Development and Maturation of Embryonic Cortical Neurons Grafted into the Damaged Adult Motor Cortex

Nissrine Ballout,Kazem Zibara,Sophie Péron,Mohamed Jaber,Isabelle Frappé,Afsaneh Gaillard

doi:10.3389/fncir.2016.00055

Abstract

Injury to the human central nervous system can lead to devastating consequences due to its poor ability to self-repair. Neural transplantation aimed at replacing lost neurons and restore functional circuitry has proven to be a promising therapeutical avenue. We previously reported in adult rodent animal models with cortical lesions that grafted fetal cortical neurons could effectively re-establish specific patterns of projections and synapses. The current study was designed to provide a detailed characterization of the spatio-temporal in vivo development of fetal cortical transplanted cells within the lesioned adult motor cortex and their corresponding axonal projections. We show here that as early as 2 weeks after grafting, cortical neuroblasts transplanted into damaged adult motor cortex developed appropriate projections to cortical and subcortical targets. Grafted cells initially exhibited characteristics of immature neurons, which then differentiated into mature neurons with appropriate cortical phenotypes where most were glutamatergic and few were GABAergic. All cortical subtypes identified with the specific markers CTIP2, Cux1, FOXP2, and Tbr1 were generated after grafting as evidenced with BrdU co-labeling. The set of data provided here is of interest as it sets biological standards for future studies aimed at replacing fetal cells with embryonic stem cells as a source of cortical neurons.

Highlights

The cerebral cortex is a six-layered structure composed of a large number of neurons classically divided into two major groups
cut-like homeobox 1 (Cux1) is a specific marker of projection neurons of the superficial layers CAM Kinase II alpha (II)/III and IV (Leone et al, 2008), while Ctip2 is used as a marker of a subset of subcerebral projection neurons of deep layer V (Arlotta et al, 2005), Foxp2 is used as a marker of layer VI cortico-thalamic projection neurons (Ferland et al, 2003) and Tbr1 is used as a marker of early-born neurons of the preplate and layer 6 (Bulfone et al, 1998)
Three out of five transplants filled the lower third of the cortical cavity, whereas the remaining two grafts appeared only as thin layers of green fluorescent protein (GFP)+ cells lying at the base or the lateral wall of the cavity

Summary

Introduction

The cerebral cortex is a six-layered structure composed of a large number of neurons classically divided into two major groups. Layer II/III callosal neurons project to the contralateral cortex, layer V neurons project to the striatum, midbrain pons, Abbreviations: CAM-K II, CAM Kinase II alpha; Cux, cut-like homeobox 1; GFP, green fluorescent protein; GFAP, glial fibrillary acidic protein; DCX, doublecortin; PSA-NCAM, polysialylated form of the neural cell adhesion molecule; GABA, γ-aminubutyric acid; NeuN, neuronal nuclei; TBS, Tris-buffered saline; TF, transcription factors; V-GLUT1, vesicular glutamate transporter 1. Projection cortical neurons from different layers express specific molecular markers (Molyneaux et al, 2007; Gaspard et al, 2008; Gaspard and Vanderhaeghen, 2011). The complexity of cerebral cortex in terms of cell diversity and specificity of projection patterns is translated into difficulties to appropriately repair damaged pathways following injury or disease

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