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Expectations for neural stem/progenitor cell (NS/PC) transplantation as a treatment for spinal cord injury (SCI) are increasing. However, whether and how grafted cells are incorporated into the host neural circuit and contribute to motor function recovery remain unknown. The aim of this project was to establish a novel non-invasive in vivo imaging system to visualize the activity of neural grafts by which we can simultaneously demonstrate the circuit-level integration between the graft and host and the contribution of graft neuronal activity to host behaviour. We introduced Akaluc, a newly engineered luciferase, under the control of enhanced synaptic activity-responsive element (E-SARE), a potent neuronal activity-dependent synthetic promoter, into NS/PCs and engrafted the cells into SCI model mice. Through the use of this system, we found that the activity of grafted cells was integrated with host behaviour and driven by host neural circuit inputs. This non-invasive system is expected to help elucidate the therapeutic mechanism of cell transplantation treatment for SCI., (© 2022. The Author(s).)

The transplantation of neural progenitor cells (NPCs) derived from human induced pluripotent stem cells (iPSCs) has beneficial effects on spinal cord injury (SCI). However, while there are many subtypes of NPCs with different regional identities, the subtype of iPSC-derived NPCs that is most appropriate for cell therapy for SCI has not been identified. Here, we generated forebrain- and spinal cord-type NPCs from human iPSCs and grafted them onto the injured spinal cord in mice. These two types of NPCs retained their regional identities after transplantation and exhibited different graft-host interconnection properties. NPCs with spinal cord regional identity but not those with forebrain identity resulted in functional improvement in SCI mice, especially in those with mild-to-moderate lesions. This study highlights the importance of the regional identity of human iPSC-derived NPCs used in cell therapy for SCI.

We used single-cell RNA sequencing (seq) on several human induced pluripotent stem (iPS) cell-derived neural stem cell (NSC) lines and one fetal brain-derived NSC line to study inherent cell type heterogeneity at proliferating neural stem cell stage and uncovered predisposed presence of neurogenic and gliogenic progenitors. We observed heterogeneity in neurogenic progenitors that differed between the iPS cell-derived NSC lines and the fetal-derived NSC line, and we also observed differences in spontaneous differentiation potential for inhibitory and excitatory neurons between the iPS cell-derived NSC lines and the fetal-derived NSC line. In addition, using a recently published glia patterning protocol we enriched for gliogenic progenitors and generated glial cells from an iPS cell-derived NSC line., (© 2019 The Authors. Genes to Cells published by Molecular Biology Society of Japan and John Wiley & Sons Australia, Ltd.)

The CNS contains many diverse neuronal subtypes, and most neurological diseases target specific subtypes. However, the mechanism of neuronal subtype specificity of disease phenotypes remains elusive. Although in vitro disease models employing human pluripotent stem cells (PSCs) have great potential to clarify the association of neuronal subtypes with disease, it is currently difficult to compare various PSC-derived subtypes. This is due to the limited number of subtypes whose induction is established, and different cultivation protocols for each subtype. Here, we report a culture system to control the regional identity of PSC-derived neurons along the anteroposterior (A-P) and dorsoventral (D-V) axes. This system was successfully used to obtain various neuronal subtypes based on the same protocol. Furthermore, we reproduced subtype-specific phenotypes of amyotrophic lateral sclerosis (ALS) and Alzheimer's disease (AD) by comparing the obtained subtypes. Therefore, our culture system provides new opportunities for modeling neurological diseases with PSCs., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

• We established a neuronal differentiation system that is the best optimized for feeder-free iPSC culture. • Region-specific neuronal subtypes can be obtained. • This culture system can generate high-purity and functional neurons. Human induced pluripotent stem cells (iPSCs) have great potential to elucidate the molecular pathogenesis of neurological/psychiatric diseases. In particular, neurological/psychiatric diseases often display brain region-specific symptoms, and the technology for generating region-specific neural cells from iPSCs has been established for detailed modeling of neurological/psychiatric disease phenotypes in vitro. On the other hand, recent advances in culturing human iPSCs without feeder cells have enabled highly efficient and reproducible neural induction. However, conventional regional control technologies have mainly been developed based on on-feeder iPSCs, and these methods are difficult to apply to feeder-free (ff) iPSC cultures. In this study, we established a novel culture system to generate region-specific neural cells from human ff-iPSCs. This system is the best optimized approach for feeder-free iPSC culture and generates specific neuronal subtypes with high purity and functionality, including forebrain cortical neurons, forebrain interneurons, midbrain dopaminergic neurons, and spinal motor neurons. In addition, the temporal patterning of cortical neuron layer specification in the forebrain was reproduced in our culture system, which enables the generation of layer-specific cortical neurons. Neuronal activity was demonstrated in the present culture system by using multiple electrode array and calcium imaging. Collectively, our ff-iPSC-based culture system would provide a desirable platform for modeling various types of neurological/psychiatric disease phenotypes. [ABSTRACT FROM AUTHOR]