Abstract
Recent advances in cell reprogramming technologies enable the in vitro generation of theoretically unlimited numbers of cells, including cells of neural lineage and specific neuronal subtypes from human, including patient-specific, somatic cells. Similarly, as demonstrated in recent animal studies, by applying morphogenetic neuroengineering principles in situ, it is possible to reprogram resident brain cells to the desired phenotype. These developments open new exciting possibilities for cell replacement therapy in stroke, albeit not without caveats. Main challenges include the successful integration of engineered cells in the ischemic brain to promote functional restoration as well as the fact that the underlying mechanisms of action are not fully understood. In this review, we aim to provide new insights to the above in the context of connectomics of morphogenetically engineered neural networks. Specifically, we discuss the relevance of combining advanced interdisciplinary approaches to: validate the functionality of engineered neurons by studying their self-organizing behavior into neural networks as well as responses to stroke-related pathology in vitro; derive structural and functional connectomes from these networks in healthy and perturbed conditions; and identify and extract key elements regulating neural network dynamics, which might predict the behavior of grafted engineered neurons post-transplantation in the stroke-injured brain.
Highlights
Stem cell therapy for ischemic stroke may extend the therapeutic window from the acute into the sub-acute and chronic stage
We propose the investigation of in vitro engineered neural networks in the context of connectomics and discuss how morphogenetic neuroengineering can be supported by advanced interdisciplinary approaches, including in vitro electrophysiology, microfluidics, and computational modeling, to obtain robust preclinical models that can promote our understanding of cell replacement therapy for stroke beyond the state-of-the-art
Recent advances in cell reprogramming technologies have led to the development of efficient, reproducible, high-yield protocols for the generation of induced pluripotent stem cells (iPSCs) and induced neural stem cells, as well as protocols for the generation of induced neurons and specific neuronal subtypes, including spinal motoneurons, dopaminergic, cholinergic, and medium spiny neurons, and cortical neurons, by direct conversion of somatic cells [31,32,33,34,35,36,37]; reviewed in Gascon et al [38]
Summary
Stem cell therapy for ischemic stroke may extend the therapeutic window from the acute into the sub-acute and chronic stage. As such, it is a interesting approach, considering that more than 80% of stroke patients are de facto not eligible for the standard clinical treatment options, i.e., thrombolysis or thrombectomy [1]. Numerous animal studies have demonstrated the potential of stem cell therapy alone, or in combination with in situ tissue engineering strategies and/or pharmacotherapeutics, for promoting functional restoration after stroke
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