Spinal Cord Development Research Articles

Role of Axon Guidance Molecules in Ascending and Descending Paths in Spinal Cord Regeneration.

Axon guidance molecules (AGM) are critical regulators of neural development and play a vital role in guiding axons to their target regions during spinal cord development. The correct wiring of neural circuits depends on these molecules' precise expression and function. Defects in axonal pathfinding, growth cone navigation, axonal branching, and synapse formation have far-reaching implications for neuronal circuit construction and function after CNS traumas, such as spinal cord injury (SCI), which affect the expression or activity of AGM. Ascending and descending paths in the spinal cord have been found to include many AGM, including Netrins, Slits, Semaphorins (Sema), Ephrins, and their receptors. In contrast to the repulsive signals like Slits and Semaphorins, which restrict axonal growth and guide axons away from unsuitable locations, Netrins are appealing guidance cues that encourage axonal growth and guidance. Defects in motor function and sensory processing can result from changes in the expression or activity of Ephrins or their receptors, which play an essential role in axonal guidance and synaptic plasticity in the spinal cord. Herein, we highlighted the expressions, functions, and mechanisms of AGM in ascending and descending spinal cord tracts, which can help us identify novel therapeutic targets to improve axonal regeneration and functional recovery after SCI.

Rspo1 and Rspo3 are required for sensory lineage neural crest formation in mouse embryos.

R-spondins (Rspos) are secreted proteins that modulate Wnt/β-catenin signaling. At the early stages of spinal cord development, Wnts (Wnt1, Wnt3a) and Rspos (Rspo1, Rspo3) are co-expressed in the roof plate, suggesting that Rspos are involved in development of dorsal spinal cord and neural crest cells in cooperation with Wnt ligands. Here, we found that Rspo1 and Rspo3, as well as Wnt1 and Wnt3a, maintained roof-plate-specific expression until late embryonic stages. Rspo1- and Rspo3-double-knock-out (dKO) embryos partially exhibited the phenotype of Wnt1 and Wnt3a dKO embryos. While the number of Ngn2-positive sensory lineage neural crest cells is reduced in Rspo-dKO embryos, development of dorsal spinal cord, including its size and dorso-ventral patterning in early development, elongation of the roof plate, and proliferation of ependymal cells, proceeded normally. Consistent with these slight defects, Wnt/β-catenin signaling was not obviously changed in developing spinal cord of dKO embryos. Our results show that Rspo1 and Rspo3 are dispensable for most developmental processes involving roof plate-derived Wnt ligands, except for specification of a subtype of neural crest cells. Thus, Rspos may modulate Wnt/β-catenin signaling in a context-dependent manner.

The Transcription Factor Ets1 Influences Axonal Growth via Regulation of Lcn2

Transcription factors are essential for the development and regeneration of the nervous system. The current study investigated key regulatory transcription factors in rat spinal cord development via RNA sequencing. The hub gene Ets1 was highly expressed in the spinal cord during the embryonic period, and then its expression decreased during spinal cord development. Knockdown of Ets1 significantly increased the axonal growth of cultured spinal cord neurons. Luciferase reporter assays and chromatin immunoprecipitation assays indicated that Ets1 could directly bind to the Lcn2 promoter and positively regulate Lcn2 transcription. In conclusion, these findings provide the first direct evidence that Ets1 regulates axon growth by controlling Lcn2 expression, and Ets1 may be a novel therapeutic target for axon regeneration in the central nervous system.

Maternal taurine as a modulator of Cl- homeostasis as well as of glycine/GABAA receptors for neocortical development.

During brain and spinal cord development, GABA and glycine, the inhibitory neurotransmitters, cause depolarization instead of hyperpolarization in adults. Since glycine and GABAA receptors (GABAARs) are chloride (Cl-) ion channel receptor, the conversion of GABA/glycine actions during development is influenced by changes in the transmembrane Cl- gradient, which is regulated by Cl- transporters, NKCC1 (absorption) and KCC2 (expulsion). In immature neurons, inhibitory neurotransmitters are released in a non-vesicular/non-synaptic manner, transitioning to vesicular/synaptic release as the neuron matures. In other word, in immature neurons, neurotransmitters generally act tonically. Thus, the glycine/GABA system is a developmentally multimodal system that is required for neurogenesis, differentiation, migration, and synaptogenesis. The endogenous agonists for these receptors are not fully understood, we address taurine. In this review, we will discuss about the properties and function of taurine during development of neocortex. Taurine cannot be synthesized by fetuses or neonates, and is transferred from maternal blood through the placenta or maternal milk ingestion. In developing neocortex, taurine level is higher than GABA level, and taurine tonically activates GABAARs to control radial migration as a stop signal. In the marginal zone (MZ) of the developing neocortex, endogenous taurine modulates the spread of excitatory synaptic transmission, activating glycine receptors (GlyRs) as an endogenous agonist. Thus, taurine affects information processing and crucial developmental processes such as axonal growth, cell migration, and lamination in the developing cerebral cortex. Additionally, we also refer to the possible mechanism of taurine-regulating Cl- homeostasis. External taurine is uptake by taurine transporter (TauT) and regulates NKCC1 and KCC2 mediated by intracellular signaling pathway, with-no-lysine kinase 1 (WNK1) and its subsequent kinases STE20/SPS1-related proline-alanine-rich protein kinase (SPAK) and oxidative stress response kinase-1 (OSR1). Through the regulation of NKCC1 and KCC2, mediated by the WNK-SPAK/OSR1 signaling pathway, taurine plays a role in maintaining Cl- homeostasis during normal brain development.

Diffusion tensor imaging of fetal spinal cord: feasibility and gestational-age-related changes.

Diffusion tensor imaging (DTI) of the fetal brain is a relatively new technique that allows evaluation of white matter tracts of the central nervous system throughout pregnancy, as well as in certain pathological conditions. The objectives of this study were to evaluate the feasibility of DTI of the spinal cord in utero and to examine gestational-age (GA)-related changes in DTI parameters during pregnancy. This was a prospective study conducted between December 2021 and June 2022 in the LUMIERE Platform, Necker-Enfants Malades Hospital, Paris, France, as part of the LUMIERE SUR LE FETUS trial. Women with a pregnancy between 18 and 36 weeks of gestation without fetal or maternal abnormality were eligible for inclusion. Sagittal diffusion-weighted scans of the fetal spine were acquired, without sedation, using a 1.5-Tesla magnetic resonance imaging scanner. Theimaging parameters were as follows: 15 non-collinear direction diffusion-weighted magnetic-pulsed gradients with a b-value 700 s/mm2 and one B0 image without diffusion-weighting; slice thickness, 3 mm; field of view (FOV), 36 mm; phase FOV, 1.00; voxel size, 4.5 × 2.8 × 3 mm3 ; number of slices, 7-10; repetition time, 2800 ms; echo time, minimum; and total acquisition time, 2.3 min. DTI parameters, including fractional anisotropy (FA) and apparent diffusion coefficient (ADC), were extracted at the cervical, upper thoracic, lower thoracic and lumbar levels of the spinal cord. Cases with motion degradation and those with aberrant reconstruction of the spinal cord on tractography were excluded. Pearson's correlation analysis was performed to evaluate GA-related changes of DTI parameters during pregnancy. During the study period, 42 pregnant women were included at a median GA of 29.3 (range, 22.0-35.7) weeks. Five (11.9%) patients were not included in the analysis because of fetal movement. Two (4.8%) patients with aberrant tractography reconstruction were also excluded from analysis. Acquisition of DTI parameters was feasible in all remaining cases (35/35). Increasing GA correlated with increasing FA averaged over the entire fetal spinal cord (r, 0.37; P < 0.01), as well as at the individual cervical (r, 0.519; P < 0.01), upper thoracic (r, 0.468; P < 0.01), lower thoracic (r, 0.425; P = 0.02) and lumbar (r, 0.427; P = 0.02) levels. There was no correlation between GA and ADC averaged over the entire spinal cord (r, 0.01; P = 0.99) or at the individual cervical (r, -0.109; P = 0.56), upper thoracic (r, -0.226; P = 0.22), lower thoracic (r, -0.052; P = 0.78) or lumbar (r, -0.11; P = 0.95) levels. This study shows that DTI of the spinal cord is feasible in normal fetuses in typical clinical practice and allows extraction of DTI parameters of the spinal cord. There is a significant GA-related change in FA in the fetal spinal cord during pregnancy, which may result from decreasing water content as observed during myelination of fiber tracts occurring in utero. This study may serve as a basis for further investigation of DTI in the fetus, including research into its potential in pathological conditions that impact spinal cord development. © 2023 International Society of Ultrasound in Obstetrics and Gynecology.

Super-resolution Ultrasound Microvascular Angiography for Spinal Cord Penumbra Imaging

After spinal cord injury (SCI) or ischemia, timely intervention in the penumbra, such as recanalization and tissue reperfusion, is essential for preservation of its function. However, limited by imaging resolution and micro-blood flow sensitivity, golden standard angiography modalities, including magnetic resonance angiography (MRA) and digital subtraction angiography (DSA), are still not applicable for spinal cord microvascular imaging. Regarding spinal cord penumbra, to the best of authors' knowledge, currently, there is no efficient in vivo imaging modality for its evaluation. With tens-of-micrometer resolution and deep penetration, advanced ultrasound localization microscopy (ULM) could potentially meet the needs of emergent diagnosis and long-term monitoring of spinal cord penumbra. ULM microvasculature imaging was performed on rats with all laminae removed to obtain the blood supply in major spinal cord segments (C5-L5). For adult rats with spinal cord penumbra induced by compression injury (1 s, 10 s and 15 s), ULM imaging was conducted. The corresponding angiography results are investigated in terms of microvessel saturation, morphology, and flow velocity. The Basso/Beattie/Bresnahan (BBB) locomotor rating scale and hematoxylin and eosin staining were utilized for model validation and comparison. The feasibility of ULM enabling spinal cord penumbra imaging and development monitoring was demonstrated. The focal injury core and penumbra can be clearly identified using the proposed method. Significant difference of perfusion can be observed after 1 s, 10 s and 15 s compression. Quantitative results show a high correlation between in vivo ultrasonic angiography, BBB functional evaluation and ex vivo histology assessment under different compression duration. It is demonstrated that the super-resolution ULM micro-vasculature imaging can be used to evaluate the penumbra in spinal cord at acute and early stage of chronic phase, providing an efficient modality for micro-hemodynamics monitoring of the spinal cord.

Single-cell chromatin accessibility profiling of cell-state-specific gene regulatory programs during mouse organogenesis.

In mammals, early organogenesis begins soon after gastrulation, accompanied by specification of various type of progenitor/precusor cells. In order to reveal dynamic chromatin landscape of precursor cells and decipher the underlying molecular mechanism driving early mouse organogenesis, we performed single-cell ATAC-seq of E8.5-E10.5 mouse embryos. We profiled a total of 101,599 single cells and identified 41 specific cell types at these stages. Besides, by performing integrated analysis of scATAC-seq and public scRNA-seq data, we identified the critical cis-regulatory elements and key transcription factors which drving development of spinal cord and somitogenesis. Furthermore, we intersected accessible peaks with human diseases/traits-related loci and found potential clinical associated single nucleotide variants (SNPs). Overall, our work provides a fundamental source for understanding cell fate determination and revealing the underlying mechanism during postimplantation embryonic development, and expand our knowledge of pathology for human developmental malformations.

P-799 Morphine causes global hypomethylation through active and passive demethylation mechanisms in mESCs hindering optimal embryonic development

Abstract Study question Can morphine create changes in the mESC methylation pattern that are potentially related to the mismatches observed during embryonic development? Summary answer Morphine creates an even more hypomethylated state of the mESC genome, which results in a delay in mESC differentiation and, consequently, an increase in pluripotency. What is known already Epigenetic changes are essential for normal development. However, some environmental factors can cause epigenetic changes that leads to health problems or diseases. Morphine is known to pass through the placental barrier and impact normal embryo development by affecting the neural tube, frontal cortex and spinal cord development, and, as a consequence, delaying nervous system development. In fact, in-utero morphine exposure has shown alterations in anxiety-like behaviours, analgesic tolerance, synaptic plasticity and the neuronal structure of offspring. Nonetheless, how morphine leads to abnormal neurogenesis and other physiological consequences during embryo development is still unknown. Study design, size, duration Considering that DNA methylation is a key epigenetic factor crucial for embryo development, our aim is to elucidate the suitability of using this opioid in pregnant women, analyzing the role of methylation in response to morphine. To study morphine effects on embryo development, we used mouse embryonic stem cells (mESCs) culture, one of the most widely used models for studying embryo development in vitro. Participants/materials, setting, methods mESCs was treated with a chronic morphine treatment (24 h, 10 μM). DNA extraction was done using a classic phenol-chloroform/isoamyl methodology, and RNA extraction with commercial Nucleozol reagent according to the manufacturer’s instructions. Liquid chromatography–mass spectrometry (LC-MS/MS) measured global genome methylation/hydroxymethylation levels, Whole Genome Bisulfite Sequencing (WGBSeq) measured cytosines methylation, and Real Time quantitative Polymerase Chain Reaction (RT-qPCR) measured gene expression. The statistical analysis (LC-MS/MS + RT-qPCR) was made by t-student. Main results and the role of chance By MS/MS approaches, we observed a global methylation decrease and a global hydroxymethylation increase in mESCs, changes that occurred after a chronic morphine treatment (24 h, 10 μM). WGBSeq identified 13329 sensitive cytosines to morphine that are involved in embryo development, signalling pathways, metabolism and/or gene expression. This suggests that morphine might impact methylation levels at developmental genes. Integrative analyses between WGBSeq and RNASeq identified Tet Methylcytosine Dioxygenase 1 (Tet1) as sensitive morphine gene. Morphine increased the gene expression of Tet1, modifying the methylation levels at the promoter. Otherwise, RNASeq and qRT-PCR analyses revealed that DNA Methyltransferase 1 (Dnmt1) gene expression decreased after morphine treatment. In conclusion, morphine induces a global hypomethylation in mESC through different mechanisms that involves active and passive demethylation, and the first one has a self-regulating mechanism that significantly enhances the demethylation process. Limitations, reasons for caution Taking into account all the ethical problems caused by the use of hESCs, this study has been carried out with mESCs. Although the physiology of mice and humans is somewhat different, this is the most recommended model for this type of pilot study. Wider implications of the findings This hypomethylation can potentially lead to a significant delay in optimal embryonic development; The global hypomethylated state of the genome is one of the most significant characteristics of stem cells. Consequently, the possible use of this and other opioids in patients who are pregnant should be strongly discouraged. Trial registration number Not applicable

Safety and Efficacy of Combined Imbrication Axle Reconstruction and Z-Type Titanium Plate Fixation for Hinge Fracture Displacement During Open-Door Laminoplasty.

Open-door laminoplasty is a classical decompression method used to treat cervical spondylotic myelopathy. However, hinge fracture displacement (HFD) is a common occurrence during this procedure. The current study aimed to investigate the safety and efficacy of a combined imbrication axle reconstruction and Z-type titanium plate fixation method for HFD during open-door laminoplasty. In total, 617 patients with cervical spondylotic myelopathy who underwent C3-C7 open-door laminoplasty from March 2015 to October 2018 were included in this retrospective study. Overall, 73 patients developed HFD during surgery. Of these, 43 underwent combined imbrication axle reconstruction and Z-type titanium plate fixation (IRZF group) and 30 underwent traditional titanium plate fixation (TF group). Data such as the operative time, intraoperative blood loss volume, and distribution of fractured hinges were recorded. Both groups were compared in terms of improvement in neurologic function, cervical curvature index, hinge fusion rate, incidence of C5 palsy, severity of axial symptoms, and development of complications. The operative time and intraoperative blood loss were slightly higher in the IRZF group than in the TF group; however, the differences were not significant (p > 0.05). Furthermore, there was no significant difference between the groups in terms of the number of fractured segments and the distribution of fractured hinges (p > 0.05). The cervical curvature index did not decline in the two groups (p > 0.05). The IRZF group had a higher hinge fusion rate than the TF group at 3 (79.6 vs. 57.1%) and 12 (93.9 vs. 74.3%) months postoperatively (p < 0.05). There was no significant difference in the incidence of C5 palsy between the two groups (9.3 vs. 6.7%; p > 0.05). However, the TF group had more severe axial symptoms than the IRZF group (p < 0.05). The neurologic function of the two groups increased postoperatively as per the Japanese Orthopaedic Association scoring system (p < 0.05). Nevertheless, there was no significant difference in terms of neurologic function at any observational time point (p > 0.05). One patient in the TF group with hinge nonunion underwent laminectomy due to lamina displacement into the spinal canal and nerve root compression. In patients with HFD, IRZF facilitates a more intimate contact between the lamina and the lateral mass and, therefore, achieves fractured hinge fusion without additional surgical trauma. This technical improvement can significantly promote neurologic recovery, decrease the severity of axial symptoms, and prevent the development of spinal cord or nerve root recompression.

Cold exposure alters proteomic profiles of the hypothalamus and pituitary in female rats

Abstract Objective Studies have shown that both short-term and long-term cold exposures disturb the biological process. The aim of the present study is to investigate the effects of intermittent cold exposure on proteomic profiles in the hypothalamus and pituitary of female Sprague-Dawley (SD) rats. Materials and methods The rats were exposed to -10°C in a cabin for 4 h per day, and the treatment lasted for 14 days. The comparative label-free LC-MS/MS analysis was performed to investigate the changes of proteomic profiles in the hypothalamus and pituitary. ELISA analysis was used to validate the expression of differential proteins. Results 22 differential proteins in the hypothalamus and 75 differential proteins in the pituitary were identified by the label-free proteomic analysis. Gene ontology annotation and enrichment analysis indicated that cold exposure disrupted protein phosphorylation, filopodium assembly, intracellular protein transport, peripheral nervous system neuron axonogenesis, spinal cord development, Golgi organization, positive regulation of pseudopodium assembly, and cell-cell adhesion. Three proteins (Cdc42, Ptprs, and Setd7) were down-regulated in the cold exposure group. Conclusion The results indicate that intermittent cold exposure alters the proteomic profiles of hypothalamus and pituitary in female rats.

Changes in medical costs for adolescent idiopathic scoliosis over the past 15 years.

Use of instrumentation has become widespread in spinal surgery due to intraoperative spinal cord monitoring, navigation, and improvement and development of implant materials. However, recent advances in spine surgery may have also led to an increase in medical costs. The purpose of this study is to investigate the trends of operative resource utilization and the costs of surgery for adolescent idiopathic scoliosis (AIS) over 15 years. Surgery for AIS was performed for 118 patients from January 2004 to December 2019 at national University Hospital. Trends were examined through retrospective calculation of the costs for outpatient, inpatient, and surgical services, and changes over time and the characteristics of fees were examined. Differences between groups were analyzed by Mann-Whitney U test and Student t-test. During the 15-year period, the length of hospital stay decreased, but costs for scoliosis surgery increased by 1.6 times and the total cost increased by 1.3 times. The fee for intensive care per day per person increased by 1.5 times. There were slight increases in MRI and CT fees, but no changes in fees for radiography, rehabilitation, subsequent visits, and prescriptions. New charges for medical supervision, medical clerk support, medical safety measures, and prevention of infection were added at different times during the 15-year period. Itemized costs related to surgery have increased with technological advances. Although these results only show changes in costs for AIS surgery, the findings indicate the challenges faced by the healthcare economy and the need for spine surgeons to understand medical costs.

Profiling spatiotemporal gene expression of the developing human spinal cord and implications for ependymoma origin

The spatiotemporal regulation of cell fate specification in the human developing spinal cord remains largely unknown. In this study, by performing integrated analysis of single-cell and spatial multi-omics data, we used 16 prenatal human samples to create a comprehensive developmental cell atlas of the spinal cord during post-conceptional weeks 5–12. This revealed how the cell fate commitment of neural progenitor cells and their spatial positioning are spatiotemporally regulated by specific gene sets. We identified unique events in human spinal cord development relative to rodents, including earlier quiescence of active neural stem cells, differential regulation of cell differentiation and distinct spatiotemporal genetic regulation of cell fate choices. In addition, by integrating our atlas with pediatric ependymomas data, we identified specific molecular signatures and lineage-specific genes of cancer stem cells during progression. Thus, we delineate spatiotemporal genetic regulation of human spinal cord development and leverage these data to gain disease insight.

BMPRII+ neural precursor cells isolated and characterized from organotypic neurospheres: an in vitro model of human fetal spinal cord development.

Roof plate secretion of bone morphogenetic proteins (BMPs) directs the cellular fate of sensory neurons during spinal cord development, including the formation of the ascending sensory columns, though their biology is not well understood. Type-II BMP receptor (BMPRII), the cognate receptor, is expressed by neural precursor cells during embryogenesis; however, an in vitro method of enriching BMPRII+ human neural precursor cells (hNPCs) from the fetal spinal cord is absent. Immunofluorescence was undertaken on intact second-trimester human fetal spinal cord using antibodies to BMPRII and leukemia inhibitory factor (LIF). Regions of highest BMPRII+ immunofluorescence localized to sensory columns. Parenchymal and meningeal-associated BMPRII+ vascular cells were identified in both intact fetal spinal cord and cortex by co-positivity with vascular lineage markers, CD34/CD39. LIF immunostaining identified a population of somas concentrated in dorsal and ventral horn interneurons, mirroring the expression of LIF receptor/CD118. A combination of LIF supplementation and high-density culture maintained culture growth beyond 10 passages, while synergistically increasing the proportion of neurospheres with a stratified, cytoarchitecture. These neurospheres were characterized by BMPRII+/MAP2ab+/-/βIII-tubulin+/nestin-/vimentin-/GFAP-/NeuN- surface hNPCs surrounding a heterogeneous core of βIII-tubulin+/nestin+/vimentin+/GFAP+/MAP2ab-/NeuN- multipotent precursors. Dissociated cultures from tripotential neurospheres contained neuronal (βIII-tubulin+), astrocytic (GFAP+), and oligodendrocytic (O4+) lineage cells. Fluorescence-activated cell sorting-sorted BMPRII+ hNPCs were MAP2ab+/-/βIII-tubulin+/GFAP-/O4- in culture. This is the first isolation of BMPRII+ hNPCs identified and characterized in human fetal spinal cords. Our data show that LIF combines synergistically with high-density reaggregate cultures to support the organotypic reorganization of neurospheres, characterized by surface BMPRII+ hNPCs. Our study has provided a new methodology for an in vitro model capable of amplifying human fetal spinal cord cell numbers for > 10 passages. Investigations of the role BMPRII plays in spinal cord development have primarily relied upon mouse and rat models, with interpolations to human development being derived through inference. Because of significant species differences between murine biology and human, including anatomical dissimilarities in central nervous system (CNS) structure, the findings made in murine models cannot be presumed to apply to human spinal cord development. For these reasons, our human in vitro model offers a novel tool to better understand neurodevelopmental pathways, including BMP signaling, as well as spinal cord injury research and testing drug therapies.

Co-occurrence of subcutaneous myxopapillary ependymoma, dermal sinus tract, and filum terminale lipoma: a review of the pathobiology of caudal spinal cord development and spinal cord tethering. Illustrative case.

Myxopapillary ependymoma (MPE) is typically benign and found in the conus medullaris and/or filum terminale, although rare cases of subcutaneous and extra-axial MPE have been reported. The co-occurrence of MPE, tethered cord syndrome (TCS) with lipoma of the filum terminale, and a dermal sinus tract is extremely rare, with only 6 reported cases in the literature. Here, the authors present the first case, to their knowledge, of an extra-axial, subcutaneous MPE co-presenting with TCS, lipoma of the filum terminale, and a dermal sinus tract and discuss the underlying pathobiology. A 14-month-old male who presented for evaluation of a dermal sinus tract underwent magnetic resonance imaging, which revealed a tethered cord with associated lipoma. At 14 months, the patient underwent spinal cord detethering with resection of his sacral dimple and sinus tract. Histopathological evaluation revealed an incidentally found MPE within the dermal sinus tract. The authors review the underlying biology of MPEs, tethered cord syndrome, and dermal sinus tracts, and explore possible points of convergence within the developmental pathways that may result in this unique concomitant presentation. Additionally, they suggest that extra-axial MPE may be underappreciated and underdiagnosed; this case suggests that extra-axial MPE may be only effectively diagnosed with histological studies.

Neuroprotective role of Noggin in spinal cord injury.

Spinal cord injury is one of the leading causes of morbidity and mortality among young adults in many countries including the United States. Difficulty in the regeneration of neurons is one of the main obstacles that leave spinal cord injury patients with permanent paralysis in most instances. Recent research has found that preventing acute and subacute secondary cellular damages to the neurons and supporting glial cells can help slow the progression of spinal cord injury pathogenesis, in part by reactivating endogenous regenerative proteins including Noggin that are normally present during spinal cord development. Noggin is a complex protein and natural inhibitor of the multifunctional bone morphogenetic proteins, and its expression is high during spinal cord development and after induction of spinal cord injury. In this review article, we first discuss the change in expression of Noggin during pathogenesis in spinal cord injury. Second, we discuss the current research knowledge about the neuroprotective role of Noggin in preclinical models of spinal cord injury. Lastly, we explain the gap in the knowledge for the use of Noggin in the treatment of spinal cord injury. The results from extensive in vitro and in vivo research have revealed that the therapeutic efficacy of Noggin treatment remains debatable due to its neuroprotective effects observed only in early phases of spinal cord injury but little to no effect on altering pathogenesis and functional recovery observed in the chronic phase of spinal cord injury. Furthermore, clinical information regarding the role of Noggin in the alleviation of progression of pathogenesis, its therapeutic efficacy, bioavailability, and safety in human spinal cord injury is still lacking and therefore needs further investigation.

Impact of Reconstructing Intercostal Artery on Spinal Cord Circulation During Open Surgery for Thoracoabdominal Aortic Aneurysm.

We evaluated the outcomes of the selective intercostal artery reconstruction for preventing spinal cord injury during thoracoabdominal aortic aneurysm repair. We retrospectively assessed 84 consecutive patients who underwent thoracoabdominal aortic aneurysm repairs between 2004 and 2016. The mean age of the patients was 57.3 years. We performed preoperative multidetector computed tomography in 74 patients (88.0%) to identify the Adamkiewicz artery. Spinal cord injury preventive measures included motor evoked potential monitoring, hypothermia induction, Adamkiewicz artery or other intercostal artery reconstruction, and cerebrospinal fluid drainage. The hospital death rate was 5.9%, and paraplegia occurred in four patients (4.7%). The Adamkiewicz artery or other intercostal arteries were reconstructed selectively in 46 patients (54.7%). Of these patients, 41 underwent postoperative multidetector computed tomography, which revealed occlusion of the reconstructed grafts in 23 patients (56.0%). There was no paraplegia in the patients who underwent reconstruction of the Adamkiewicz artery, which was patent on postoperative multidetector computed tomography. Univariate analysis showed no significant effect of various risk factors on the development of spinal cord injury. Outcome of open surgery for thoracoabdominal aortic aneurysm in our institution regarding spinal cord injury was satisfactory. The benefits of Adamkiewicz artery reconstruction remain inconclusive, and further larger studies are required to identify its validation for spinal cord protection in thoracoabdominal aortic aneurysm repair.

Functional Anatomy of the Spinal Tracts Based on Evolutionary Perspectives.

The development of spinal cord represents evolutionary progression. The primitive tract is responsible for functions related to basic survival such as locomotion. In contrast, the developed tracts are involved in perceiving the external environment and controlling conscious movements. There are also differences in the arrangement of spinal tracts between the 2 categories. Tracts serving developed functions are located in the deep layer of the lateral funiculus, whereas primitive tracts occupy other areas. Decussation correlates with tract pathways, with primitive tracts projecting ipsilaterally and developing tracts decussating early. Understanding these principles provides insights into spinal tract organization.

Updates on Intraoperative Neurophysiology During Surgery for Spinal Dysraphism.

Spinal dysraphism is a group of disorders resulting from an embryologic failure of spinal cord development which can lead to a radicular-medullary mechanical stretch that generates vascular compromise and hypoxic-ischemic damage to the nervous structures of the conus-cauda region.Thus, the clinical relevance of the different types of spinal dysraphism is related to the possible neurologic deficits resulting from spinal cord tethering. The clinical presentation is heterogenous: from asymptomatic to very compromised patients. The indications and the time of a detethering surgery are still subject of debate, although there is an agreement on the high standards of treatment that have to be offered by the surgery. Intraoperative neurophysiology (ION) contributes to the safety of tethered cord surgery in reducing the risks of iatrogenic neurological damages.

Generation of dorsoventral human spinal cord organoids via functionalizing composite scaffold for drug testing

The spinal cord possesses highly complex, finely organized cytoarchitecture guided by two dorsoventral morphogenic organizing centers. Thus, generation of human spinal cord tissue invitro is challenging. Here, we demonstrated a novel method for generation of human dorsoventral spinal cord organoids using composite scaffolds. Specifically, the spinal cord ventralizing signaling Shh agonist (SAG) was loaded into a porous chitosan microsphere (PCSM), then thermosensitive Matrigel was coated on the surface to form composite microspheres withfunctional sustained-release SAG, termed as PCSM-Matrigel@SAG. Using PCSM-Matrigel@SAG as the core to induce 3D engineering of human spinal cord organoids from human pluripotent stem cells (ehSC-organoids), we found ehSC-organoids could form dorsoventral spinal cord-like cytoarchitecture with major domain-specific progenitors and neurons. Besides, these ehSC-organoids also showed functional calcium activity. In summary, these ehSC-organoids are of great significance for modeling spinal cord development, drug screening as 3D models for motor neuron diseases, and spinal cord injury repair.

Single-cell chromatin accessibility identifies enhancer networks driving gene expression during spinal cord development in mouse.

Spinal cord development is precisely orchestrated by spatiotemporal gene regulatory programs. However, the underlying epigenetic mechanisms remain largely elusive. Here, we profiled single-cell chromatin accessibility landscapes in mouse neural tubes spanning embryonic days 9.5-13.5. We identified neuronal-cell-cluster-specific cis-regulatory elements in neural progenitors and neurons. Furthermore, we applied a novel computational method, eNet, to build enhancer networks by integrating single-cell chromatin accessibility and gene expression data and identify the hub enhancers within enhancer networks. It was experimentally validated invivo for Atoh1 that knockout of the hub enhancers, but not the non-hub enhancers, markedly decreased Atoh1 expression and reduced dp1/dI1 cells. Together, our work provides insights into the epigenetic regulation of spinal cord development and a proof-of-concept demonstration of enhancer networks as a general mechanism in transcriptional regulation.