Intrastriatal grafts derived from fetal striatal primordia. I. Phenotypy and modular organization

Abstract

Fetal striatal grafts display a striking modularity of composition. With acetylcholinesterase (AChE) histochemistry, the tissue of such grafts can be divided into regions with strong AChE staining of the neuropil and regions in which AChE staining of the neuropil is weak. In the experiments reported here, we reexamined the nature of this modularity. Striatal grafts were made by injecting dissociated cells of E15 ganglionic eminence into the striatum of adult rats, which 7 days before had recived intrastriatal deposits of ibotenic acid. Some donors had been exposed to 3H-thymidine at E11-E15. After 9-17 month survivals, the anatomical organization of the grafts was studied by histochemistry, immunohistochemistry, and autoradiography. In every graft, the AChE-rich regions formed patches (P regions) in a larger AChE-poor surround (NP regions). Neurons labeled with 3H-thymidine appeared in both P and NP regions, suggesting that donor cells were distributed in each type of region and that neither type of tissue, P or NP, was composed exclusively of host tissue. In the AChE-rich P regions, markers characteristic of normal perinatal and mature rat striatum were expressed by medium-sized cells: calcium-binding protein (calbindin D28k) immunostaining, metenkephalin (mENK) immunostaining, and, more rarely, somatostatin (SOM) immunostaining. In the NP regions, however, medium-sized cells expressing calbindin and mENK immunostaining were very rare, and there was an abundance of neuronal types not found in normal mature striatal tissue. These included (1) large, multipolar, calbindin-positive neurons with well-ramified, densely stained dendrites, (2) large, SOM-positive neurons with prominent dendritic trees, and (3) mENK-positive cells smaller than typical striatal, medium-sized, mENK-immunoreactive neurons. In Nissl stains, the AChE-rich P regions resembled the normal striatum of mature animals, whereas the AChE-poor NP regions did not. These findings suggest that the P regions of fetal striatal grafts achieve a phenotypy similar to that of normal striatum at maturity and during much of postnatal development. The dominant expression of perikaryal calbindin-like immunoreactivity in the P regions further suggests that these zones have a high proportion of tissue resembling striatal matrix. By contrast, expression of marker antigens in the NP zones of the grafts suggests that these zones are predominantly composed of nonstriatal tissue or that they have the phenotypy of immature striatum intermixed with some nonstriatal cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Intrastriatal transplantation of cross-species fetal striatal cells reduces abnormal movements in a primate model of Huntington disease.

“…Although the trophic graft mechanisms in other transplant models may account for some graft effects (38)(39)(40), available rodent models of HD show that the implanted striatal neurons can substitute for the damaged striato-pallidal neuronal connections (23)(24)(25)(26)(27). Physiological (15)(16)(17), neurochemical (41,42), and anatomical studies (23)(24)(25)(26)(27) suggest that a partial restoration of striatal input and output circuitry by implanted striatal neurons can occur.…”

“…Physiological (15)(16)(17), neurochemical (41,42), and anatomical studies (23)(24)(25)(26)(27) suggest that a partial restoration of striatal input and output circuitry by implanted striatal neurons can occur. Therefore, the striatal implants may provide a reconstruction of neuronal connections and a partial restoration of GABA transmission in the previously deafferented globus pallidus.…”

Cell therapy in Huntington’s disease

“…Striatal grafts in rats typically have a "patchy" appearance comprising both striatal-like and nonstriatallike compartments, depending on the morphology, neurochemical phenotypes, and receptors expressed by the cells. 52 The striatum develops from the lateral and medial ridges of the ganglionic eminence (LGE and MGE, respectively) in the floor of the embryonic lateral ventricle. 53 Traditionally, striatal grafts comprised the whole ganglionic eminence (i.e., containing both medial and lateral parts).…”

Differential regulation of neuropeptide mRNA expression in intrastriatal striatal transplants by host dopaminergic afferents.

“…In fact, grafted striatal neurons establish synaptic connections with the host globus pallidus (1) and, in turn, receive innervation from the principal striatal afferent systems (i.e., nigral dopaminergic, cortical and thalamic inputs) (1-5). The host dopamine (DA) afferents terminate specifically in those areas (or patches) of the graft that display striatum-like features (e.g., dopamineand cyclic-AMP-related phosphoprotein, DARPP-32, and calbindin immunoreactivity) (4,5). These striatum-like patches, which express both striosomal and matrix markers (4,5), also contain the majority of efferent projecting graft neurons (5).…”

“…These grafts have been shown to integrate both anatomically and functionally with the host brain circuitry. In fact, grafted striatal neurons establish synaptic connections with the host globus pallidus (1) and, in turn, receive innervation from the principal striatal afferent systems (i.e., nigral dopaminergic, cortical and thalamic inputs) (1)(2)(3)(4)(5). The host dopamine (DA) afferents terminate specifically in those areas (or patches) of the graft that display striatum-like features (e.g., dopamineand cyclic-AMP-related phosphoprotein, DARPP-32, and calbindin immunoreactivity) (4,5).…”