LONG-TERM ENHANCED CHROMAFFIN CELL-SURVIVAL AND BEHAVIORAL RECOVERY IN HEMIPARKINSONIAN RATS WITH CO-GRAFTED POLYMER-ENCAPSULATED HUMAN NGF-SECRETING CELLS

The transplantation of genetically modified cells represents one poten tial means of delivering trophic factors to the brain to support the s urvival of host neurons and to increase the survival of co-grafted cel ls. The present study examined the ability of encapsulated baby hamste r kidney (BHK) fibroblasts, which were genetically modified to produce human nerve growth factor (hNGF), to provide long-term trophic suppor t to co-grafted adrenal chromaffin cells. Following polymer encapsulat ion, BHK-hNGF cells were grafted into the striatum of hemiparkinsonian rats together with unencapsulated adrenal medullary chromaffin cells. Secretion of hNGF from the encapsulated cells, morphology of these ce lls, apomorphine-induced rotational behavior of the host animals, and survival of the co-grafted chromaffin cells were examined 1, 6, and 12 months after transplantation. Analysis of retrieved capsules revealed that the BHK cells survived and continued to release hNGF at a level of 2-3 ng/day even 12 months after transplantation. Although the anima ls receiving adrenal medulla alone did not show recovery of apomorphin e-induced rotational behavior, the animals receiving adrenal medulla w ith intrastriatal hNGF-secreting cells showed a significant decrease ( 40-50%) in apomorphine-induced rotation within 1 month postimplantatio n that remained stable for the la-month test period. Tyrosine hydroxyl ase immunocytochemistry further revealed that while survival of chroma ffin cells without hNGF support was poor, cografting of adrenal medull a and BHK-hNGF cells dramatically (26- to 32-fold) increased chromaffi n cell survival 1, 6, and 12 months after transplantation. These resul ts demonstrate that (1) encapsulated BHK cells survive for extended pe riods of time in vivo while continuing to secrete hNGF, (2) the contin ued secretion of hNGF provides trophic support for co-grafted adrenal chromaffin cells, and (3) the increased chromaffin cell survival is as sociated with long-term, stable behavioral recovery. These data furthe r support the potential use of this approach for treating Parkinson's disease. (C) 1997 Academic Press.