Transplantation Of Fetal Striatal Tissue Research Articles

A commentary on "Differentiation of pluripotent stem cells into striatal projection neurons: a pure MSN fate may not be sufficient".

Proof-of-concept has long been gained from both Huntington's disease (HD) animal models and pilot clinical trials that transplantation of fetal striatal tissue has the potential to offer a substitutive therapy to HD patients (Peschanski et al., 1995; Bachoud-Levi et al., 2006; Reuter et al., 2008; Paganini et al., 2014). Nonetheless, in the stem cell era, the body of knowledge so far obtained from fetal tissue as cell source may well be handed over to the clinical exploitation of neural stem cells (Tabar and Studer, 2014).

Fetal striatal grafting slows motor and cognitive decline of Huntington's disease

ObjectiveTo assess the clinical effect of caudate-putaminal transplantation of fetal striatal tissue in Huntington's disease (HD).MethodsWe carried out a follow-up study on 10 HD transplanted patients and 16 HD not-transplanted...

Fetal Striatal Transplants Restore Electrophysiological Sensitivity to Dopamine in the Lesioned Striatum of Rats with Experimental Huntington’s Disease

Dopamine (DA), a major neurotransmitter used in the striatum, is involved in movement disorders such as Parkinson’s disease and Huntington’s chorea. With the loss of neurons in the striatum of patients with Huntington’s disease (HD), there is an associated downregulation of DA receptors, which may alter DA-mediated responses. In the present study, DA-mediated electrophysiological depression was studied in animals with quinolinic acid (QA)-induced experimental HD. QA was directly applied to the right striatum of adult female Sprague-Dawley rats. Animals receiving QA developed ipsilateral rotation after the application of apomorphine. Fetal striatal tissue transplants grafted 1 month after lesioning attenuated apomorphine-induced rotation. Six months after lesioning, the animals were anesthetized with urethane for electrophysiological study. DA, applied directly to neurons by pressure microejection, inhibited spontaneous single-unit activity in the striatal neurons of nonlesioned, lesioned and lesioned/grafted rats. QA lesioning reduced responses to DA in the striatal neurons. The dose of DA required to inhibit striatal neuron activity in the lesioned rats was significantly increased compared to that in the nonlesioned rats. Transplantation of fetal striatal tissue restored the electrophysiological sensitivity to DA in the lesioned striatum. The dose of DA used to suppress striatal neuron activity was reduced after grafting. Immunohistostaining showed survival of γ-aminobutyric acid neurons at the graft site. Tyrosine hydroxylase-positive terminals were found innervating the striatal grafts. In conclusion, our data demonstrate that fetal striatal transplants restore electrophysiological sensitivity to DA in the lesioned striatum of animals with experimental HD.

Fetal striatal transplants restore electrophysiological sensitivity to dopamine in the lesioned striatum of rats with experimental Huntington's disease.

Dopamine (DA), a major neurotransmitter used in the striatum, is involved in movement disorders such as Parkinson's disease and Huntington's chorea. With the loss of neurons in the striatum of patients with Huntington's disease (HD), there is an associated downregulation of DA receptors, which may alter DA-mediated responses. In the present study, DA-mediated electrophysiological depression was studied in animals with quinolinic acid (QA)-induced experimental HD. QA was directly applied to the right striatum of adult female Sprague-Dawley rats. Animals receiving QA developed ipsilateral rotation after the application of apomorphine. Fetal striatal tissue transplants grafted 1 month after lesioning attenuated apomorphine-induced rotation. Six months after lesioning, the animals were anesthetized with urethane for electrophysiological study. DA, applied directly to neurons by pressure microejection, inhibited spontaneous single-unit activity in the striatal neurons of nonlesioned, lesioned and lesioned/grafted rats. QA lesioning reduced responses to DA in the striatal neurons. The dose of DA required to inhibit striatal neuron activity in the lesioned rats was significantly increased compared to that in the nonlesioned rats. Transplantation of fetal striatal tissue restored the electrophysiological sensitivity to DA in the lesioned striatum. The dose of DA used to suppress striatal neuron activity was reduced after grafting. Immunohistostaining showed survival of gamma-aminobutyric acid neurons at the graft site. Tyrosine hydroxylase-positive terminals were found innervating the striatal grafts. In conclusion, our data demonstrate that fetal striatal transplants restore electrophysiological sensitivity to DA in the lesioned striatum of animals with experimental HD.

T1 and T2 weighted magnetic resonance imaging of excitotoxin lesions and neural transplants in rat brain in vivo

On T 1 - and T 2 -weighted magnetic resonance (MR) images obtained at 0.14 T the rat brain was visible in the rat head as an area of relative high signal intensity. The enlarged lateral ventricles produced by intrastriatal injections of the excitotoxin kainic acid (KA) were clearly visible as areas of low signal intensity in T 1 -weighted images but could not be differentiated from normal brain tissue on T 2 -weighted images for the protocols utilized. Repeated T 1 -weighted MR images of individual rats demonstrated a progression in the extent of the lesions over an approximately 14-week period following the injection of KA. On the T 2 -weighted images, areas of relatively high signal intensity corresponding to tissue on the lesioned side of the brain were evident. As the lesion progressed and the remaining tissue visible on the T 1 -weighted images decreased, the region of high signal intensity visible on the T 2 -weighted images diminished. This area of high signal intensity on the T 2 -weighted images appeared to correspond to tissue undergoing a neurodegenerative process. MR images from continguous slices of brain demonstrated the extent of the KA-induced degeneration throughout the brain, although volume averaging of multiple brain structures was a possible confounding factor. Features apparently corresponding to fetal striatal tissue transplants growing within the enlarged lateral ventricle were visible on T 1 -weighted images but could not be discriminated on the T 2 -weighted images. MR imaging is useful for monitoring in vivo the anatomical location and progression of excitotoxin lesions and the location of fetal striatal tissue transplants in lesioned rat brain.

A magnetic resonance imaging contrast agent differentiates between the vascular properties of fetal striatal tissue transplants and gliomas in rat brain in vivo

The tumors formed by rat C-6 glioma cells were isointense with the normal rat brain on precontrast T 1 weighted magnetic resonance (MR) images. Following i.v. peripheral administration of the MR imaging contrast agent gadolinium (Gd)-DTPA, there was no significant change in the signal intensity from normal brain tissue. However, the tumor appeared as areas of high signal intensity demonstrating the abnormal vascular properties of the tumor. Fetal rat striatal tissue transplanted into unlesioned adult rat striatum appeared isointense with the host brain on precontrast T 1 weighted images and there was no evidence for enhancement of the transplanted tissue relative to host brain following i.v. administration of Gd-DTPA. Using this technique we found no evidence with respect to permeability of the contrast agent of an abnormal blood-brain barrier within the striatal transplant in vivo.

Fetal striatal tissue grafts into excitotoxin-lesioned striatum: Pharmacological and behavioral aspects

In an excitotoxin animal model of Huntington's disease (HD), fetal striatal tissue transplants survive and grow in the host brain and reverse the behavioral, and, hence, functional deficits produced by the lesion. In the present study we found recovery of apomorphine-induced rotation behavior in unilateral excitotoxin-lesioned rats indicating that the transplant reverses this functional pharmacologic deficit induced by the lesion. It might, therefore, by expected that the transplanted fetal striatal tissue would possess similar pharmacological characteristics as the host striatum. However, autoradiographic localization of D 1 and D 2 dopamine receptors demonstrated that the transplanted tissue expressed relatively small numbers of these receptor subtypes. Furthermore, there was a relative deficit of [ 3H]forskolin binding to the stimulatory guanine nucleotide regulatory subunit/adenylate cyclase complex in the fetal striatal tissue transplants. Therefore, transplanted tissue which is neurochemically dissimilar to the host striatum is capable of reversing deficits in both drug-induced and spontaneous locomotor activity.

Magnetic resonance imaging of rat brain following kainic acid-induced lesions and fetal striatal tissue transplants

Use of a small diameter (5.1 cm) radiofrequency coil provided relatively high resolution magnetic resonance (MR) images of rat heads at 0.14 Tesla. On T1-weighted images, the rat brain was clearly visible in the rat head as a region of high signal intensity. No structures were distinguished within the normal rat brain. In contrast, in the brains of rats receiving unilateral kainic acid lesions of the striatum, enlarged lateral ventricles, which are characteristics of the lesion, were clearly visible as dark areas of low signal intensity. Extrastriatal damage on the lesioned side of the brain was also evident in some of the images. Fetal striatal tissue transplants growing within the lesioned striata were also identified in the MR images. The transplanted tissue appeared as areas of high intermediate signal intensity, similar to the host brain. MR imaging is a useful technique for monitoring excitotoxin lesions of brain and fetal striatal tissue transplants in vivo.

Chapter 8 A novel rotational behavior model for assessing the restructuring of striatal dopamine effector systems: are transplants sensitive to peripherally acting drugs?

Publisher Summary This chapter discusses the effects on apomorphine-induced turning behavior of rat fetal striatal tissue transplants into the lesioned striatum, and determines whether fetal striatal grafts might also possess a non-intact blood-brain barrier and permit the entry of drugs into the brain, which normally do not penetrate the blood-brain barrier, and therefore, are without central actions. The data presented in the chapter may indicate that the transplanted material possesses similar pharmacological properties as the original host tissue, and is capable of functionally restructuring damage to a complex neurochemical system. Domperidone, a dopamine receptor antagonist, which does not readily cross the bloodbrain barrier, significantly attenuated the behavioral effects of apomorphine in rats, which had received bilateral transplants of rat fetal striatal tissue into unlesioned striata prior to challenge with apomorphine. Thus, the transplants appeared to allow access to the brain of a drug, which normally acts in the periphery, and it is suggested that other therapeutic agents may be allowed site-selective entry into the brain via transplanted tissue.

Behavioral recovery following kainic acid lesions and fetal implants of the striatum occurs independent of dopaminergic mechanisms

Transplantation of fetal striatal tissue into rats witkainic acid lesions of the striatum reversed the spontaneous locomotor abnormalities caused by the lesions, but had no effect on the lesion-induced hyperactivity that followed amphetamine or apomorphine injection. Conversely, transplants into intact (non-lesioned) striatum led to abnormalities in spontaneous locomotion, but did not effect locomotion under amphetamine or apomorphine conditions. Dopamine autoradiography found a relative absence of dopamine receptors within the transplants. These results suggest that the mechanism whicaccounts for transplant-induced recovery of spontaneous locomotion is independent of striatal dopamine mechanisms.