An immunohistochemical study was done for the presence of tyrosine hydroxylase (noradrenergic innervation), neuron-specific protein PGP9.5, and anterior pituitary hormones (beta-subunit of follicle-stimulating hormone, growth hormone, beta-subunit of luteinizing hormone, prolactin, and beta-subunit of thyroid-stimulating hormone) in cultured thymic fragments before and after transplantation in congenitally athymic and euthymic rats. The cultured thymic fragments consisted of epithelial cells and were depleted of lymphocytes. After implantation in syngeneic and allogeneic athymic recipients and in syngeneic euthymic recipients, a recovery of the original architecture was found within 6 weeks; rejection occurred within 3 weeks for allogeneic transplantation in euthymic rats. During culture nerve-like profiles almost disappeared from the tissue, and reappeared simultaneously with the influx of host-derived cells and the restoration of the original thymic architecture. A high immunoreactivity for hormones and PGP9.5 was found in epithelial cells after culture and in the first phase after transplantation. These epithelial cells may represent precursor-epithelial cells, based on their unusual ultrastructure and combined expression of markers that in the normal thymus occur only on subcapsular/medullary epithelium or on cortex epithelium. These data indicate a potential role of the neuroendocrine function of the thymus during restoration of the thymus architecture starting from precursor-like epithelial cells.