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 biology of neurons and glia. Here, we have used a human embryonal carcinoma cell line (NTera2/cl.D1 or NT2 cells) that resembles neural progenitor cells to study how an in vivo environment influences and regulates the fate of these cells.


METHODS
To understand the mechanisms that coordinately regulate the proliferation, death, and differentiation of NT2 cells, we examined these processes by transplanting human NT2 cells in 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 anatomical site into which the NT2 grafts were implanted. The NT2 cells continued to proliferate and undergo cell death but showed a very limited capacity to differentiate into neurons after implantation into the subarachnoid space and superficial neocortex. At this site, the NT2 cell grafts rapidly formed bulky tumors that were lethal within 70 days postimplantation. Further, NT2 cell grafts in the lateral ventricles, liver, and muscle behaved in a similar manner. In contrast, NT2 cells implanted 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 differentiation of large numbers of NT2 cells into postmitotic, immature, neuron-like cells.


CONCLUSIONS
These results suggest that signal molecules or other "cues" (e.g., cell-cell contacts) capable of regulating the proliferation, death, and differentiation of human NT2 cells are biologically active in the adult mouse caudoputamen. Thus, the transplantation of human NT2 cells into the central nervous system of immunodeficient mice may serve as an in vivo model system for studies of the formation and re-modeling of the developing central nervous system.
Miyazono
M
M
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, USA.
Lee
V M
VM
Trojanowski
J Q
JQ
D000818:Animals; D016923:Cell Death / Q000502:physiology*; D002454:Cell Differentiation / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008099:Liver; D051379:Mice; D008819:Mice, Nude; D016513:Mice, SCID; D009132:Muscles; D009368:Neoplasm Transplantation / Q000473:pathology*; D018243:Teratocarcinoma / Q000737:chemistry / Q000473:pathology*; D014407:Tumor Cells, Cultured