contrast, implants of CP from aged rats were only
modestly effective and were much less potent than young CP transplants. These data
demonstrate that alginate-encapsulated CP cells can be retained for extremely long
periods of time
in vitro
, but they also directly link the natural aging process with a
diminished neuroprotective capacity. Additional studies are warranted in improving
the long-term potency of encapsulation when chronic neurodegenerative disorders
are being contemplated as targets for CP cell therapy.
4.12 Conclusions
Maintenance of CNS homeostasis is vital to brain function. The CP appears to play
vital roles in the stable integrity of the CNS, via its main secretory function that
allows therapeutic molecules to penetrate the brain, but guards against the entry of
immune cells. Therapeutic strategies exploiting the growth factor secretion and
immune regulatory properties of CP may prove directly relevant to treating brain dis-
orders. Indeed, the transplant studies conducted to date lend support to the use of CP
for repairing the diseased and/or aging brain. Subsequent studies are needed to clearly
elucidate the mechanisms of action by which these therapeutic benefits are achieved
with CP, in order to further improve the functional outcomes. Envisioned mechanism-
driven experiments include determining whether CP functions within parenchymal
tissue in the same manner as within the CSF, and conducting vis-à-vis comparisons
between native ability of CP to secrete a physiologically balanced and temporally
adjusted cocktail of bioactive compounds versus delivery of single agents. Equally
critical to advancing CP cell therapy are translational research issues such as examin-
ing the potential clinical indication with emphasis on optimizing the donor source and
age of the transplanted cells, determining whether specific cell types within the CP
(i.e., purified epithelial cells) are most beneficial, and identifying the optimal postin-
jury timing, transplant location and dosage, of cells to be grafted into the CNS.
