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Intrathecal delivery of adipose-derived mesenchymal stem cells in traumatic spinal cord injury: Phase I trial
In the CELLTOP Phase I trial, stem cells were harvested from patients with spinal cord injury and injected into their central nervous system after processing. The procedure was safe, with no reported serious adverse events during the 2-year follow-up period.
- Mohamad Bydon
- , Wenchun Qu
- & Allan B. Dietz
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Article
| Open Access
Intercellular communication atlas reveals Oprm1 as a neuroprotective factor for retinal ganglion cells
How the neighboring cells contribute to the survival and functions of neuronal cells remains elusive. Here, authors identified the cell-cell interactions between retinal ganglion cells (RGCs) and other cells after RGC injury and discovered the μ-opioid receptor promotes RGC resilience.
- Cheng Qian
- , Ying Xin
- & Jiang Qian
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Fully bioresorbable hybrid opto-electronic neural implant system for simultaneous electrophysiological recording and optogenetic stimulation
Bioresorbable neural implants offer a promising solution to the challenges of secondary surgeries required for the removal of implanted devices. Here, the authors introduce a fully bioresorbable flexible hybrid opto-electronic system for simultaneous electrophysiological recording and optogenetic stimulation.
- Myeongki Cho
- , Jeong-Kyu Han
- & Ki Jun Yu
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A phase I/IIa safety and efficacy trial of intratympanic gamma-secretase inhibitor as a regenerative drug treatment for sensorineural hearing loss
Pharmacological inhibition of gamma-secretase induced partial recovery of hearing in animal models. Here, the authors present the safety and efficacy results and key learnings of the First in Human Phase I/IIa study of a gamma-secretase inhibitor in patients with acquired Hearing Loss.
- Anne G. M. Schilder
- , Stephan Wolpert
- & Athanasios G. Bibas
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Dual electrical stimulation at spinal-muscular interface reconstructs spinal sensorimotor circuits after spinal cord injury
Electrical signals with characteristic parameters for reconstructing neural circuits remain incompletely understood, limiting the therapeutic potential of electrical neuromodulation techniques. Here, the authors demonstrate that dual electrical stimulation at 10–20 Hz rebuilds the spinal sensorimotor neural circuit after spinal cord injury, indicating the characteristic signals of circuit remodeling.
- Kai Zhou
- , Wei Wei
- & Yaobo Liu
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Common and divergent gene regulatory networks control injury-induced and developmental neurogenesis in zebrafish retina
The molecular mechanisms controlling injury-dependent neuronal regeneration are largely unknown. Here, the authors use integrated multiomic analysis to characterize gene regulatory networks controlling injury-induced neurogenesis in zebrafish retina
- Pin Lyu
- , Maria Iribarne
- & Seth Blackshaw
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Article
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Fully implanted battery-free high power platform for chronic spinal and muscular functional electrical stimulation
Electrical stimulation of the neuromuscular system holds promise for therapeutic biomedical applications, but is currently restricted by power. Here, the authors introduce fully implantable resonator-based designs achieving ±20 V compliance and >300 mW output, enabling multichannel, biphasic, current-controlled operation to evoke functional gate patterns for 6-weeks in freely behaving rats.
- Alex Burton
- , Zhong Wang
- & Philipp Gutruf
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An on-demand bioresorbable neurostimulator
Despite promising advantages, bioresorbable electronics face practical limitations due to unpredictable device lifetimes. Here, the authors introduce an on-demand bioresorbable neurostimulator powered by biosafe ultrasound to treat peripheral nerve injury and neuropathies.
- Dong-Min Lee
- , Minki Kang
- & Sang-Woo Kim
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Small leucine-rich proteoglycans inhibit CNS regeneration by modifying the structural and mechanical properties of the lesion environment
The mechanical properties of central nervous system (CNS) scar tissue are considered to contribute to axon regeneration failure. Here, the authors identify members of the small leucine-rich proteoglycan family as modulators of the inhibitory viscoelastic response of CNS lesions.
- Julia Kolb
- , Vasiliki Tsata
- & Daniel Wehner
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Glia instruct axon regeneration via a ternary modulation of neuronal calcium channels in Drosophila
Limited neuron regeneration is the key barrier to recovery after central nervous system damage. Here, the authors show that axon regeneration is regulated by glia in a multi-layered manner controlling regeneration-dependent neuronal calcium channels.
- Shannon Trombley
- , Jackson Powell
- & Yuanquan Song
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Article
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Circadian clock regulator Bmal1 gates axon regeneration via Tet3 epigenetics in mouse sensory neurons
Injured peripheral neurons activate pro-growth gene programs, yet the mechanisms remain unclear. Here, the authors show that disruption of circadian clock factor Bmal1 accelerates axon regeneration through augmented epigenetic responses after injury.
- Dalia Halawani
- , Yiqun Wang
- & Hongyan Zou
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Article
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Spinal cord repair is modulated by the neurogenic factor Hb-egf under direction of a regeneration-associated enhancer
Zebrafish can regenerate after paralyzing spine injuries and regain locomotor ability, unlike mammals. Here authors show that the neurogenic factor Hb-egf promotes spinal cord regeneration in zebrafish and is regulated by an enhancer that can similarly direct expression in the pro-regenerative setting of neonatal mice.
- Valentina Cigliola
- , Adam Shoffner
- & Kenneth D. Poss
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Single-cell analysis reveals region-heterogeneous responses in rhesus monkey spinal cord with complete injury
The cellular responses below the lesion remain unclear after spinal cord injury (SCI). Here, authors show region-heterogeneous responses in the SCI monkey by single-cell transcriptomics analysis and uncover the mechanism of scaffold-based SCI repair.
- Yongheng Fan
- , Xianming Wu
- & Jianwu Dai
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Porous microneedle patch with sustained delivery of extracellular vesicles mitigates severe spinal cord injury
Efficient delivery of extracellular vesicles to the injured spinal cord, with minimal damage, remains challenging. Here, the authors fabricate a minimally invasive microneedle device, which provides efficient and sustained extracellular vesicle delivery for spinal cord injury treatment.
- Ao Fang
- , Yifan Wang
- & Xuhua Wang
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Androgens show sex-dependent differences in myelination in immune and non-immune murine models of CNS demyelination
Androgen effects have been poorly studied in demyelinating diseases in females. Here, authors show androgen requirement for proper myelin regeneration in females and the critical need to consider male-female differences in multiple sclerosis patients.
- Amina Zahaf
- , Abdelmoumen Kassoussi
- & Elisabeth Traiffort
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Segmental motor recovery after cervical spinal cord injury relates to density and integrity of corticospinal tract projections
How the segmental innervation of upper limb muscles recovers after spinal cord injury is not fully understood. Here the authors show associations between corticospinal tract sparing and upper extremity recovery in spinal cord injury.
- Gustavo Balbinot
- , Guijin Li
- & Jose Zariffa
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Ciliary neurotrophic factor-mediated neuroprotection involves enhanced glycolysis and anabolism in degenerating mouse retinas
Rhee et al. demonstrates that the potent neuroprotective agent CNTF significantly impacts metabolism of degenerating retinas, thus revealing cellular mechanisms underlying enhanced neuronal viability and providing insight for the ongoing CNTF clinical trials.
- Kun Do Rhee
- , Yanjie Wang
- & Xian-Jie Yang
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Guidance landscapes unveiled by quantitative proteomics to control reinnervation in adult visual system
Long-distance regeneration in the adult central nervous system shows severe guidance defects preventing circuit reformation. Here, the authors reveal a comprehensive map of guidance cues in the adult visual system that can be used to modulate the path of regenerating axons to achieve circuit repair.
- Noemie Vilallongue
- , Julia Schaeffer
- & Homaira Nawabi
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| Open Access
The alarmin interleukin-1α triggers secondary degeneration through reactive astrocytes and endothelium after spinal cord injury
The neuroimmune interactions driving secondary degeneration in the injured spinal cord remain elusive. Here, the authors reveal that damaged microglia release IL-1α, resulting in neutrophil infiltration and the loss of mature oligodendrocytes through astrocytic and endothelial IL-1R1 in mice.
- Floriane Bretheau
- , Adrian Castellanos-Molina
- & Steve Lacroix
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Lesion environments direct transplanted neural progenitors towards a wound repair astroglial phenotype in mice
Effects of lesion environments on transplanted neural progenitor cells (NPC) are not well characterized. Here, the authors show that NPC transplanted into CNS lesions generate cells that share transcriptional and functional features with host wound repair astroglia in mice.
- T. M. O’Shea
- , Y. Ao
- & M. V. Sofroniew
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Single cell atlas of spinal cord injury in mice reveals a pro-regenerative signature in spinocerebellar neurons
Matson et al. performed single nucleus sequencing of the “spared” spinal cord tissue distal to an injury in mice. They found that spinocerebellar neurons expressed a pro-regenerative gene signature and showed axon outgrowth after injury.
- Kaya J. E. Matson
- , Daniel E. Russ
- & Ariel J. Levine
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Effects of biological sex mismatch on neural progenitor cell transplantation for spinal cord injury in mice
In this study, Pitonak et al. report that transplantation of neural progenitor cells derived from male donors trigger an immune rejection response following transplantation into sites of spinal cord injury in female mice.
- Michael Pitonak
- , Miriam Aceves
- & Jennifer N. Dulin
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Wireless charging-mediated angiogenesis and nerve repair by adaptable microporous hydrogels from conductive building blocks
Traumatic brain injury can cause long-term disability and thus constitutes a substantial healthcare burden worldwide. Here, the authors report a conductive microporous hydrogel to improve angiogenesis and recovery of brain function in traumatic brain lesions.
- Ru-Siou Hsu
- , Ssu-Ju Li
- & Shang-Hsiu Hu
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Microengineered devices enable long-term imaging of the ventral nerve cord in behaving adult Drosophila
Minimally invasive procedures for tracking neural activity are important for understanding of neural networks. Here the authors describe microfabricated implants and windows that enable long-term recordings of motor circuit activity in Drosophila, allowing them to watch how neurons change their structure and activity over weeks.
- Laura Hermans
- , Murat Kaynak
- & Pavan Ramdya
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An open-label pilot study of recombinant granulocyte-colony stimulating factor in Friedreich’s ataxia
Work in a mouse model of Friedreich’s ataxia has shown that administration of the cytokine granulocyte-colony stimulating factor (G-CSF) could have beneficial neuroprotective effects. Here the authors perform a pilot study of Lenograstim (recombinant G-CSF) in patients with Friedreich’s ataxia.
- Kevin C. Kemp
- , Anastasia Georgievskaya
- & Alastair Wilkins
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| Open Access
Transcription factor network analysis identifies REST/NRSF as an intrinsic regulator of CNS regeneration in mice
Here the authors couple an integrative genomic analysis with substantial in vitro and in vivo experimental validation, identifying REST as a novel suppressor of a pro-regenerative gene program and CNS axon regeneration in mice.
- Yuyan Cheng
- , Yuqin Yin
- & Daniel H. Geschwind
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Brain-wide reconstruction of inhibitory circuits after traumatic brain injury
Traumatic brain injury is often followed by changes in neural connectivity. This study describes how inputs to a population of inhibitory neurons change to favor local over long-range connectivity in a mouse model of traumatic brain injury.
- Jan C. Frankowski
- , Alexa Tierno
- & Robert F. Hunt
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Chondroitin sulfate proteoglycans prevent immune cell phenotypic conversion and inflammation resolution via TLR4 in rodent models of spinal cord injury
Inflammation resolution failure is a pathological hallmark of spinal cord injury. Here, the authors show in rodents that chondroitin sulfate proteoglycans contribute to failed resolution by preventing immune cells at the injury core from converting to a pro-resolution phenotype, and this is mediated by TLR4.
- Isaac Francos-Quijorna
- , Marina Sánchez-Petidier
- & Elizabeth J. Bradbury
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Selective plasticity of callosal neurons in the adult contralesional cortex following murine traumatic brain injury
Which contralesional circuits adapt after traumatic brain injury (TBI) is unclear. Here the authors used in vivo imaging, retrograde labeling, rabies tracing, clearing and functional imaging to demonstrate that callosal neurons selectively adapt after TBI in mice.
- Laura Empl
- , Alexandra Chovsepian
- & Florence M. Bareyre
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Spinal cord injury impairs cardiac function due to impaired bulbospinal sympathetic control
By combining experimental models with prospective clinical studies, the authors show that spinal cord injury causes a rapid reduction in cardiac function that precedes structural changes, and that the loss of descending sympathetic control is the major cause of reduced cardiac function following spinal cord injury.
- Mary P. M. Fossey
- , Shane J. T. Balthazaar
- & Christopher R. West
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Electrical modulation of transplanted stem cells improves functional recovery in a rodent model of stroke
Paul George and colleagues developed a conductive polymer system to enable stem cell delivery and electrical modulation in vivo. Employing this system improved functional stroke recovery in rodents and identified important repair pathways.
- Byeongtaek Oh
- , Sruthi Santhanam
- & Paul M. George
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An injury-induced serotonergic neuron subpopulation contributes to axon regrowth and function restoration after spinal cord injury in zebrafish
The mechanisms involved in regeneration of the spinal cord after injury are unclear. Here, the authors show that a subpopulation of intraspinal serotonergic neurons localized at the injury site stimulates axonal regrowth of interneurons via 5-HT1B receptor, resulting in recovery of function following SCI in zebrafish.
- Chun-Xiao Huang
- , Yacong Zhao
- & Jianren Song
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| Open Access
Efficient protein incorporation and release by a jigsaw-shaped self-assembling peptide hydrogel for injured brain regeneration
The extracellular matrix contributes to tissue regeneration by binding and releasing growth factors. Here the authors present the jigsaw-shaped self-assembling peptide JigSAP as an artificial ECM and show that VEGF-JigSAP has therapeutic effects on the subacute-chronic phase of brain stroke.
- Atsuya Yaguchi
- , Mio Oshikawa
- & Itsuki Ajioka
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Longitudinal functional imaging of VIP interneurons reveals sup-population specific effects of stroke that are rescued with chemogenetic therapy
Stroke profoundly disrupts cortical excitability which impedes recovery, but how stroke affects inhibitory interneurons is poorly understood. Here, the authors show that functional impairments after stroke are associated with the disruption of a highly active subpopulation of interneurons expressing vasoactive intestinal peptide (VIP), which could be ameliorated by chemogenetic stimulation.
- Mohamad Motaharinia
- , Kim Gerrow
- & Craig E. Brown
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| Open Access
Confronting false discoveries in single-cell differential expression
Differential expression analysis of single-cell transcriptomics allows scientists to dissect cell-type-specific responses to biological perturbations. Here, the authors show that many commonly used methods are biased and can produce false discoveries.
- Jordan W. Squair
- , Matthieu Gautier
- & Grégoire Courtine
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| Open Access
Pericyte-derived fibrotic scarring is conserved across diverse central nervous system lesions
Fibrotic scar tissue limits central nervous system regeneration. Here, Dias et al. show that fibrotic scarring is common in mice and humans, following distinct lesions to the adult brain and spinal cord, and derives from a discrete population of GLAST-expressing perivascular cells.
- David O. Dias
- , Jannis Kalkitsas
- & Christian Göritz
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Locomotion dependent neuron-glia interactions control neurogenesis and regeneration in the adult zebrafish spinal cord
The mechanisms stimulating adult neurogenesis are unclear. Here, the authors show the contribution of cholinergic and GABAergic signalling within the locomotor network to spinal cord neurogenesis during homeostasis and regeneration, showing neurogenesis depends on circuit activity in the adult zebrafish.
- Weipang Chang
- , Andrea Pedroni
- & Konstantinos Ampatzis
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Article
| Open Access
Prokineticin-2 prevents neuronal cell deaths in a model of traumatic brain injury
Prokineticin-2 (Prok2) is a secreted protein involved in many physiological processes. Here, the authors show that Prok2 prevents neuronal cell ferroptosis after traumatic brain injury and its administration before cortical injury reduces neuronal degeneration, and motor and cognitive impairments.
- Zhongyuan Bao
- , Yinlong Liu
- & Jing Ji
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Article
| Open Access
Barrel cortex plasticity after photothrombotic stroke involves potentiating responses of pre-existing circuits but not functional remapping to new circuits
Definitive evidence for functional remapping after stroke remains lacking. Here, the authors performed in vivo intrinsic signal imaging and two-photon calcium imaging of sensory-evoked responses before and after photothrombotic stroke and found no evidence of remapping of lost functionalities to new circuits in peri-infarct cortex.
- William A. Zeiger
- , Máté Marosi
- & Carlos Portera-Cailliau
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Article
| Open Access
The Atr-Chek1 pathway inhibits axon regeneration in response to Piezo-dependent mechanosensation
The Atr-Check1 pathway is involved in cell cycle and the DNA damage response. Here, the authors show that the Atr-Check1 pathway can inhibit axon regeneration in response to Piezo-mediated mechanosensation, affecting functional recovery.
- Feng Li
- , Tsz Y. Lo
- & Yuanquan Song
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Article
| Open Access
Human stem cells harboring a suicide gene improve the safety and standardisation of neural transplants in Parkinsonian rats
Stem cell grafts present a risk of tissue overgrowth/tumors. Here, the authors utilise a human pluripotent stem cell line carrying a FailSafe suicide gene to not only ablate proliferative cells, but through timely gene activation, improve the purity of neural grafts in Parkinsonian rats.
- Isabelle R. de Luzy
- , Kevin C. L. Law
- & Clare L. Parish
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Article
| Open Access
Co-occupancy identifies transcription factor co-operation for axon growth
After injury to the nervous system, many neurons fail to initiate transcriptional programs needed for axon growth. Here the authors examine co-operative binding of factors to regulatory DNA to predict combinations that improve axon growth when ectopically co-expressed.
- Ishwariya Venkatesh
- , Vatsal Mehra
- & Murray G. Blackmore
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Article
| Open Access
Multi-pronged neuromodulation intervention engages the residual motor circuitry to facilitate walking in a rat model of spinal cord injury
Deep brain stimulation and epidural electrical stimulation of the spinal cord enable locomotion in humans with spinal cord injury (SCI) but the potential synergy between both approaches is unclear. The authors show that a complex technological approach is required to enable volitional walking in rats with SCI.
- Marco Bonizzato
- , Nicholas D. James
- & Gregoire Courtine
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Article
| Open Access
Overcoming the inhibitory microenvironment surrounding oligodendrocyte progenitor cells following experimental demyelination
Demyelination results in impairments in oligodendrocyte progenitor cell recruitment. Here the authors identify sulfatase 1/2 as a potential modulator of myelination by modulating the microenvironment around oligodendrocyte progenitor cells.
- Darpan Saraswat
- , Hani J. Shayya
- & Fraser J. Sim
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Article
| Open Access
Host interneurons mediate plasticity reactivated by embryonic inhibitory cell transplantation in mouse visual cortex
Transplantation of embryonic interneurons can restore juvenile plasticity to the adult host visual cortex. Here, the authors show that transplanted embryonic interneurons reactivate cortical plasticity via Neuregulin/ErbB4 signaling in host parvalbumin interneurons.
- XiaoTing Zheng
- , Kirstie J. Salinas
- & Sunil P. Gandhi
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| Open Access
Transneuronal delivery of hyper-interleukin-6 enables functional recovery after severe spinal cord injury in mice
The CNS has limited ability to regenerate following injury, Here, the authors show that a single injection of AAV-hyper-interleukin-6 in the sensory motor cortex results in corticospinal and raphe spinal tracts regeneration in the injured spinal cord as well as functional recovery in mice.
- Marco Leibinger
- , Charlotte Zeitler
- & Dietmar Fischer
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Article
| Open Access
Enriched conditioning expands the regenerative ability of sensory neurons after spinal cord injury via neuronal intrinsic redox signaling
Pre conditioning injury or environmental enrichment have been shown to promote axon regeneration. Here the authors show that environmental enrichment, combined with preconditioning injury promotes regeneration via a redox signalling dependent mechanism.
- Francesco De Virgiliis
- , Thomas H. Hutson
- & Simone Di Giovanni
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Article
| Open Access
Chronic neuronal activation increases dynamic microtubules to enhance functional axon regeneration after dorsal root crush injury
Central axons have limited regenerative ability following injury. Here, the authors show that chronic activation of DRG neurons results in highly dynamic microtubules at the distal axons and enhanced axonal regrowth and synaptogenesis in the spinal cord affecting functional recovery.
- Di Wu
- , Ying Jin
- & Veronica J. Tom
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Article
| Open Access
Protrudin functions from the endoplasmic reticulum to support axon regeneration in the adult CNS
Increasing the supply of growth machinery to axons is a potential strategy for promoting repair after injury. Here the authors demonstrate that the endoplasmic reticulum adaptor molecule Protrudin provides cellular components that support axonal regeneration in the adult CNS.
- Veselina Petrova
- , Craig S. Pearson
- & James W. Fawcett
Shared inflammatory glial cell signature after stab wound injury, revealed by spatial, temporal, and cell-type-specific profiling of the murine cerebral cortex