Abstract
Brain injuries causing chronic sensory or motor deficit, such as stroke, are among the leading causes of disability worldwide, according to the World Health Organization; furthermore, they carry heavy social and economic burdens due to decreased quality of life and need of assistance. Given the limited effectiveness of rehabilitation, novel therapeutic strategies are required to enhance functional recovery. Since cell-based approaches have emerged as an intriguing and promising strategy to promote brain repair, many efforts have been made to study the functional integration of neurons derived from pluripotent stem cells (PSCs), or fetal neurons, after grafting into the damaged host tissue. PSCs hold great promises for their clinical applications, such as cellular replacement of damaged neural tissues with autologous neurons. They also offer the possibility to create in vitro models to assess the efficacy of drugs and therapies. Notwithstanding these potential applications, PSC-derived transplanted neurons have to match the precise sub-type, positional and functional identity of the lesioned neural tissue. Thus, the requirement of highly specific and efficient differentiation protocols of PSCs in neurons with appropriate neural identity constitutes the main challenge limiting the clinical use of stem cells in the near future. In this Review, we discuss the recent advances in the derivation of telencephalic (cortical and hippocampal) neurons from PSCs, assessing specificity and efficiency of the differentiation protocols, with particular emphasis on the genetic and molecular characterization of PSC-derived neurons. Second, we address the remaining challenges for cellular replacement therapies in cortical brain injuries, focusing on electrophysiological properties, functional integration and therapeutic effects of the transplanted neurons.
Highlights
Brain injuries represent a large variety of disabling pathologies
Motono et al reported the generation of pluripotent stem cells (PSCs)-derived anterior cortical neurons by blocking both the canonical and non-canonical WNT signaling with an inhibitor of Porcupine (PORCN), a membrane-bound O-acyltransferase involved in the palmitoylation, and subsequent secretion, of WNT proteins (Motono et al, 2016)
Among the challenges faced by the clinical application of cell-based therapies is the choice of the cell source
Summary
Brain injuries represent a large variety of disabling pathologies. They may originate from different causes and affect distinct brain locations, leading to an enormous multiplicity of various symptoms ranging from cognitive deficits to sensorimotor disabilities. Motono et al reported the generation of PSC-derived anterior cortical neurons (low COUP-TF1 / high SP8 expression) by blocking both the canonical and non-canonical WNT signaling with an inhibitor of Porcupine (PORCN), a membrane-bound O-acyltransferase involved in the palmitoylation, and subsequent secretion, of WNT proteins (Motono et al, 2016). These results remain to be confirmed by whole genome expression profiling of the cells and a more extensive analysis of their morphology and connectivity following homotopic and heterotopic transplantation, they are yet another example of how culture conditions profoundly influence the positional identity of PSC-derived cortical neurons.
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