Dose-Dependent Doxycycline-Mediated Adrenocorticotropic Hormone Secretion from Encapsulated Tet-On Proopiomelanocortin Neuro2A Cells in the Subarachnoid Space

摘要

ABSTRACTWe previously reported that polymer-encapsulated mouse neuroblastoma cells that are capable of secreting-endorphin may reduce pain sensitivity in rats after capsule implantation into the cerebrospinal fluid (CSF)-filled subarachnoid space of the spinal cord. The neuroblastoma cells carry the proopiomelanocortin (POMC) gene that encodes the precursor of adrenocorticotropic hormone (ACTH) and-endorphin. To control the expression of these hormones in the present study, a promoter that is inducible by administration of tetracycline derivatives such as doxycycline (Dox) was linked to the POMC gene. Encapsulated cells in the CSF space of rats stimulated by four intraperitoneal doses of Dox responded with ACTH expression as determined in a subsequence 36-hrin vitroincubation. The amount of ACTH released was dependent on thein vivoDox dose. These findings indicate that gene expression in xenogeneic cells in the CSF space can be manipulated by injection of a relatively innocuous drug, and suggest that this system may be applicable to cell transplantation therapy in patients with central nervous system diseases that require temporary control of ligand delivery.