Long-term integration and neuronal differentiation of human embryonal carcinoma cells (NTera-2) transplanted into the caudoputamen of nude mice.

Abstract

NTera-2 (NT2) cells are a human embryonal carcinoma (EC) cell line derived from a teratocarcinoma that differentiate exclusively into postmitotic neurons in vitro following retinoic acid (RA) treatment. Like other EC cell lines, NT2 cells rapidly form lethal tumors following transplantation into peripheral sites or many regions of the brain. However, when grafts are confined to the caudoputamen (CP), the NT2 cells differentiate into postmitotic neuronlike cells and do not form lethal tumors. To examine the long-term fate of such grafts, we studied NT2 cell transplants in the CP of nude mice that survived for > 1 year. NT2 cells in these grafts acquired molecular markers of fully mature neurons including the low, middle, and high molecular weight neurofilament proteins, microtubule-associated protein 2, tau, and synaptophysin. Furthermore, neuronlike cells in long-term CP grafts formed synaptic structures, and their processes became myelinated, whereas tyrosine hydroxylase (TH)-positive neuronlike cells in the grafts increased with progressively longer postimplantation survival times. Soluble extracts of the adult mouse CP augmented TH expression in RA-treated NT2 cells in vitro. These data suggest that the adult mouse CP is a source of factor(s) that inhibits tumor formation and induce a catecholaminergic neuronal phenotype in these human NT2 cells in vivo and in vitro. Identification of these factors could accelerate efforts to elucidate mechanisms that regulate progenitor cell fate and the commitment of neurons to specific neurotransmitter phenotypes.