The use of genetically altered astrocytes to provide nerve growth factor to adrenal chromaffin cells grafted into the striatum

Lee A. Cunningham*, John T. Hansen, M. Priscilla Short, M. Churchill Bohn

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

67 Scopus citations

Abstract

Transplantation of adrenal chromaffin cells into the striatum of Parkinson's disease patients is unlikely to become a reliable therapy unless techniques are devised to improve cell survival. To address this issue, we investigated the use of genetically altered astrocytes that constitutively secrete β-nerve growth factor (NGF) to provide trophic support for adrenal chromaffin cells grafted into the dopamine-denervated striatum of the rat. Primary rat astrocytes were altered genetically in vitro by infection with a retroviral vector harboring a mouse β-NGF transgene under constitutive long terminal repeat transcriptional control. Confluent cultures of these genetically altered astrocytes secrete NGF into their culture medium at a rate of approximately 9 pg/105 cells/h. This rate of NGF secretion is at least 10-fold higher than that of confluent sister cultures of uninfected astrocytes. The effects of the NGF-secreting astrocytes on the survival and neuronal transformation of dissociated adrenal chromaffin cells were assessed in vitro and following transplantation into the dopamine-denervated striatum of the adult rat. In vitro experiments demonstrated that neuritic outgrowth is stimulated when postnatal day 12 chromaffin cells are grown on a monolayer of the genetically altered astrocytes. When co-grafted with genetically altered astrocytes, young postnatal chromaffin cells displayed extensive neuritic outgrowth within the host brain 2 weeks postimplantation, whereas chromaffin cells grafted alone or with normal astrocytes retain an endocrine-like morphology. Survival of the chromaffin cells is also enhanced 3-6-fold when co-grafted with the genetically altered astrocytes. In addition, the neuronally transformed chromaffin cells appear to lose adrenergic properties as assessed by diminished immunoreactivity to the adrenergic marker, phenylethanolamine-N-methyltransferase. Although their survival is also enhanced approximately 4-fold relative to controls, adult chromaffin cells do not convert to a neuronal morphology when co-grafted with the genetically altered astrocytes. These studies demonstrate that rat astrocytes carrying a mouse NGF transgene provide trophic support for intrastriatal chromaffin cell grafts.

Original languageEnglish (US)
Pages (from-to)192-202
Number of pages11
JournalBrain research
Volume561
Issue number2
DOIs
StatePublished - Oct 11 1991

Keywords

  • 6-Hydroxydopamine
  • Parkinson's disease
  • Retroviral vector
  • Striatum
  • Transplantation

ASJC Scopus subject areas

  • Neuroscience(all)
  • Molecular Biology
  • Clinical Neurology
  • Developmental Biology

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