Grafting of encapsulated BDNF-producing fibroblasts into the injured spinal cord without immune suppression in adult rats.
Grafting of genetically modified cells that express therapeutic products is a promising strategy in spinal cord repair. We have previously grafted BDNF-producing fibroblasts (FB/BDNF) into injured spinal cord of adult rats, but survival of these cells requires a strict protocol of immune suppression with cyclosporin A (CsA). To develop a transplantation strategy without the detrimental effects of CsA, we studied the properties of FB/BDNF that were encapsulated in alginate-poly-L-ornithine, which possesses a semipermeable membrane that allows production and diffusion of a therapeutic product while protecting the cells from the host immune system. Our results show that encapsulated FB/BDNF, placed in culture, can survive, secrete bioactive BDNF and continue to grow for at least one month. Furthermore, encapsulated cells that have been stored in liquid nitrogen retain the ability to grow and express the transgene. Encapsulated FB/BDNF survive for at least one month after grafting into an adult rat cervical spinal cord injury site in the absence of immune suppression. Transgene expression decreased within two weeks after grafting but resumed when the cells were harvested and re-cultured, suggesting that soluble factors originating from the host immune response may contribute to the downregulation. In the presence of capsules that contained FB/BDNF, but not cell-free control capsules, there were many axons and dendrites at the grafting site. We conclude that alginate encapsulation of genetically modified cells may be an effective strategy for delivery of therapeutic products to the injured spinal cord and may provide a permissive environment for host axon growth in the absence of immune suppression.
Tobias
C A
CA
Department of Neurobiology and Anatomy, MCP Hahnemann University, Philadelphia, Pennsylvania 19129, USA.
Dhoot
N O
NO
Wheatley
M A
MA
Tessler
A
A
Murray
M
M
Fischer
I
I
D000464:Alginates / Q000627:therapeutic use; D000818:Animals; D001672:Biocompatible Materials / Q000627:therapeutic use; D019208:Brain-Derived Neurotrophic Factor / Q000276:immunology / Q000627:therapeutic use*; D002214:Capsules; D002642:Chick Embryo; D005260:Female; D005347:Fibroblasts / Q000276:immunology / Q000637:transplantation*; D015870:Gene Expression / Q000187:drug effects* / Q000502:physiology; D017930:Genes, Reporter / Q000187:drug effects / Q000502:physiology; D020723:Glucuronic Acid; D006085:Graft Survival / Q000276:immunology*; D006603:Hexuronic Acids; D010455:Peptides / Q000276:immunology / Q000627:therapeutic use; D051381:Rats; D017207:Rats, Sprague-Dawley; D013119:Spinal Cord Injuries / Q000188:drug therapy* / Q000276:immunology; D013501:Surface-Active Agents / Q000627:therapeutic use
D000464:Alginates; D001672:Biocompatible Materials; D019208:Brain-Derived Neurotrophic Factor; D002214:Capsules; D006603:Hexuronic Acids; D010455:Peptides; D013501:Surface-Active Agents; C008973:polyornithine; D020723:Glucuronic Acid