Enhanced vascularization and survival of neural transplants with ex vivo angiogenic gene transfer

D. Casper, S. J. Engstrom, G. R. Mirchandani, A. Pidel, D. Palencia, P. H. Cho, M. Brownlee, D. Edelstein, H. J. Federoff, W. J. Sonstein

Research output: Contribution to journalArticle

33 Citations (Scopus)

Abstract

Restoration of brain function by neural transplants is largely dependent upon the survival of donor neurons. Unfortunately, in both rodent models and human patients with Parkinson's disease the survival rate of transplanted neurons has been poor. We have employed a strategy to increase the availability of nutrients to the transplant by increasing the rate at which blood vessels are formed. Replication-deficient HSV-1 vectors containing the cDNA for human vascular endothelial growth factor (HSVhvegf) and the bacterial β-galactosidase gene (HSVlac) have been transduced in parallel into nonadherent neuronal aggregate cultures made of cells from embryonic day 15 rat mesencephalon. Gene expression from HSVlac was confirmed in fixed preparations by staining with X-gal. VEGF expression as determined by sandwich ELISA assay of culture supernatant was up to 322-fold higher in HSVhvegf-infected than HSVlac-infected sister cultures. This peptide was also biologically active, inducing endothelial cell proliferation in vitro. Adult Sprague-Dawley rats received bilateral transplants into the striatum, with HSVlac on one side and HSVhvegf on the other. At defined intervals up to 8 weeks, animals were sacrificed and vibratome sections of the striatum were assessed for various parameters of cell survival and vascularization. Results demonstrate dose-dependent increases in blood vessel density within transplants transduced with HSVhvegf. These transplants were vascularized at a faster rate up to 4 weeks after transplantation. After 8 weeks, the average size of the HSVhvegf-infected transplants was twice that of controls. In particular, the survival of transplanted dopaminergic neurons increased 3.9-fold. Taken together these experiments provide convincing evidence that the rate of vascularization may be a major determinant of neuronal survival that can be manipulated by VEGF gene transduction.

Original languageEnglish (US)
Pages (from-to)331-349
Number of pages19
JournalCell Transplantation
Volume11
Issue number4
StatePublished - 2002

Fingerprint

Gene transfer
Transplants
Human Herpesvirus 1
Complementary DNA
Genes
Neurons
Blood vessels
Vascular Endothelial Growth Factor A
Blood Vessels
Rats
Galactosidases
Bacterial Genes
Survival
Dopaminergic Neurons
Endothelial cells
Cell proliferation
Mesencephalon
Gene expression
Peptides
Nutrients

Keywords

  • Angiogenesis
  • Dopaminergic neurons
  • Ex vivo gene therapy
  • Neural transplantation
  • Parkinson's disease
  • Vascularization
  • VEGF

ASJC Scopus subject areas

  • Cell Biology
  • Transplantation

Cite this

Casper, D., Engstrom, S. J., Mirchandani, G. R., Pidel, A., Palencia, D., Cho, P. H., ... Sonstein, W. J. (2002). Enhanced vascularization and survival of neural transplants with ex vivo angiogenic gene transfer. Cell Transplantation, 11(4), 331-349.

Enhanced vascularization and survival of neural transplants with ex vivo angiogenic gene transfer. / Casper, D.; Engstrom, S. J.; Mirchandani, G. R.; Pidel, A.; Palencia, D.; Cho, P. H.; Brownlee, M.; Edelstein, D.; Federoff, H. J.; Sonstein, W. J.

In: Cell Transplantation, Vol. 11, No. 4, 2002, p. 331-349.

Research output: Contribution to journalArticle

Casper, D, Engstrom, SJ, Mirchandani, GR, Pidel, A, Palencia, D, Cho, PH, Brownlee, M, Edelstein, D, Federoff, HJ & Sonstein, WJ 2002, 'Enhanced vascularization and survival of neural transplants with ex vivo angiogenic gene transfer', Cell Transplantation, vol. 11, no. 4, pp. 331-349.
Casper D, Engstrom SJ, Mirchandani GR, Pidel A, Palencia D, Cho PH et al. Enhanced vascularization and survival of neural transplants with ex vivo angiogenic gene transfer. Cell Transplantation. 2002;11(4):331-349.
Casper, D. ; Engstrom, S. J. ; Mirchandani, G. R. ; Pidel, A. ; Palencia, D. ; Cho, P. H. ; Brownlee, M. ; Edelstein, D. ; Federoff, H. J. ; Sonstein, W. J. / Enhanced vascularization and survival of neural transplants with ex vivo angiogenic gene transfer. In: Cell Transplantation. 2002 ; Vol. 11, No. 4. pp. 331-349.
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