Alfred V. Vasconcellos

Intracerebral Transplantation of Porcine Choroid Plexus Provides Structural and Functional Neuroprotection in a Rodent Model of Stroke

Background and Purpose— Choroid plexus (CP) secretes a cocktail of neurotrophic factors. In the present study, CP from neonatal pigs was encapsulated within alginate microcapsules for in vitro and in vivo neuroprotective studies. Methods— In vitro studies involved serum deprivation of rat embryonic cortical neurons and treatment with a range of concentrations of conditioned media from CP. For in vivo studies, rats received a 1-hour middle cerebral artery occlusion followed by intracranial transplantation of encapsulated or unencapsulated CP, empty capsules, or no transplant. Behavioral testing was conducted on days 1 to 3 after transplantation. Cerebral infarction was analyzed using 2,3,5-triphenyl-tetrazolium chloride staining at 3 days after transplantation. Results— Conditioned media from CP produced a significant dose-dependent protection of serum-deprived cortical neurons. Enzyme-linked immunosorbent assay confirmed secretion of GDNF, BDNF, and NGF from CP. Parallel in vivo studies showed that CP transplants improved behavioral performance and decreased the volume of infarction. Both encapsulated and unencapsulated CP transplants were effective; however, more robust benefits accompanied encapsulated transplants. Conclusions— These data are the first to demonstrate the neuroprotective potential of transplanted CP and raise the intriguing possibility of using these cells as part of the treatment regimen for stroke and other neurological disorders.

Neuroprotection by encapsulated choroid plexus in a rodent model of Huntington's disease.

Choroid plexus from neonatal pigs was encapsulated in alginate microcapsules and transplanted into the rat striatum. Three days later, the same animals received unilateral injections of quinolinic acid (225 nmol) into the ipsilateral striatum. Choroid plexus transplants ameliorated the weight loss and motor impairments resulting from QA. Histological analysis demonstrated that choroid plexus transplants reduced the volume of striatal damage and protected ChAT-, but not NADPH-diaphorase-positive neurons. These data are the first to demonstrate that transplanted choroid plexus cells can protect striatal neurons from excitotoxic damage and that this strategy may ultimately prove relevant for the treatment of Huntingtons disease.

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.

Subcutaneous Transplantation of Islets into Streptozocin-Induced Diabetic Rats:

Pancreatic islet transplantation into type 1 diabetic patients is currently being performed by intraportal infusion. This method, albeit reproducible, has some disadvantages including potential development of portal hypertension, hemorrhage, and an inability to retrieve or detect the transplanted tissue. Other transplant sites have been examined in animal models including the omentum, peritoneal cavity, and the spleen. A transplant site that has not been successful in supporting functional islet tissue transplantation in humans is the subcutaneous space due primarily to the lack of a well-defined vascular bed. This site has many favorable characteristics such as ease of access for transplantation and potential for removal of the transplanted tissue with a minimally invasive surgical procedure. This report addresses the evaluation of a subcutaneously placed device for the support of rat syngeneic islet transplantation in a streptozocin-induced diabetic model. The data generated support the use of this device for islet engraftment. In addition, beta cell function in this device compared favorably with the function of islets transplanted to the renal subcapsular space as well as islets within the native pancreas.

Choroid plexus transplants in the treatment of brain diseases.

Abstract:  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.

The Choroid Plexus

The choroid plexus (CP) produces cerebrospinal fluid (CSF) and forms a portion of the physical structure of the CSF-blood barrier. More recently, the CP been implicated in other basic aspects of neural functioning, such as surveying the chemical and immunological status of the brain, detoxifying the brain, secreting a nutritive cocktail of polypeptides for neuronal function and survival, and participating in repair processes following trauma. The CP also has a role in maintaining the extracellular milieu of the brain by actively modulating the chemical exchange between the CSF and brain parenchyma and by secreting numerous growth factors into the CSF. Preclinical and clinical studies in aging and neurodegeneration demonstrate anatomical and physiological changes in the CP, suggesting effects not only in normal development and pathological conditions, but also in potential endogenous repair processes following trauma. CP dysfunction in central nervous system (CNS) diseases, and the endogenous secretion of growth factors, indicates that transplantable CP might enable delivery of growth factors to the brain while avoiding the conventional molecular and genetic alterations associated with modifying cells to secrete selected products. Thus, this enables the possibility of replacing or transplanting CP as a means of treating acute and chronic brain diseases. This chapter focuses on the various functions of the CP, how these functions are altered in aging and neurodegeneration, and recent demonstrations of the therapeutic potential of transplanted CP for neural trauma.

Elevator Pitch: InCytu, Inc.

InCytu, Inc. is an applied biotechnology company developing cell therapy delivery devices that promote targeted tissue healing/regeneration or modulate the immune system.