Fetal neostriatal transplants in the rat: A light and electron microscopic Golgi study

Helm, Gregory A.; Palmer, Patricia E.; Bennett, James P.

doi:10.1016/0306-4522(90)90104-c

Cited by 31 publications

(3 citation statements)

References 46 publications

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“…Grafts in these lesions have a characteristic heterogeneous appearance composed of striatum-like tissue (patch zones) and nonstriatum-like tissue (nonpatch zones) when visualized using acetylcholinesterase (AChE) 20,31,64 and antibodies against the dopamine receptor-related phosphoprotein (DARPP-32). 17,33,35,63,66 The patch zones contain morphologically distinctive striatal neurons, 8,10,23,38,48,52,56,64,[66][67][68][69] neurotransmitters, 7,9,26,27,35,39,52,53,56,59 and dopamine receptors. 18,35,38,49 It is currently unknown to what extent the severity of host striatal damage affects graft development and maturation.…”

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confidence: 99%

Effects of severity of host striatal damage on the morphological development of intrastriatal transplants in a rodent model of Huntington's disease: implications for timing of surgical intervention

Watts¹,

Dunnett²

1998

Journal of Neurosurgery

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confidence: 99%

Effects of severity of host striatal damage on the morphological development of intrastriatal transplants in a rodent model of Huntington's disease: implications for timing of surgical intervention

Watts¹,

Dunnett²

1998

Journal of Neurosurgery

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“…The first support for this hypothesis was provided by the demonstration of functional recovery in a series of experiments involving bilateral transplantation of whole ganglionic eminence (WGE)derived tissue cell suspensions into neostriatum of rats that had previously received bilateral striatal lesions made with the axon sparing excitotoxin ibotenic acid. These grafts were seen to provide extensive neuronal replacement of new striatal like structures in the lesioned area, that stained for a variety of neurochemical and receptor markers of normal striatum, and contained large numbers of neurons exhibiting both the predominant morphology of DARPP-32 positive medium spiny GABAergic projection neurons (Graybiel et al, 1989, Wictorin et al, 1989b and smaller numbers of neurons with the morphological features of all six major striatal cell types (Helm et al, 1990, Clarke et al, 1994.…”

Section: Integration Of Grafted Neurons Into Basal Ganglia Circuitrymentioning

confidence: 99%

Mechanisms and use of neural transplants for brain repair

Dunnett

Björklund

2017

Functional Neural Transplantation IV - Translation to Clinical Application, Part A

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Under appropriate conditions, neural tissues transplanted into the adult mammalian brain can survive, integrate, and function so as to influence the behavior of the host, opening the prospect of repairing neuronal damage, and alleviating symptoms associated with neuronal injury or neurodegenerative disease. Alternative mechanisms of action have been postulated: nonspecific effects of surgery; neurotrophic and neuroprotective influences on disease progression and host plasticity; diffuse or locally regulated pharmacological delivery of deficient neurochemicals, neurotransmitters, or neurohormones; restitution of the neuronal and glial environment necessary for proper host neuronal support and processing; promoting local and long-distance host and graft axon growth; formation of reciprocal connections and reconstruction of local circuits within the host brain; and up to full integration and reconstruction of fully functional host neuronal networks. Analysis of neural transplants in a broad range of anatomical systems and disease models, on simple and complex classes of behavioral function and information processing, have indicated that all of these alternative mechanisms are likely to contribute in different circumstances. Thus, there is not a single or typical mode of graft function; rather grafts can and do function in multiple ways, specific to each particular context. Consequently, to develop an effective cell-based therapy, multiple dimensions must be considered: the target disease pathogenesis; the neurodegenerative basis of each type of physiological dysfunction or behavioral symptom; the nature of the repair required to alleviate or remediate the functional impairments of particular clinical relevance; and identification of a suitable cell source or delivery system, along with the site and method of implantation, that can achieve the sought for repair and recovery.

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“…However, from the earliest grafting experiments it is clear that different neuronal types develop within the striatal tissue grafted. For example Golgi experiments highlighted the presence of at least 5 types of medium sized, spiny neurons as well as aspiny neurons (Helm et al, 1990 ), and non-striatal (e.g., pyramidal) as well as striatal cell types (Clarke et al, 1994 ). Early use of neurochemical stains revealed two morphologically distinct regions, acetylcholinesterase (AChE positive) “P-zones” (30–40%) and AChE negative non-P (NP)- zones (Isacson et al, 1987 ; Graybiel et al, 1989 ; Wictorin et al, 1989 ; Pakzaban et al, 1993 ), with the latter having at least three fold less DARPP-32 positive MSNs (Wictorin and Björklund, 1989 ; Nakao et al, 1994 ).…”

Section: Cell Morphologymentioning

confidence: 99%

Differentiation of pluripotent stem cells into striatal projection neurons: a pure MSN fate may not be sufficient

Reddington

Rosser

Dunnett

2014

Front. Cell. Neurosci.

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Huntington’s disease (HD) is an autosomal dominant inherited disorder leading to the loss inter alia of DARPP-32 positive medium spiny projection neurons (“MSNs”) in the striatum. There is no known cure for HD but the relative specificity of cell loss early in the disease has made cell replacement by neural transplantation an attractive therapeutic possibility. Transplantation of human fetal striatal precursor cells has shown “proof-of-principle” in clinical trials; however, the practical and ethical difficulties associated with sourcing fetal tissues have stimulated the need to identify alternative source(s) of donor cells that are more readily available and more suitable for standardization. We now have available the first generation of protocols to generate DARPP-32 positive MSN-like neurons from pluripotent stem cells and these have been successfully grafted into animal models of HD. However, whether these grafts can provide stable functional recovery to the level that can regularly be achieved with primary fetal striatal grafts remains to be demonstrated. Of particular concern, primary fetal striatal grafts are not homogenous; they contain not only the MSN subpopulation of striatal projection neurons but also include all the different cell types that make up the mature striatum, such as the multiple populations of striatal interneurons and striatal glia, and which certainly contribute to normal striatal function. By contrast, present protocols for pluripotent stem cell differentiation are almost entirely targeted at specifying just neurons of an MSN lineage. So far, evidence for the functionality and integration of stem-cell derived grafts is correspondingly limited. Indeed, consideration of the features of full striatal reconstruction that is achieved with primary fetal striatal grafts suggests that optimal success of the next generations of stem cell-derived replacement therapy in HD will require that graft protocols be developed to allow inclusion of multiple striatal cell types, such as interneurons and/or glia. Almost certainly, therefore, more sophisticated differentiation protocols will be necessary, over and above replacement of a specific population of MSNs. A rational solution to this technical challenge requires that we re-address the underlying question—what constitutes a functional striatal graft?

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Fetal neostriatal transplants in the rat: A light and electron microscopic Golgi study

Cited by 31 publications

References 46 publications

Effects of severity of host striatal damage on the morphological development of intrastriatal transplants in a rodent model of Huntington's disease: implications for timing of surgical intervention

Effects of severity of host striatal damage on the morphological development of intrastriatal transplants in a rodent model of Huntington's disease: implications for timing of surgical intervention

Mechanisms and use of neural transplants for brain repair

Differentiation of pluripotent stem cells into striatal projection neurons: a pure MSN fate may not be sufficient

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