Long-term survival and integration of porcine expanded neural precursor cell grafts in a rat model of Parkinson's disease.
Porcine fetal neural tissue has been considered as an alternative source to human allografts for transplantation in neurodegenerative disorders by virtue of the fact that it can overcome the ethical and practical difficulties using human fetal neural tissue. However, primary porcine neural xenografts are rejected while porcine expanded neural precursor neural cells (PNPCs) seem to be less immunogenic and thus survive better [Armstrong, R.J., Harrower, T.P., Hurelbrink, C.B., McLaughin, M., Ratcliffe, E.L., Tyers, P., Richards, A., Dunnett, S.B., Rosser, A.E., Barker, R.A., 2001a. Porcine neural xenografts in the immunocompetent rat: immune response following grafting of expanded neural precursor cells. Neuroscience 106, 201-216]. In this study, we extended these observations to investigate the long-term survival of such transplants in immunosuppressed rats. Unilateral 6 OHDA lesioned rats received grafts into the dopamine denervated striatum of either primary porcine fetal neural tissue dissected from the E26 cortex or cortically derived neural stem cells which had been derived from the same source but expanded in vitro for 21 days. All cortically derived neural stem cell grafts survived up to 5 months in contrast to the poor survival of primary porcine xenografts. Histological analysis demonstrated good graft integration with fibers extending into the surrounding host tissue including white matter with synapse formation, and in addition there was evidence of host vascularization and myelinated fibers within the graft area. This study has therefore shown for the first time the reliable long-term survival of grafts derived from porcine expanded neural precursors in a rat model of PD, with maturation and integration into the host brain. This demonstrates that such xenografted cells may be able to recreate the damaged circuitry in PD although strategies for dopaminergic differentiation of the porcine neural precursor cell remain to be refined.
Harrower
T P
TP
Cambridge Centre for Brain Repair, Forvie Site, Robinson Way, Cambridge CB2 2PY, UK. drsharrower@aol.com
Tyers
P
P
Hooks
Y
Y
Barker
R A
RA
D000818:Animals; D001921:Brain / Q000033:anatomy & histology; D016827:CD8 Antigens / Q000276:immunology; D002454:Cell Differentiation / Q000187:drug effects; D016572:Cyclosporine / Q000627:therapeutic use; D053331:Ectodysplasins; D004622:Embryo, Mammalian / Q000033:anatomy & histology; D005260:Female; D006084:Graft Rejection / Q000276:immunology / Q000517:prevention & control; D007166:Immunosuppressive Agents / Q000627:therapeutic use; D008565:Membrane Proteins / Q000276:immunology; D009186:Myelin Sheath / Q000502:physiology; D009412:Nerve Fibers / Q000502:physiology; D009474:Neurons / Q000637:transplantation*; D016627:Oxidopamine; D010300:Parkinson Disease / Q000628:therapy*; D011247:Pregnancy; D051381:Rats; D017207:Rats, Sprague-Dawley; D033581:Stem Cell Transplantation; D013239:Stereotyped Behavior / Q000187:drug effects; D013552:Swine; D013563:Sympathectomy, Chemical; D013565:Sympatholytics; D013569:Synapses / Q000187:drug effects / Q000502:physiology; D014183:Transplantation, Heterologous; D048069:Tumor Necrosis Factors / Q000276:immunology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D016827:CD8 Antigens; C506018:EDA protein, human; D053331:Ectodysplasins; D007166:Immunosuppressive Agents; D008565:Membrane Proteins; D013565:Sympatholytics; D048069:Tumor Necrosis Factors; D016572:Cyclosporine; D016627:Oxidopamine; D014446:Tyrosine 3-Monooxygenase