ADRENAL CHROMAFFIN CELLS TRANSDIFFERENTIATE IN RESPONSE TO BASIC FIBROBLAST GROWTH-FACTOR AND SHOW DIRECTED OUTGROWTH TO A NERVE GROWTH-FACTOR SOURCE IN-VIVO

Chromaffin cells exposed to basic fibroblast growth factor (bFCF) in v itro express characteristics of sympathetic neurons, extend neurites, and become dependent on nerve growth factor (NGF) for survival. We exp lored whether the growth factor responsiveness of chromaffin cells cou ld be exploited to enhance the transdifferentiation, neurite outgrowth and functional efficacy of chromaffin cells implanted into rats with unilateral 6-hydroxydopamine lesions. Cografts of neonatal chromaffin cells and fibroblasts genetically modified to produce bFGF were placed into the dopamine-depleted striatum of adult rats. Either control-tra nsfected or NGF-producing fibroblasts were then transplanted 1 mm dist al to the cograft. Chromaffin cells transdifferentiated under the infl uence of bFGF, as indicated by the growth of neurites and the expressi on of neuron-specific proteins. Distal grafts of NGF-producing fibrobl asts successfully induced chromaffin neurites to traverse through the host parenchyma to the NGF source. In the absence of NGF fibroblast gr afts, neither neurite extension nor good, long-term survival of the ch romaffin-derived neurons was observed. Assessments of apomorphine-indu ced rotational behavior 2- and 4-weeks postgrafting revealed no behavi oral improvements in any of the groups. These results indicate that lo calized sources of growth factors are effective in inducing the transd ifferentiation of grafted chromaffin cells as well as the extension of chromaffin-derived neurites into the host parenchyma. Such chromaffin cell-derived neurons are, however, functionally ineffective in this r at model of Parkinson's disease. Whether the lack of behavioral improv ement reflected the tropic growth of neurites to an inappropriate stri atal region or the noradrenergic nature of the chromaffin cell-derived neurons remains to be clarified. Nonetheless, these results caution t hat promoting transdifferentiation and neurite extension from engrafte d chromaffin cells may not be sufficient to achieve desired functional effects of such grafts. (C) 1995 Academic Press,Inc.