Grafts of extra-adrenal chromaffin cells as aggregates show better survival rate and regenerative effects on parkinsonian rats than dispersed cell grafts.

The objective was to discern the neuroregenerative effect of grafts of extra-adrenal cells of the Zuckerkandl's paraganglion (ZP) in the nigrostriatal circuit, by using the retrograde model of parkinsonism in rats. The antiparkinsonian efficacy of two types of grafting procedures was studied (cell aggregates vs. dispersed cells), and GDNF and TGFbeta(1) (dopaminotrophic factors) as well as dopamine presence in extra-adrenal tissue was analyzed. Extra-adrenal chromaffin cells are noradrenergics, tissue dopamine is low, and they express both GDNF and TGFbeta(1). Grafts of cell aggregates, not of dispersed cells, exerted a trophic regeneration of the host striatum, leading to amelioration of motor deficits. Sprouting of spared dopaminergic fibers within the striatum, reduction of dopamine axon degeneration, and/or enhanced phenotypic expression of TH would explain striatal regeneration. Grafted cells as aggregates showed a better survival rate than dispersed cells, and they express higher levels of GDNF. Higher survivability and GDNF content together with the neurorestorative and dopaminotrophic action of both GDNF and TGFbeta(1) could account for striatal recovery and functional amelioration after grafting ZP cell aggregates. Finally, nigral degeneration and partial degeneration of ventral tegmental area were not precluded after transplantation, indicating that the trophic effect of grafts was local within the host striatum.

Functional regeneration in a rat Parkinson's model after intrastriatal grafts of glial cell line-derived neurotrophic factor and transforming growth factor beta1-expressing extra-adrenal chromaffin cells of the Zuckerkandl's organ.

Intrabrain transplantation of chromaffin cell aggregates of the Zuckerkandl's organ, an extra-adrenal paraganglion that has never been tested for antiparkinsonian treatment, induced gradual improvement of functional deficits in parkinsonian rats. These beneficial effects were related to long survival of grafted cells, striatal reinnervation, and enhancement of dopamine levels in grafted striatum. Grafted cells were not dopaminergics, but they expressed glial cell line-derived neurotrophic factor (GDNF) and transforming growth factor-beta(1). These factors were detected in the host striatal tissue, indicating that chromaffin cells secreted them after grafting. Because glial cell line-derived neurotrophic factor possesses neurorestorative properties over dopaminergic neurons, and transforming growth factor-beta(1) is a cofactor that potentiates the neurotrophic actions of GDNF, functional regeneration was likely caused by the chronic trophic action of neurotrophic factors delivered by long-surviving grafted cells. This work should stimulate research on the clinical applicability of transplants of the Zuckerkandl's organ in Parkinson's disease.