Fetal cortical allografts project massively through the adult cortex

doi:10.1016/j.neuroscience.2004.04.011

Neuroscience

Volume 126, Issue 3, 2004, Pages 631-637

https://doi.org/10.1016/j.neuroscience.2004.04.011 Get rights and content

Abstract

Allogeneic embryonic CNS tissue grafts placed in the mature brain are classically considered to lack significant long-range efferents. This problem was reexamined using ‘green’ cells from mice expressing ubiquitously an ‘enhanced’ green fluorescent protein as an alternative to classical tract tracing methods. The present study shows that fetal cortical neurons (E15; occipital origin) grafted in the occipitoparietal region of the adult cortex project massively throughout ipsilateral telencephalic structures. Two out of the nine grafted subjects had additional but sparse efferents in the visual thalamus, superior colliculus and pons.

Section snippets

Selection of donor tissue and grafting procedure

Grafts were blocks of presumptive occipital cortical areas excised from transgenic E15 mice embryos overexpressing the eGFP under the control of a chicken β-actin promoter [C57BI/6-TgN(β-act-EGFP)Osb strain; a generous gift from Dr. M. Okabe, Osaka University; Okabe et al., 1997]. Under anesthesia (Avertin; 25 μl/g), the blocks were implanted the same day into brain cavities made into the posterior cortex of adult albino mice (18 weeks old; N=9; NMRI strain; R. Janvier, France). The skull over

Results

On skull opening, transplants of presumptive occipital origin were found occupying 2.5–5.0 mm² of host cortical tissue in both somatosensory (Som; Fig. 1A) and visual (Vis; Fig. 1A) areas. In all cases, (i) aspirative lesions impinged on the white matter (arrowhead; Fig. 1B); and (ii) approximately 0.5–1 mm² of the graft base contacted the hippocampus (oriens layer) directly (Fig. 1B, C). Close to the graft boundaries, dislocated eGFP-labeled donor astrocytes were clearly evidenced, mainly in

Discussion

The central goal of this study was to examine whether E15–16 occipital tissue allografts placed in the occipital cortex of mature rodents project to normally targeted brain areas. The topography of these efferents has been reviewed extensively (Wiesendanger and Wiesendanger, 1982, Carey and Neal, 1985, Olavarria and Van Sluyters, 1985, Serizawa et al., 1994, Sefton and Dreher, 1995, Zilles and Wree, 1995, McDonald and Mascagni, 1996). Briefly, in addition to reciprocal connections, ipsilateral

Acknowledgements

This work was supported in part by the CNRS and by a grant from the Fondation pour la Recherche Médicale (FDT20020705037/1) awarded to Miss L. Domballe. Thanks to Dr. A. Cantereau for confocal imaging.

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Axonal Extensions along Corticospinal Tracts from Transplanted Human Cerebral Organoids
2020, Stem Cell Reports
Citation Excerpt :
We found that 10w-organoids, which are in the CPN-generating stage, have a lower risk of graft overgrowth. In previous studies describing the transplantation of embryonic cerebral cortex, E14–E15 mice, which corresponds to the CPN-generating stage, were used as the grafts (Ballout et al., 2016, 2019; Gaillard et al., 2004, 2007; Peron et al., 2017), which would explain why graft overgrowth did not become a problem in those studies. The observed enhancement of the graft survival and axonal extensions of 10w-organoids by delaying the transplantation 1 week after the cortical resection suggests that adjusting the host brain environment is a possible approach to promoting axonal extensions from cerebral organoids.
The reconstruction of lost neural circuits by cell replacement is a possible treatment for neurological deficits after cerebral cortex injury. Cerebral organoids can be a novel source for cell transplantation, but because the cellular composition of the organoids changes along the time course of the development, it remains unclear which developmental stage of the organoids is most suitable for reconstructing the corticospinal tract. Here, we transplanted human embryonic stem cell-derived cerebral organoids at 6 or 10 weeks after differentiation (6w- or 10w-organoids) into mouse cerebral cortices. 6w-organoids extended more axons along the corticospinal tract but caused graft overgrowth with a higher percentage of proliferative cells. Axonal extensions from 10w-organoids were smaller in number but were enhanced when the organoids were grafted 1 week after brain injury. Finally, 10w-organoids extended axons in cynomolgus monkey brains. These results contribute to the development of a cell-replacement therapy for brain injury and stroke.
Mechanisms and use of neural transplants for brain repair
2017, Progress in Brain Research
Citation Excerpt :
This was further supported by the observation that the growth and extension of the graft-derived GFP-positive fibers were much more restricted in nonlesioned hosts where the intrinsic dopamine projections were left intact. A second example comes from studies performed in Afsaneh Gaillard's Lab using transplants of GFP-expressing cortical tissue, obtained from E14 transgenic mice, and grafted to a cavity made in the sensorimotor cortex of adult wild-type mice (Gaillard et al., 2004, 2007). Again, the results are striking: The graft-derived, GFP-expressing axons could be traced over large distances, within white matter tracts, not only to the contralateral cortex, but also to a number of subcortical targets, including striatum, thalamus, pontine nuclei, and the cervical spinal cord.
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.
Area-specific reestablishment of damaged circuits in the adult cerebral cortex by cortical neurons derived from mouse embryonic stem cells
2015, Neuron
Citation Excerpt :
However, studies using more sensitive and specific tools to lesion the cortex and to trace the projections of the grafted cells have reported that grafted embryonic cortex neurons could display specific patterns of long-range projections, at least in some conditions (Fricker-Gates et al., 2002; Gaillard et al., 2007; Hernit-Grant and Macklis, 1996). Most strikingly, it was reported that grafted embryonic cortex neurons could effectively reestablish specific patterns of subcortical projections and synapses following cortical lesions (Gaillard et al., 2004, 2007). While these studies open the possibility of cell transplantation for cortical repair, the very limited accessibility of human fetal cortical tissue constitutes a serious limitation to consider such approaches in a clinical setting.
Pluripotent stem-cell-derived neurons constitute an attractive source for replacement therapies, but their utility remains unclear for cortical diseases. Here, we show that neurons of visual cortex identity, differentiated in vitro from mouse embryonic stem cells (ESCs), can be transplanted successfully following a lesion of the adult mouse visual cortex. Reestablishment of the damaged pathways included long-range and reciprocal axonal projections and synaptic connections with targets of the damaged cortex. Electrophysiological recordings revealed that some grafted neurons were functional and responsive to visual stimuli. No significant integration was observed following grafting of the same neurons in motor cortex, or transplantation of embryonic motor cortex in visual cortex, indicating that successful transplantation required a match in the areal identity of grafted and lesioned neurons. These findings demonstrate that transplantation of mouse ESC-derived neurons of appropriate cortical areal identity can contribute to the reconstruction of an adult damaged cortical circuit.
Restoration of damaged cortical pathways by neural grafting
2018, Medecine/Sciences
Neuronal replacement therapy: previous achievements and challenges ahead
2017, npj Regenerative Medicine
A delay between motor cortex lesions and neuronal transplantation enhances graft integration and improves repair and recovery
2017, Journal of Neuroscience

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Fetal cortical allografts project massively through the adult cortex

Abstract

Section snippets

Selection of donor tissue and grafting procedure

Results

Discussion

Acknowledgements

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