Prolonged human neural stem cell maturation supports recovery in injured rodent CNS

Lu, Paul; Ceto, Steven; Wang, Yaozhi; Graham, Lori; Wu, Di; Kumamaru, Hiromi; Staufenberg, Eileen; Tuszynski, Mark H.

doi:10.1172/jci92955

Cited by 99 publications

(83 citation statements)

References 56 publications

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“…Human H9 cell RNA was provided by Yuanyuan Li and Mark H. Tuszynski (UC San Diego). H9 cells were grown as previously described (Lu et al 2017) and RNA isolated using a Qiagen RNA kit. K562 cells from Dr. Xiang-Dong Fu (UC San Diego) were grown in RPMI 1640 + L-Glutamine with heat inactivated 10% FBS (Biowest S1620, lot 61N16) and 1 × Pen/Strep (Gibco 15140-163) and 1 × L-Glutamine (Gibco 25030-164) in T75 flasks at 37°C with 5% CO 2 .…”

Section: Rna Isolation and Samplesmentioning

confidence: 99%

Identification and dynamic quantification of regulatory elements using total RNA

et al. 2019

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The spatial and temporal regulation of transcription initiation is pivotal for controlling gene expression. Here, we introduce capped-small RNA-seq (csRNA-seq), which uses total RNA as starting material to detect transcription start sites (TSSs) of both stable and unstable RNAs at single-nucleotide resolution. csRNA-seq is highly sensitive to acute changes in transcription and identifies an order of magnitude more regulated transcripts than does RNA-seq. Interrogating tissues from species across the eukaryotic kingdoms identified unstable transcripts resembling enhancer RNAs, pri-miRNAs, antisense transcripts, and promoter upstream transcripts in multicellular animals, plants, and fungi spanning 1.6 billion years of evolution. Integration of epigenomic data from these organisms revealed that histone H3 trimethylation (H3K4me3) was largely confined to TSSs of stable transcripts, whereas H3K27ac marked nucleosomes downstream from all active TSSs, suggesting an ancient role for posttranslational histone modifications in transcription. Our findings show that total RNA is sufficient to identify transcribed regulatory elements and capture the dynamics of initiated stable and unstable transcripts at singlenucleotide resolution in eukaryotes.

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Section: Rna Isolation and Samplesmentioning

confidence: 99%

Identification and dynamic quantification of regulatory elements using total RNA

et al. 2019

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“…On the other hand, the spinal neurons that are lost during and after the injury need to be replaced in order to rebuild the local neuronal circuits. In this regard, stem cell transplantation has been reported to achieve certain success (Lu et al, 2017;Tuszynski et al, 2014), however long-term survival of transplanted cells in the injury site has been an unsolved issue (Goldman, 2016). Niu et al, 2013).…”

Section: Introductionmentioning

confidence: 99%

Regeneration of dorsal spinal cord neurons after injury viain situNeuroD1-mediated astrocyte-to-neuron conversion

Puls

Ding

Pan

et al. 2019

Preprint

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Spinal cord injury (SCI) often leads to impaired motor and sensory functions, partially because the injury-induced neuronal loss cannot be easily replenished through endogenous mechanisms. In vivo neuronal reprogramming has emerged as a novel technology to regenerate neurons from endogenous glial cells by forced expression of neurogenic transcription factors.We have previously demonstrated successful astrocyte-to-neuron conversion in mouse brains with injury or Alzheimer's disease by overexpressing a single neural transcription factor NeuroD1 via retroviruses. Here we demonstrate regeneration of dorsal spinal cord neurons from reactive astrocytes after SCI via adeno-associated virus (AAV), a more clinically relevant gene delivery system. We find that NeuroD1 converts reactive astrocytes into neurons in the dorsal horn of stab-injured spinal cord with high efficiency (~95%). Interestingly, NeuroD1converted neurons in the dorsal horn mostly acquire glutamatergic neuronal subtype, expressing spinal cord-specific markers such as Tlx3 but not brain-specific markers such as Tbr1, suggesting that the astrocytic lineage and local microenvironment affect the cell fate of conversion. Electrophysiological recordings show that the NeuroD1-converted neurons can functionally mature and integrate into local spinal cord circuitry by displaying repetitive action potentials and spontaneous synaptic responses. We further show that NeuroD1-mediated neuronal conversion can occur in the contusive SCI model, allowing future studies of evaluating this reprogramming technology for functional recovery after SCI. In conclusion, this study may suggest a paradigm shift for spinal cord repair using in vivo astrocyte-to-neuron conversion technology to generate functional neurons in the grey matter.3 Introduction:

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“…Slow neurogenesis and recovery is even more evident in mammalian models and in particular when human cells have been used to repair injury. For example, grafted human cells in rat spinal cord mature over many months and functional recovery is detected only after one year in line with the slow differentiation process (Lu et al, 2017). Using an endogenous reservoir of neural precursors, which are 'ready to go', provides efficient means to rapidly initiate tissue repair allowing time for the slower regenerative processes such as neurogenesis to commence.…”

Section: Discussionmentioning

confidence: 99%

Early migration of precursor neurons initiates cellular and functional regeneration after spinal cord injury in zebrafish

Vandestadt

Vanwalleghem

Castillo

et al. 2019

Preprint

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Zebrafish have a remarkable capacity to regenerate following spinal cord (SC) injury but the responsible cellular events are not well understood. We used in vivo imaging and genetics to pin-point specific cellular processes controlling SC regeneration in zebrafish. We identified two temporally and mechanistically distinct phases of cellular regeneration in the SC. The initial phase relies on migration of precursor neurons to the injury, enabling rapid functional recovery, and activation of quiescent neural progenitor cells (NPCs). A second phase of regenerative neurogenesis compensates for both the lost tissue and cells depleted due to precursor neuron migration. We propose a critical role of precursor neurons recruitment in initiating neuronal circuit recovery and buying sufficient time for regenerative neurogenesis to take place. Taken together, our data suggests an unanticipated role of precursor cell recruitment in driving neural repair and functional recovery during the regenerative response. Graphical Abstract

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Prolonged human neural stem cell maturation supports recovery in injured rodent CNS

Cited by 99 publications

References 56 publications

Identification and dynamic quantification of regulatory elements using total RNA

Identification and dynamic quantification of regulatory elements using total RNA

Regeneration of dorsal spinal cord neurons after injury viain situNeuroD1-mediated astrocyte-to-neuron conversion

Early migration of precursor neurons initiates cellular and functional regeneration after spinal cord injury in zebrafish

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