Recovery of neurological functions in non-human primate model of Parkinson's disease by transplantation of encapsulated neonatal porcine choroid plexus cells.

Parkinson's disease (PD) is a neurodegenerative disease that is primarily characterized by degeneration of dopaminergic (DA) neurons in the substantia nigra (SN) and a loss of their fibre projections in the striatum. We utilized the neonatal porcine choroid plexus (CP), an organ that secretes cerebrospinal fluid containing various types of neurotrophic and neuroprotective factors, to ameliorate the Parkinsonian symptoms in MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated rhesus monkeys without requiring immunosuppression. We demonstrate that transplanted encapsulated CP clusters (eCPs) significantly improved neurological functions in MPTP-treated monkeys during the course of six months after transplantation (p < 0.001) when compared with monkeys implanted with empty capsules or subjected to sham surgery. The improvement in neurological scores was accompanied by a corresponding improvement in apomorphine-induced circling behaviour (p < 0.001) as well as increased tyrosine hydroxylase (TH) staining in the striatum. Our results suggest that eCPs are a promising cell therapeutic agent to treat Parkinson's disease.

Restoration of motor control and dopaminergic activity in rats with unilateral 6-hydroxy-dopamine lesions.

AIM: To restore motor function and dopaminergic activity in the nigrostriatum of rats with unilateral 6-hydroxy-dopamine lesions using implants of encapsulated porcine choroid plexus cells. MATERIALS & METHODS: Neonatal porcine choroid plexus cells were prepared and maintained in culture, then encapsulated within alginate-polyornithine capsules (600-660 µm). Rats were unilaterally injected with 6-hydroxy-dopamine into the striatum. Those with lesions verified after 2 and 4 weeks were selected for experiments. Rats were implanted adjacent to the lesion with ten capsules 2-4 days later with (treated, n = 12) or without (control, n = 10) choroid plexus cells. RESULTS: The choroid plexus cells were shown to produce a wide range of neurorestorative proteins. The treated group had a 60% improvement in motor behavior compared with the control group (p < 0.01). The treated group also had a significant improvement in nigrostriatal dopaminergic activity (31%, p < 0.02). CONCLUSION: Capsules containing porcine choroid plexus cells release therapeutic molecules that stimulate regeneration of the lesioned nigrostriatum in rats.

Choroid plexus transplants in the treatment of brain diseases.

The choroid plexus (CP) produces and secretes numerous biologically active neurotrophic factors into the cerebrospinal fluid (CSF). These circulate throughout the brain and spinal cord, maintaining neuronal networks and associated cells. In neurodegenerative disease and in acute brain injury there is local up-regulation of neurotrophin production close to the site of the lesion. Treatment by direct injection of neurotrophins and growth factors close to these lesion sites has repeatedly been demonstrated to improve recovery. It has therefore been proposed that transplanting viable choroid plexus cells close to the lesion might provide a novel means for continuous delivery of these molecules directly to the site of injury. Recent publications describe how transplanted CP, either free or in an immunoprotected encapsulated form, deliver therapeutic molecules to the desired site. This review briefly describes the accumulated evidence that CP cells support neuronal cells in vitro and have therapeutic properties when transplanted to treat acute and chronic brain disease and injury in animal models.

Extensive neuroprotection by choroid plexus transplants in excitotoxin lesioned monkeys.

Huntington's disease (HD) results from degeneration of striatal neurons. Choroid plexus (CP) cells secrete neurotrophic factors, and CP transplants are neuroprotective in rat models of HD. To determine if similar neuroprotective effects could be obtained in primates, porcine CP was encapsulated in alginate capsules. PCR confirmed that the CP cells expressed transthyretin and immunocytochemistry demonstrated typical ZO-1 and tubulin staining. In vitro, CP conditioned media enhanced the survival and preserved neurite number and length on serum deprived neurons. Cynomolgus primates were transplanted with CP-loaded capsules into the caudate and putamen followed by quinolinic acid (QA) lesions 1 week later. Control monkeys received empty capsules plus QA. Choroid plexus transplants significantly protected striatal neurons as revealed by stereological counts of NeuN-positive neurons (8% loss vs. 43% in controls) and striatum volume (10% decrease vs. 40% in controls). These data indicate that CP transplants might be useful for preventing the degeneration of neurons in HD.

Heritable transgenesis of Parastrongyloides trichosuri: a nematode parasite of mammals.

Germline transformation of a parasitic nematode of mammals has proven to be an elusive goal. We report here the heritable germline transformation of Parastrongyloides trichosuri, a nematode parasite whose natural hosts are Australian possums of the genus Trichosurus. This parasite can undergo multiple free-living life cycles and these replicative cycles can be maintained indefinitely in the laboratory. Transformation was achieved by microinjection of DNA into the ovary syncytium of either free-living or parasitic adult females. By selecting for the transgenic progeny of successive free-living life cycles, it was possible to establish and maintain transgenic lines. All three transgenic lines tested were shown capable of establishing patent infections in possums and to transmit the functional transgene to their progeny. The transgene, driven by the Pt hsp-1 promoter, was constitutively expressed in intestinal cells at all stages of both parasitic and free-living life cycles, although gene silencing appears to occur in some transgenic progeny. This is the first report of heritable transgenesis in a parasitic nematode of a mammal and we discuss a variety of previously inaccessible experimental avenues that will now be possible with this powerful model system.

The choroid plexus in the rise, fall and repair of the brain.

The choroid plexuses (CPs) are involved in the most-basic aspects of neural function including maintaining the extracellular milieu of the brain by actively modulating chemical exchange between the CSF and brain parenchyma, surveying the chemical and immunological status of the brain, detoxifying the brain, secreting a nutritive "cocktail" of polypeptides and participating in repair processes following trauma. This diversity of functions may mean that even modest changes in the CP can have far-reaching effects. Indeed, changes in the anatomy and physiology of the CP have been linked to aging and several CNS diseases. It is also possible that replacing diseased or transplanting healthy CP might be useful for treating acute and chronic brain diseases. This review focuses on the wide-ranging and under-appreciated functions of the CP, alterations of these functions in aging and neurodegeneration, and recent demonstrations of the therapeutic potential of transplanted CP for neural trauma.

A role of the choroid plexus in transplantation therapy.

The choroid plexuses (CPs) play pivotal roles in the most basic aspects of neural function. Some of the roles of the CP include maintaining the extracellular milieu of the brain by actively modulating chemical exchange between the CSF and brain parenchyma, surveying the chemical and immunological status of the brain, detoxifying the brain, secreting a nutritive "cocktail" of polypeptides, and participating in repair processes following trauma. This diversity of functions suggests that even modest changes in the CP can have far reaching effects. Indeed, changes in the anatomy and physiology of the CP have been linked to several CNS diseases. It is also possible that replacing diseased CP or transplanting healthy CP might be useful for treating acute and chronic brain diseases. Here we describe the wide-ranging functions of the CP, alterations of these functions in aging and neurodegeneration, and recent demonstrations of the therapeutic potential of transplanted CP for neural trauma.

The choroid plexus: function, pathology and therapeutic potential of its transplantation.

The choroid plexus (CP) produces cerebrospinal fluid (CSF) and forms the blood-CSF barrier. However, the CP may have additional functions in the CNS beyond these traditional roles. Preclinical and clinical studies in ageing and neurodegeneration demonstrate anatomical and physiological changes in CP, suggesting roles in normal and pathological conditions and potentially endogenous repair processes following trauma. One of the broadest functions of the CP is establishing and maintaining the extracellular milieu throughout the brain and spinal cord, in part by secreting numerous growth factors into the CSF. The endogenous secretion of growth factors raises the possibility that transplantable CP might enable delivery of these molecules to the brain, while avoiding the conventional molecular and genetic alterations associated with modifying cells to secrete selected products. This review describes some of the anatomical and functional changes of CP in ageing and neurodegeneration, and recent demonstrations of the therapeutic potential of transplanted CP for neural trauma.