Reprogramming of astrocytes to neuronal-like cells in spinal cord injury: a systematic review.

STUDY DESIGN: A Systematic Review OBJECTIVES: To determine the therapeutic efficacy of in vivo reprogramming of astrocytes into neuronal-like cells in animal models of spinal cord injury (SCI). METHODS: PRISMA 2020 guidelines were utilized, and search engines Medline, Web of Science, Scopus, and Embase until June 2023 were used. Studies that examined the effects of converting astrocytes into neuron-like cells with any vector in all animal models were included, while conversion from other cells except for spinal astrocytes, chemical mechanisms to provide SCI models, brain injury population, and conversion without in-vivo experience were excluded. The risk of bias was calculated independently. RESULTS: 5302 manuscripts were initially identified and after eligibility assessment, 43 studies were included for full-text analysis. After final analysis, 13 manuscripts were included. All were graded as high-quality assessments. The transduction factors Sox2, Oct4, Klf4, fibroblast growth factor 4 (Fgf4) antibody, neurogenic differentiation 1 (Neurod1), zinc finger protein 521 (Zfp521), ginsenoside Rg1, and small molecules (LDN193189, CHIR99021, and DAPT) could effectively reprogramme astrocytes into neuron-like cells. The process was enhanced by p21-p53, or Notch signaling knockout, valproic acid, or chondroitin sulfate proteoglycan inhibitors. The type of mature neurons was both excitatory and inhibitory. CONCLUSION: Astrocyte reprogramming to neuronal-like cells in an animal model after SCI appears promising. The molecular and functional improvements after astrocyte reprogramming were demonstrated in vivo, and further investigation is required in this field.

Anti-inflammatory, antioxidant, and immunomodulatory effects of Berberis vulgaris and its constituent berberine, experimental and clinical, a review.

Berberis vulgaris (B. vulgaris or barberry) is a medicinal plant that has been used for various purposes in traditional medicine. Berberine is one of the main alkaloids isolated from B. vulgaris and other plants. Both B. vulgaris and berberine have shown anti-inflammatory, antioxidant, and immunomodulatory effects in different experimental models and clinical trials. This review aims to summarize the current evidence on the mechanisms and applications of B. vulgaris and berberine in modulating inflammation, oxidative stress, and immune responses. The literature search was performed using PubMed, Scopus, and Google Scholar databases until August 2023. The results indicated that B. vulgaris and berberine could inhibit the production of pro-inflammatory cytokines, such as tumor necrosis factor-alpha (TNF-α), interleukin-1ß (IL-1ß), interleukin 6 (IL-6), and interleukin-17 (IL-17), and enhance the expression of anti-inflammatory cytokines, such as interleukin 10 (IL-10) and transforming growth factor-ß (TGF-ß), in various cell types and tissues. B. vulgaris and berberine can also scavenge free radicals, increase antioxidant enzymes, such as superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx), and reduce lipid peroxidation and DNA damage. B. vulgaris and berberine have been reported to exert beneficial effects in several inflammatory, oxidative, and immune-related diseases, such as diabetes, obesity, cardiovascular diseases, neurodegenerative diseases, autoimmune diseases, allergic diseases, and infections. However, more studies are needed to elucidate the optimal doses, safety profiles, and potential interactions of B. vulgaris and berberine with other drugs or natural compounds.

Spinal Cord Injury Affects Gene Expression of Transmembrane Proteins in Tissue and Release of Extracellular Vesicle in Blood: In Silico and In Vivo Analysis.

OBJECTIVE: Spinal cord injury (SCI) can disrupt membrane transmission by affecting transmembrane channels or neurotransmitter release. This study aimed to explore gene expression changes of transmembrane proteins underlying SCI through bioinformatics approaches and confirming in SCI model in rats. MATERIALS AND METHODS: In this experimental study, the differentially expressed genes (DEGs) in acute and subacute SCI were obtained based on microarray data downloaded from the gene expression omnibus (GEO). Transmembrane proteins of DEGs were recognized by using the UniProt annotation and transmembrane helices prediction (TMHMM) methods. The model of SCI was established through a weight-dropping procedure in rats. To confirm the SCI model, hematoxylin and eosin (H and E) staining was performed. Total mRNA was extracted from spinal cord tissues, and the RNA expression profile of some of the significantly changed genes in the previous part that has been confirmed by real-time polymerase chain reaction (PCR). Blood was collected from rats before sacrificing. Extracellular vesicles (EVs) were isolated by high-speed centrifugation from plasma. For the assessment of protein expression, western blotting was used. RESULTS: Based on bioinformatics analysis, we candidated a set of membrane proteins in SCI's acute and sub-acute phases, and confirmed significant upregulation in Grm1, Nrg1, CD63, Enpp3,and Cxcr4 between the acute and control groups and downregulation in Enpp3 between acute and subacute groups at the RNA level. Considering CD63 as an EV marker, we examined the protein expression of CD9 and CD63 in the plasma-derived EVs, and CD9 has significant expression between acute and control groups. We also demonstrate no significant CD63 and Cxcr4 expressions between groups. CONCLUSION: Our results provide new insight into the relationship between candidate transmembrane protein expression and different stages of SCI using in-silico approaches. Also, results show the release of EVs in blood in each group after SCI helping enlarge strategies to enhance recovery following SCI.

Tannic acid-mediated synthesis of flower-like mesoporous MnO2 nanostructures as T1-T2 dual-modal MRI contrast agents and dual-enzyme mimetic agents.

This study introduces a simple method for preparing a new generation of MnO2 nanomaterials (MNMs) using tannic acid as a template. Two shapes of MnO2 NMs, flower-like M1-MnO2 and near-spherical M2-MnO2, were prepared and compared as dual-active nanozymes and contrast agents in magnetic resonance imaging (MRI). Various parameters, including the crystallinity, morphology, magnetic saturation (Ms), surface functionality, surface area, and porosity of the MNMs were investigated. Flower-like M1-MnO2 NMs were biocompatible and exhibited pH-sensitive oxidase and peroxidase mimetic activity, more potent than near-spherical M2-MnO2. Furthermore, the signal intensity and r1 relaxivity strongly depended on the crystallinity, morphology, pore size, and specific surface area of the synthesized MNMs. Our findings suggest that flower-like M1-MnO2 NM with acceptable dual-enzyme mimetic (oxidase-like and peroxidase-like) and T1 MRI contrast activities could be employed as a promising theranostic system for future purposes.

In Situ Cross-Linkable Hyaluronic-Ferulic Acid Conjugate Containing Bucladesine Nanoparticles Promotes Neural Regeneration after Spinal Cord Injury.

Dysfunctional clinical outcomes following spinal cord injury (SCI) result from glial scar formation, leading to the inhibition of new axon growth and impaired regeneration. Nevertheless, nerve regeneration after SCI is possible, provided that the state of neuron development in the injured environment is improved. Hence, biomaterial-based therapy would be a promising strategy to endow a desirable environment for tissue repair. Herein, we designed a novel multifunctional injectable hydrogel with antioxidant, neuroprotective, and neuroregenerative effects. Bucladesine-encapsulated chitosan nanoparticles (BCS NPs) were first prepared and embedded in a matrix of thiol-functionalized hyaluronic acid modified with ferulic acid (HASH-FA). The target hydrogel (HSP-F/BCS) was then created through Michael-type addition between HASH-FA containing BCS NPs and four-arm polyethylene glycol-maleimide (4-Arm-PEG-Mal). The obtained hydrogel with shear thinning behavior showed viscoelastic and mechanical properties similar to the normal nerve tissue. FA conjugation significantly improved the antioxidant activity of HA, and suppressed intracellular ROS formation. In situ injection of the HSP-F/BCS hydrogel in a rat contusion model of SCI inhibited glial scar progression, reduced microglia/macrophage infiltration, promoted angiogenesis, and induced myelinated axon regeneration. As a result, a significant improvement in motor performance was observed compared to other experimental groups. Taken together, the HSP-F/BCS hydrogel developed in this study could be a promising system for SCI repair.

Stimulation of spinal cord according to recorded theta hippocampal rhythm during rat move on treadmill.

OBJECTIVES: Several studies have revealed that after spinal cord injury (SCI), in acute and sub-acute phase the spinal cord neurons below the injury are alive and could stimulate by use of electrical pulses. Spinal cord electrical stimulation could generate movement for paralyzed limbs and is a rehabilitation strategy for paralyzed patients. An innovative idea for controlling spinal cord electrical stimulation onset time is presented in current study. METHODS: In our method, the time of applying electrical pulse on the spinal cord is according to rat behavioral movement and two movements behaviors are recognized only based on rat EEG theta rhythm on the treadmill line. Briefly, 5 rats were placed on the treadmill and the animals experienced zero or 12 m/min speeds. RESULTS: These speeds were recognized based on EEG signals and off-line periodogram analysis. Finally, the electrical stimulation pulses had been applied to the spinal cord if the results of the EEG analysis had detected running behavior. CONCLUSIONS: These findings may guide future research in utilizing theta rhythms for the recognition of animal motor behavior and designing electrical stimulation systems based on it.

Targeting reactive astrocytes by pH-responsive ligand-bonded polymeric nanoparticles in spinal cord injury.

In spinal cord injuries, axonal regeneration decreases with the activation of astrocytes followed by glial scar formation. Targeting reactive astrocytes has been recently performed by unsafe viral vectors to inhibit gliosis. In the current study, biocompatible polymeric nanoparticles were selected as an alternative for viruses to target reactive astrocytes for further drug/gene delivery applications. Lipopolysaccharide-bonded chitosan-quantum dots/poly acrylic acid nanoparticles were prepared by ionic gelation method to target reactive astrocytes both in vitro and in spinal cord-injured rats. Owing to their biocompatibility and pH-responsive behavior, chitosan and poly acrylic acid were the main components of nanoparticles. Nanoparticles were then chemically labeled with quantum dots to track the cell uptake and electrostatically interacted with lipopolysaccharide as a targeting ligand. In vitro and in vivo studies were performed in triplicate and all data were expressed as the mean ± the standard error of the mean. Smart nanoparticles with optimum size (61.9 nm) and surface charge (+ 12.5 mV) successfully targeted primary reactive astrocytes extracted from the rat cerebral cortex. In vitro studies represented high cell viability (96%) in the exposure of biocompatible nanoparticles. The pH-responsive behavior of nanoparticles was proved by their internalization into the cell's nuclei due to the swelling and endosomal escape of nanoparticles in acidic pH. In vivo studies demonstrated higher transfection of nanoparticles into reactive astrocytes compared to the neurons. pH-responsive ligand-bonded chitosan-based nanoparticles are good alternatives for viral vectors in targeted delivery applications for the treatment of spinal cord injuries.

Dopamine Receptors Gene Expression Pattern and Locomotor Improvement Differ Between Female and Male Zebrafish During Spinal Cord Auto Repair.

The dopaminergic system, a spinal cord (SC) motor circuit regulator, is administrated by sexual hormones and evolutionary conserved in all vertebrates. Accordingly, we hypothesized that the dopamine receptor (DAR) expression pattern may be dissimilar in female and male zebrafish SC auto repair. We implemented an uncomplicated method to induce spinal cord injury (SCI) on fully reproductive adult zebrafish, in both genders. SCI was induced using a 28-gauge needle at 9th-10th vertebra without skin incision. Thereupon, lesioned SC was harvested for DAR gene expression analysis; zebrafish were tracked routinely for any improvement in swim distance, speed, and their roaming capabilities/preference. Our findings revealed discrepancies between drd2a, drd2b, drd3, drd4a, and drd4b expression patterns at 1, 7, and 14 days postinjury (DPI) between female and male zebrafish. The receptors were mostly upregulated at 7 DPI in both genders, whereas drd2a and drd2b were mostly maximized in females. Surprisingly, drd3 was measured greater even in intact SC in males. In addition, female zebrafish were able to swim farther distances more accelerated, in multiple directions, by engaging more caudal muscles compared with males, of course with no statistical significance. Indeed, females were able to generate whole-body rotation and move forward using the muscles downstream to the lesion site, whereas the coordinated movement in males was accomplished by rostral muscles. In conclusion, there are differences in DAR gene expression pattern throughout SC autonomous recovery between adult female and male zebrafish, and also, female locomotion seems to ameliorate more rapidly.

Mouse Degenerating Optic Axons Survived by Human Embryonic Stem Cell-Derived Neural Progenitor Cells.

Objective: Any damage to the optic nerve can potentially lead to degeneration of non-regenerating axons and ultimately death of retinal ganglion cells (RGCs) that in most cases, are not curable by surgery or medication. Neuroprotective functions of different types of stem cells in the nervous system have been evaluated in many studies investigating the effectiveness of these cells in various retinal disease models. Neural progenitor cells (NPCs) secrete an assortment of trophic factors that are vital to the protection of the visual system. We aimed to assess the therapeutic potentials of NPCs in an ONC mouse model. Materials and Methods: In this experimental study, NPCs were produced using noggin and retinoic acid from human embryonic stem cells (hESCs). Fifty mice were divided into the following three groups: i. Intact , ii. Vehicle [optic nerve crush+Hank's balanced salt solution (HBSS)], and iii. Treatment (optic nerve crush+NPCs). The visual behavior of the mice was examined using the Visual Cliff test, and in terms of RGC numbers, they were assessed by Brn3a immunostaining and retrograde tracing using DiI injection. Results: Intravenous injection of 50,000 NPCs through visual cliff did not produce any visual improvement. However, our data suggest that the RGCs protection was more than two-times in NPCs compared to the vehicle group as examined by Brn3a staining and retrograde tracing. Conclusion: Our study indicated that intravenous injection of NPCs could protect RGCs probably mediated by trophic factors. Due to this ability and good manufacturing practices (GMP) grade production feasibility, NPCs may be used for optic nerve protection.

In vitro characterization of subventricular zone isolated neural stem cells, from adult monkey and rat brain.

Neural stem cells (NSCs) are multipotent, self-renewable cells who are capable of differentiating into neurons, astrocytes, and oligodendrocytes. NSCs reside at the subventricular zone (SVZ) of the adult brain permanently to guarantee a lifelong neurogenesis during neural network plasticity or undesirable injuries. Although the specious inaccessibility of adult NSCs niche hampers their in vivo identification, researchers have been seeking ways to optimize adult NSCs isolation, expansion, and differentiation, in vitro. NSCs were isolated from rhesus monkey SVZ, expanded in vitro and then characterized for NSCs-specific markers expression by immunostaining, real-time PCR, flow cytometry, and cell differentiation assessments. Moreover, cell survival as well as self-renewal capacity were evaluated by TUNEL, Live/Dead and colony assays, respectively. In the next step, to validate SVZ-NSCs identity in other species, a similar protocol was applied to isolate NSCs from adult rat's SVZ as well. Our findings revealed that isolated SVZ-NSCs from both monkey and rat preserve proliferation capacity in at least nine passages as confirmed by Ki67 expression. Additionally, both SVZ-NSCs sources are capable of self-renewal in addition to NESTIN, SOX2, and GFAP expression. The mortality was measured meager with over 95% viability according to TUNEL and Live/Dead assay results. Eventually, the multipotency of SVZ-NSCs appraised authentic after their differentiation into neurons, astrocytes, and oligodendrocytes. In this study, we proposed a reliable method for SVZ-NSCs in vitro maintenance and identification, which, we believe is a promising cell source for therapeutic approach to recover neurological disorders and injuries condition.

Influence of gelatin and collagen incorporation on peroxidase-mediated injectable pectin-based hydrogel and bioactivity of fibroblasts.

Pectin has recently attracted increasing attention for biomedical and pharmaceutical applications. Due to the lack of adhesion molecules in polysaccharides, phenolic hydroxyl conjugated gelatin was added to enzymatically-gellable peroxidase-modified pectin derivative and compared with phenolic hydroxyl -pectin/collagen. Both pectin and gelatin were modified by tyramine hydrochloride in the presence of EDC/NHS. The phenolic hydroxyl -pectin/phenolic hydroxyl -gelatin, phenolic hydroxyl-pectin/collagen, and phenolic hydroxyl -pectin hydrogels were prepared using horseradish peroxidase and hydrogen peroxide. The hydrogels were characterized by gelation time analysis. Morphology, enzymatic biodegradation, mechanical and swelling properties as well as water vapor transmission rate were also evaluated. Fibroblasts were cultured for 7 days, and the survival rate was evaluated using conventional MTT assay. Hydrogels composed of Ph-pectin/Ph-gelatin showed decreased biodegradation rate, and WVTR and further improved mechanical performance in comparison with other groups. Both phenolic hydroxyl -pectin/collagen and phenolic hydroxyl -pectin/phenolic hydroxyl -gelatin hydrogels exhibited porous structures. The hydrogels composed of collagen promoted cell survival rate 1.4 and 3.5 times compared to phenolic hydroxyl -gelatin and phenolic hydroxyl -pectin based hydrogels at the end of 7 days, respectively (p < 0.001). The study demonstrated the potential of enzymatically-gellable pectin-based hydrogels as cost-effective frameworks for use in tissue engineering applications.

Effect of Physico-Chemical Properties of Nanoparticles on Their Intracellular Uptake.

Cellular internalization of inorganic, lipidic and polymeric nanoparticles is of great significance in the quest to develop effective formulations for the treatment of high morbidity rate diseases. Understanding nanoparticle-cell interactions plays a key role in therapeutic interventions, and it continues to be a topic of great interest to both chemists and biologists. The mechanistic evaluation of cellular uptake is quite complex and is continuously being aided by the design of nanocarriers with desired physico-chemical properties. The progress in biomedicine, including enhancing the rate of uptake by the cells, is being made through the development of structure-property relationships in nanoparticles. We summarize here investigations related to transport pathways through active and passive mechanisms, and the role played by physico-chemical properties of nanoparticles, including size, geometry or shape, core-corona structure, surface chemistry, ligand binding and mechanical effects, in influencing intracellular delivery. It is becoming clear that designing nanoparticles with specific surface composition, and engineered physical and mechanical characteristics, can facilitate their internalization more efficiently into the targeted cells, as well as enhance the rate of cellular uptake.

HSP70/IL-2 Treated NK Cells Effectively Cross the Blood Brain Barrier and Target Tumor Cells in a Rat Model of Induced Glioblastoma Multiforme (GBM).

Natural killer (NK) cell therapy is one of the most promising treatments for Glioblastoma Multiforme (GBM). However, this emerging technology is limited by the availability of sufficient numbers of fully functional cells. Here, we investigated the efficacy of NK cells that were expanded and treated by interleukin-2 (IL-2) and heat shock protein 70 (HSP70), both in vitro and in vivo. Proliferation and cytotoxicity assays were used to assess the functionality of NK cells in vitro, after which treated and naïve NK cells were administrated intracranially and systemically to compare the potential antitumor activities in our in vivo rat GBM models. In vitro assays provided strong evidence of NK cell efficacy against C6 tumor cells. In vivo tracking of NK cells showed efficient homing around and within the tumor site. Furthermore, significant amelioration of the tumor in rats treated with HSP70/Il-2-treated NK cells as compared to those subjected to nontreated NK cells, as confirmed by MRI, proved the efficacy of adoptive NK cell therapy. Moreover, results obtained with systemic injection confirmed migration of activated NK cells over the blood brain barrier and subsequent targeting of GBM tumor cells. Our data suggest that administration of HSP70/Il-2-treated NK cells may be a promising therapeutic approach to be considered in the treatment of GBM.

Co-delivery of minocycline and paclitaxel from injectable hydrogel for treatment of spinal cord injury.

Spinal cord injury (SCI) induces pathological and inflammatory responses that create an inhibitory environment at the site of trauma, resulting in axonal degeneration and functional disability. Combination therapies targeting multiple aspects of the injury, will likely be more effective than single therapies to facilitate tissue regeneration after SCI. In this study, we designed a dual-delivery system consisting of a neuroprotective drug, minocycline hydrochloride (MH), and a neuroregenerative drug, paclitaxel (PTX), to enhance tissue regeneration in a rat hemisection model of SCI. For this purpose, PTX-encapsulated poly (lactic-co-glycolic acid) PLGA microspheres along with MH were incorporated into the alginate hydrogel. A prolonged and sustained release of MH and PTX from the alginate hydrogel was obtained over eight weeks. The obtained hydrogels loaded with a combination of both drugs or each of them alone, along with the blank hydrogel (devoid of any drugs) were injected into the lesion site after SCI (at the acute phase). Histological assessments showed that the dual-drug treatment reduced inflammation after seven days. Moreover, a decrease in the scar tissue, as well as an increase in neuronal regeneration was observed after 28 days in rats treated with dual-drug delivery system. Over time, a fast and sustained functional improvement was achieved in animals that received dual-drug treatment compared with other experimental groups. This study provides a novel dual-drug delivery system that can be developed to test for a variety of SCI models or neurological disorders.

Protocol for purification and culture of astrocytes: useful not only in 2 days postnatal but also in adult rat brain.

Astrocytes play the key roles in the physiology and pathology of the CNS. Thereupon, in this manuscript, we aim to demonstrate that the protocol for purification and culture of astrocytes is useful not only in 2 days postnatal but also in adult rat brain. Also, the mentioned protocol is a simple and efficient primary cell culture technique. The whole-brain was isolated from the skull and the meninges were removed carefully. Afterward, the cerebral hemispheres were mechanically and enzymatically digested. Then, the cell suspension was seeded in T25 culture flask and was incubated at 37 °C in the CO2 incubator. The first shaking was performed after 7-8 days and on day 14, second shaking was done. After 2-3 passage, the culture was analyzed. By passaging, the majority of extracted cells were astrocytes presenting with a polygonal to fusiform and flat morphology that expressed GFAP, GLAST, and S100ß. The expression of neural, neuronal and oligodendrocyte markers was not detected in extracted cells. The patch-clamp recording comfirmed the purity of isolated astrocytes as well. The isolated cells from adult rat brain were astrocytes that expressed specific astrocyte markers after 3 and 10 passages. This method is suggested to obtain a population of astrocytes that may provide a beneficial tool for different neurophysiological and pathophysiological studies.

Human embryonic stem cell-derived neural stem cells encapsulated in hyaluronic acid promotes regeneration in a contusion spinal cord injured rat.

spinal cord injury (SCI) is a traumatic damage that can causes a loss of neurons around the lesion site and resulting in locomotor and sensory deficits. Currently, there is widely attempts in improvement of treatment strategy and cell delivering to the central nervous system (CNS). The usage of hyaluronic acid (HA), the main components of the ECM in CNS tissue and neural stem cells (NSCs) niche, is a good selection that can increase of viability and differentiation of NSCs. Importantly, we demonstrate that encapsulation of human embryonic stem cell derived-neural stem cells (hESC-NS) in HA-based hydrogel can increased differentiation these cells into oligodendrocytes and improved locomotor function.

An Overview of Extrinsic and Intrinsic Mechanisms Involved in Astrocyte Development in the Central Nervous System.

Over the past few decades, our knowledge about the function of the central nervous system (CNS) and astrocytes has improved, and research has confirmed the key roles that astrocytes play in the physiology and pathology of the CNS. Here, we reviewed the intrinsic and extrinsic mechanisms that regulate the development of astrocytes, which are generated from radial glial cells. These regulatory systems modulate various signaling pathways and transcription factors. In this review, four stages of astrocyte development-specification (patterning and switch), migration, proliferation, and maturation, are discussed. In astrocyte patterning, VA1-VA3 domains create the astrocyte subtypes by differential expression of Slit1 and Reelin in the spinal cord. In the brain, patterning creates several astrocyte subtypes by different organizing centers. At the switch step, the janus kinase-signal transducer and activator of transcription pathway governs the transition of neurogenesis to gliogenesis. Bone marrow protein and Notch pathways are also important players of the progliogenic switch. Intrinsic regulation is mediated by DNA methylation transferases, and polycomb group complexes can intrinsically affect the development of astrocytes. In the next stage, these cells proliferate and migrate to their final location. Astrocyte maturation is accomplished through the development of cellular processes, molecular markers, and functions.

In vivo conversion of rat astrocytes into neuronal cells through neural stem cells in injured spinal cord with a single zinc-finger transcription factor.

BACKGROUND: Spinal cord injury (SCI) results in glial scar formation and irreversible neuronal loss, which finally leads to functional impairments and long-term disability. Our previous studies have demonstrated that the ectopic expression of Zfp521 reprograms fibroblasts and astrocytes into induced neural stem cells (iNSCs). However, it remains unclear whether treatment with Zfp521 also affects endogenous astrocytes, thus promoting further functional recovery following SCI. METHODS: Rat astrocytes were transdifferentiated into neural stem cells in vitro by ZFP521 or Sox2. Then, ZFP521 was applied to the spinal cord injury site of a rat. Transduction, real-time PCR, immunohistofluorescence, and function assessments were performed at 6 weeks post-transduction to evaluate improvement and in vivo lineage reprogramming of astrocytes. RESULTS: Here, we show that Zfp521 is more efficient in reprogramming cultured astrocytes compared with Sox2. In the injured spinal cord of an adult rat, resident astrocytes can be reprogrammed into neurons through a progenitor stage by Zfp521. Importantly, this treatment improves the functional abilities of the rats as evaluated by the Basso, Beattie, and Bresnahan (BBB) locomotor rating scale and further by calculation of its subscores. There was enhanced locomotor activity in the hind limbs, step length, toe spread, foot length, and paw area. In addition, motor evoked potential recordings demonstrated the functional integrity of the spinal cord. CONCLUSIONS: These results have indicated that the generation of iNSCs or neurons from endogenous astrocytes by in situ reprogramming might be a potential strategy for SCI repair.

Neuropathological and genomic characterization of glioblastoma-induced rat model: How similar is it to humans for targeted therapy?

Glioblastoma multiforme (GBM) is a unique aggressive tumor and mostly develops in the brain, while rarely spreading out of the central nervous system. It is associated with a high mortality rate; despite tremendous efforts having been made for effective therapy, tumor recurrence occurs with high prevalence. To elucidate the mechanisms that lead to new drug discovery, animal models of tumor progression is one of the oldest and most beneficial approaches to not only investigating the aggressive nature of the tumor, but also improving preclinical research. It is also a useful tool for predicting novel therapies' effectiveness as well as side effects. However, there are concerns that must be considered, such as the heterogeneity of tumor, biological properties, pharma dynamic, and anatomic shapes of the models, which have to be similar to humans as much as possible. Although several methods and various species have been used for this approach, the real recapitulation of the human tumor has been left under discussion. The GBM model, which has been verified in this study, has been established by using the Rat C6 cell line. By exploiting bioinformatic tools, the similarities between aberrant gene expression and pathways have been predicted. In this regard, 610 common genes and a number of pathways have been detected. Moreover, while magnetic resonance imaging analysis enables us to compare tumor features between these two specious, pathological findings provides most of the human GBM characteristics. Therefore, the present study provides genomics, pathologic, and imaging evidence for showing the similarities between human and rat GBM models.