PROLIFERATION, CELL-DEATH, AND NEURONAL DIFFERENTIATION IN TRANSPLANTED HUMAN EMBRYONAL CARCINOMA (NTERA2) CELLS DEPEND ON THE GRAFT SITE IN NUDE AND SEVERE COMBINED IMMUNODEFICIENT MICE

BACKGROUND: Embryonal carcinoma cell lines have been used to study the induction and progression of tumors, the mechanisms governing lineage commitment in the central nervous system, and the developmental biolo gy of neurons and glia. Here, we have used a human embryonal carcinoma cell line (NTera2/cl.D1 or NT2 cells) that resembles neural progenito r cells to study how an in vivo environment influences and regulates t he fate of these cells. EXPERIMENTAL DESIGN: To understand the mechani sms that coordinately regulate the proliferation, death, and different iation of NT2 cells, we examined these processes by transplanting huma n NT2 cells into the brains and peripheral tissues (liver, muscle) of immunodeficient mice. RESULTS: We demonstrate that the proliferation, differentiation, and death of NT2 cells were modulated by the anatomic al site into which the NT2 grafts were implanted. The NT2 cells contin ued to proliferate and undergo cell death but showed a very limited ca pacity to differentiate into neurons after implantation into the subar achnoid space and superficial neocortex. At this site, the NT2 cell gr afts rapidly formed bulky tumors that were lethal within 70 days posti mplantation. Further, NT2 cell grafts in the lateral ventricles, liver , and muscle behaved in a similar manner. In contrast, NT2 cells impla nted into the caudoputamen ceased proliferating and showed no evidence of necrosis or apoptosis after postimplantation survival intervals of more than 20 weeks. This occurred in parallel with the progressive di fferentiation of large numbers of NT2 cells into postmitotic, immature , neuron-like cells. CONCLUSIONS: These results suggest that signal mo lecules or other ''cues'' (e.g., cell-cell contacts) capable of regula ting the proliferation, death, and differentiation of human NT2 cells are biologically active in the adult mouse caudoputamen. Thus, the tra nsplantation of human NT2 cells into the central nervous system of imm unodeficient mice may serve as an in vivo model system for studies of the formation and re-modeling of the developing central nervous system .