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Therapeutic potential of induced neural stem cells for spinal cord injury

ABSTRACT: The spinal cord does not spontaneously regenerate after injury and a treatment that ensures functional recovery after spinal cord injury (SCI) is still not available. Recently, fibroblasts have been directly converted into induced neural stem cells (iNSCs) following the forced expression of different combinations of transcription factors. Although directly converted iNSCs have been considered as a potentialcell source for clinical applications, their therapeutic potential has not been investigated yet. Here we show that iNSCs directly converted from mouse fibroblasts enhance the functional recovery after SCI in rats. Mouse embryonic fibroblasts (MEFs) were directly converted into iNSCs using four transcription factors (Brn4, Sox2, Klf4 and c-Myc). iNSCs showed gene expression profiles similar to cNSCs as determined by microarray analysis.

ORGANISM(S): Mus musculus

PROVIDER: GSE51331 | GEO | 2013/10/01

SECONDARY ACCESSION(S): PRJNA222413

REPOSITORIES: GEO

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Therapeutic potential of induced neural stem cells for spinal cord injury

Project description:The spinal cord does not spontaneously regenerate after injury and a treatment that ensures functional recovery after spinal cord injury (SCI) is still not available. Recently, fibroblasts have been directly converted into induced neural stem cells (iNSCs) following the forced expression of different combinations of transcription factors. Although directly converted iNSCs have been considered as a potentialcell source for clinical applications, their therapeutic potential has not been investigated yet. Here we show that iNSCs directly converted from mouse fibroblasts enhance the functional recovery after SCI in rats. Mouse embryonic fibroblasts (MEFs) were directly converted into iNSCs using four transcription factors (Brn4, Sox2, Klf4 and c-Myc). iNSCs showed gene expression profiles similar to cNSCs as determined by microarray analysis. MEFs were derived from C3H mouse strain embryos at embryonic day (E)13.5 after removing the head and all internal organs including the gonads and the spinal cord. 5x10^4 fibroblasts were transduced with replication-defective retroviral particles coding for Sox2, Klf4, c-Myc, and Brn4. After 48 h, the transduced fibroblasts were cultured in standard NSC medium. iNSC clusters were observed 4-5 weeks after transduction and expanded. Both MEFs and cNSCs were used as negative and positive control, respectively.

2013-10-01 | E-GEOD-51331 | biostudies-arrayexpress

Transcription profiling time series analyzing the molecular events in rat spinal cord sections following mechanical injury

Project description:Summary: Spinal cord injury (SCI) is a damage to the spinal cord induced by trauma or disease resulting in a loss of mobility or feeling. SCI is characterized by a primary mechanical injury followed by a secondary injury in which several molecular events are altered in the spinal cord often resulting in loss of neuronal function. Hypothesis: Spinal cord injury (SCI) induces a cascade of molecular events including the activation of genes associated with transcription factors, inflammation, oxidative stress, ionic imbalance, apoptosis and neuroregeneration which suggests the existance of endogenous reparative attempts. However, not all mechanisms following SCI are well known. Specific Aim: The goal of this project is to analyze the molecular events following spinal cord injury 1 cm above, below, and at the site of injury (T9), aiming at finding potential new targets to improve recovery and therapy.

2007-09-04 | E-GEOD-464 | biostudies-arrayexpress

Generation of induced motor neurons (iMNs) from human fibroblasts facilitates locomotor recovery after spinal cord injury

Project description:Generation of autologous motor neurons holds a great promise for cell replacement therapy to treat spinal cord injury (SCI). Direct conversion allows the generation of target cell types from somatic cells, however, current protocols are not practicable for therapeutic purposes since converted cells are post-mitotic populations that are not readily scalable. Therefore, therapeutic effects of directly converted neurons have not been elucidated yet. Here, we show that human fibroblasts can be converted into induced motor neurons (iMNs) by sequential induction of OCT4 and LHX3. Our strategy enables large production of pure iMNs through self-renewing iMN-intermediate cell stage which is distinct from neural progenitors. iMNs exhibited the hallmarks of spinal motor neurons including cellular morphology, marker expression, electrophysiological property, synaptic activity, and formation of neuromuscular junctions. Remarkably, transplantation of iMNs showed therapeutic effects, promoting locomotor functional recovery in SCI model. Taken together, our advanced strategy will provide tools to acquire sufficient iMNs that may represent a promising cell source for personalized cell therapy.

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Transcription profiling time series of Rattus norvegicus raphe magnus and sensorimotor cortex samples following moderate spinal cord injury

Project description:Summary: Spinal cord injury (SCI) is a damage to the spinal cord induced by trauma or disease resulting in a loss of mobility or feeling. SCI is characterized by a primary mechanical injury followed by a secondary injury in which several molecular events are altered in the spinal cord often resulting in loss of neuronal function. Analysis of the areas directly (spinal cord) and indirectly (raphe and sensorimotor cortex) affected by injury will help understanding mechanisms of SCI. Hypothesis: Areas of the brain primarily affected by spinal cord injury are the Raphe and the Sensorimotor cortex thus gene expression profiling these two areas might contribute understanding the mechanisms of spinal cord injury. Specific Aim: The project aims at finding significantly altered genes in the Raphe and Sensorimotor cortex following an induced moderate spinal cord injury in T9.

2007-10-08 | E-GEOD-2270 | biostudies-arrayexpress

CNS Regeneration

Project description:Summary: Spinal cord injury (SCI) is a damage to the spinal cord induced by trauma or desease resulting in a loss of mobility or feeling. SCI is characterized by a primary mechanical injury followed by a secondary injury in which several molecular events are altered in the spinal cord often resulting in loss of neuronal function. Hypothesis: Spinal cord injury (SCI) induces a cascade of molecular events including the activation of genes associated with transcription factors, inflammation, oxidative stress, ionic imbalance, apoptosis and neuroregeneration which suggests the existance of endogenous reparative attempts. However, not all mechanisms following SCI are well known. Specific Aim: The goal of this project is to analyze the molecular events following spinal cord injury 1 cm above, below, and at the site of injury (T9), aiming at finding potential new targets to improve recovery and therapy. Keywords: other

2003-07-16 | GSE464 | GEO

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Project description:Traumatic spinal cord injury (SCI) often leads to loss of locomotor function. Neuroplasticity of spinal circuitry underlies some functional recovery and therefore represents a therapeutic target to improve locomotor function following SCI. However, the cellular and molecular mechanisms mediating neuroplasticity below the lesion level are not fully understood. The present study performed a gene expression profiling in the rat lumbar spinal cord at 1 and 3 weeks after contusive SCI at T9 compared to control rat that received sham injury (laminectomy). The below-level gene expression profiles were compared with those of animals that were subjected to treadmill locomotor training. Rat lumbar spinal cords were taken for the microarray analysis at 1 and 3 weeks after contusive spinal cord injury at the T9 level. Another group of rats received treadmill locomotor training for 3 weeks, and theirs spinal cords were harvested for the microarray. The changes in gene expression after spinal cord injury were analyzed at the two time points. The influence of treadmill locomotor training was evaluated by comparing gene expression profiles between animals with or without treadmill training.

2013-11-27 | E-GEOD-52763 | biostudies-arrayexpress

Integrated systems analysis reveals conserved gene networks underlying response to spinal cord injury

Project description:Spinal cord injury (SCI) is a devastating neurological condition for which there are currently no effective treatment options to restore function. A major obstacle to the development of new therapies is our fragmentary understanding of the coordinated pathophysiological processeses triggered by damage to the human spinal cord. An additional challenge to translation of preclinical therapies is the reliance of clinical trials on standardized neurological assessments to enrol and stratify patients, rather than objective injury biomarkers. Here, we describe a systems biology approach to integrate decades of small-scale experiments with unbiased, genome-wide gene expression from the human spinal cord, revealing a gene regulatory network signature of the pathophysiological response to SCI. Our integrative analyses converge on an evolutionarily conserved gene subnetwork enriched for genes associated with the response to SCI by small-scale experiments, and whose expression is upregulated in a severity-dependent manner following injury and downregulated in functional recovery. We validate the severity-dependent upregulation of this subnetwork in prospective transcriptomic and proteomic studies. Our analysis provides a systems-level view of the coordinated molecular processes activated in response to SCI. Further, our results nominate quantitative biomarkers of injury severity and functional recovery, with the potential to facilitate development and translation of novel therapies.

2018-09-25 | PXD010192 | Pride

Spinal Cord Trauma Supraspinal Tracts

Project description:Summary: Spinal cord injury (SCI) is a damage to the spinal cord induced by trauma or disease resulting in a loss of mobility or feeling. SCI is characterized by a primary mechanical injury followed by a secondary injury in which several molecular events are altered in the spinal cord often resulting in loss of neuronal function. Analysis of the areas directly (spinal cord) and indirectly (raphe and sensorimotor cortex) affected by injury will help understanding mechanisms of SCI. Hypothesis: Areas of the brain primarily affected by spinal cord injury are the Raphe and the Sensorimotor cortex thus gene expression profiling these two areas might contribute understanding the mechanisms of spinal cord injury. Specific Aim: The project aims at finding significantly altered genes in the Raphe and Sensorimotor cortex following an induced moderate spinal cord injury in T9. Keywords: other

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Activity-induced changes in the liver transcriptome after chronic spinal cord injury

Project description:Spinal cord injury (SCI) is a devastating clinical condition resulting in significant disabilities for affected individuals. Apart from local injury within the spinal cord, SCI patients develop a myriad of complications characterized by multi-organ dysfunction. Disorders, such as lung injury, cardiovascular disease, liver damage, kidney and urinary tract dysfunction, alterations in gut microbiome, neuropathic pain, depression and altered immune responses are common in SCI patients. Such whole body, systemic responses hinder the functional recovery and can be life-threatening in SCI population. Investigations of organ specific gene expression analyses can provide a better understanding of the injury response and identify molecular targets. Consequently, this can be used to develop treatment for SCI, promoting functional recovery and overall quality of life.

2019-04-29 | GSE124819 | GEO

Transcriptional changes in soleus muscle for rats exposed to different activities after contusion injury to the spinal cord and transcriptional changes in soleus muscle with complete spinal cord transection injury

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