Role of intracranial bone marrow mesenchymal stem cells in stroke recovery: A focus on post-stroke inflammation and mitochondrial transfer.

Stem cell therapy has become a hot research topic in the medical field in recent years, with enormous potential for treating a variety of diseases. In particular, bone marrow mesenchymal stem cells (BMSCs) have wide-ranging applications in the treatment of ischemic stroke, autoimmune diseases, tissue repair, and difficult-to-treat diseases. BMSCs can differentiate into multiple cell types and exhibit strong immunomodulatory properties. Although BMSCs can regulate the inflammatory response activated after stroke, the mechanism by which BMSCs regulate inflammation remains unclear and requires further study. Recently, stem cell therapy has emerged as a potentially effective approach for enhancing the recovery process following an ischemic stroke. For example, by regulating post-stroke inflammation and by transferring mitochondria to exert therapeutic effects. Therefore, this article reviews the therapeutic effects of intracranial BMSCs in regulating post-stroke inflammation and mitochondrial transfer in the treatment of stroke, providing a basis for further research.

Mitochondrial Transplantation and Immune Response of Human Bone Marrow Mesenchymal Stem Cells for the Therapeutic of Ischemic Stroke.

Ischemic stroke is the leading cause of death and disability worldwide, with increasing incidence and mortality, imposing a significant social and economic burden on patients and their families. However, cerebral vascular occlusion leads to acute loss of neurons and destruction of synaptic structures. The limited treatment options cannot adequately address intra-neuronal mitochondrial dysfunction due to stroke. Therefore, stem cell-derived mitochondria transplantation plays an important role in neuronal protection and recovery after stroke, when combined with the intracranial and extracranial immunoregulatory effects of stem cell therapy, revealing the mechanism of transferred mitochondria in stem cells in protecting neurological function among chronic-phase ischemic stroke by affecting the endogenous apoptotic pathway of neuronal cells. This research elaborated on the mitochondrial dysfunction in neurons after ischemic stroke, followed by human bone marrow mesenchymal stem cells (hBMSC) rescued damaged neurons by mitochondrial transfer through tunneling nanotubes (TNTs), and the immunomodulatory effect of the preferential transfer of stem cells to the spleen when transplanted into the body.which created an immune environment for nerve repair, as well as improved neurological recovery after the chronic phase of stroke. This review is expected to provide a novel idea for applying intracranial stem cell transplantation in chronic-phase ischemic stroke treatment.

Effects of long-term regular oral aspirin combined with atorvastatin to prevent ischemic stroke on human gut microbiota.

PURPOSE: Every year, there is a large number of people take aspirin and atorvastatin to prevent ischemic stroke, but the effect of these drugs on gut microbiota remains unknown. We aimed to examine the effects of long-term regular oral aspirin with atorvastatin to prevent ischemic stroke on human gut microbiota. METHODS: A cross-sectional study of 20 participants with the drugs over one year and the other 20 gender- and age-matching participants without medication were recruited from the Affiliated Hospital of Guizhou Medical University. The medication habits and dietary information were obtained using a questionnaire. Fecal samples collected from all participants were subjected to 16S rRNA sequencing of the microbiome. The datasets were analyzed using bioinformatics approaches. RESULTS: The Alpha diversity showed that compared with controls, medication participants had lower ACE and Chao1 index, while no difference in the Shannon index and Simpson index. The Beta diversity analysis revealed significant shifts in the taxonomic compositions of the two groups. Linear discriminant analysis effect size (LEfSe) analysis combined with receiver operating characteristic (ROC) curves revealed the marker bacteria associated with taking medication were g_Parabacteroides（AUC = 0.855）, g_Bifidobacterium（AUC = 0.815）, s_Bifidobacterium_longum_subsp（AUC = 0.8075）, and with no taking medication was g_Prevotella_9（AUC = 0.76）. CONCLUSIONS: Our findings indicated that long-term regular oral aspirin and atorvastatin modulate the human gut microbiota. Taking these drugs may affect the preventive effect of ischemic stroke by changing the abundance of specific gut microbiota.

Immune response treated with bone marrow mesenchymal stromal cells after stroke.

Stroke is a leading cause of death and long-term disability worldwide. Tissue plasminogen activator (tPA) is an effective treatment for ischemic stroke. However, only a small part of patients could benefit from it. Therefore, finding a new treatment is necessary. Bone marrow mesenchymal stromal cells (BMSCs) provide a novel strategy for stroke patients. Now, many patients take stem cells to treat stroke. However, the researches of the precise inflammatory mechanism of cell replacement treatment are still rare. In this review, we summarize the immune response of BMSCs treated to stroke and may provide a new perspective for stem cell therapy.

Extended Ischemic Recovery After Implantation of Human Mesenchymal Stem Cell Aggregates Indicated by Sodium MRI at 21.1 T.

Extended therapeutic application remains a significant issue in the use of stem cell therapies to treat ischemic stroke. Along these lines, neurological recovery in a rodent model of ischemic stroke was evaluated following implantation of human mesenchymal stem cell aggregates (hMSC-agg), labeled with micron-sized particles of iron oxide, directly into the lateral ventricle contralateral to the ischemic lesion hemisphere. Longitudinally, disease progression and response to hMSC-agg therapy were assessed by 1H and 23Na magnetic resonance imaging (MRI) at 21.1 T to investigate cellular localization, migration, and recovery over an extended timeframe. MRI provides quantifiable metrics of tissue status through sodium distributions in addition to traditional proton imaging. Quantitative 23Na MRI revealed a significant decrease of sodium concentrations following hMSC aggregate implantation, indicating recovery of homeostasis. This result correlates positively with extended neurological recovery assessed by behavioral analysis and immunohistochemistry. These findings demonstrate the potential of implanted hMSC aggregate therapy to provide extended treatment for ischemic stroke, as well as the robustness of MRI for monitoring such approaches. This method potentially can be translated to a clinical setting for the assessment of extended cell therapy efficacy.

PRL1 Promotes Glioblastoma Invasion and Tumorigenesis via Activating USP36-Mediated Snail2 Deubiquitination.

Regenerating liver phosphatase 1 (PRL1) is an established oncogene in various cancers, although its biological function and the underlying mechanisms in glioblastoma multiforme (GBM) remain unclear. Here, we showed that PRL1 was significantly upregulated in glioma tissues and cell lines, and positively correlated with the tumor grade. Consistently, ectopic expression of PRL1 in glioma cell lines significantly enhanced their tumorigenicity and invasion both in vitro and in vivo by promoting epithelial-mesenchymal transition (EMT). Conversely, knocking down PRL1 blocked EMT in GBM cells, and inhibited their invasion, migration and tumorigenic growth. Additionally, PRL1 also stabilized Snail2 through its deubiquitination by activating USP36, thus revealing Snail2 as a crucial mediator of the oncogenic effects of PRL1 in GBM pathogenesis. Finally, PRL1 protein levels were positively correlated with that of Snail2 and predicted poor outcome of GBMs. Collectively, our data support that PRL1 promotes GBM progression by activating USP36-mediated Snail2 deubiquitination. This novel PRL1/USP36/Snail2 axis may be a promising therapeutic target for glioblastoma.

Human parthenogenetic neural stem cell grafts promote multiple regenerative processes in a traumatic brain injury model.

International Stem Cell Corporation human parthenogenetic neural stem cells (ISC-hpNSC) have potential therapeutic value for patients suffering from traumatic brain injury (TBI). Here, we demonstrate the behavioral and histological effects of transplanting ISC-hpNSC intracerebrally in an animal model of TBI. Methods: Sprague-Dawley rats underwent a moderate controlled cortical impact TBI surgery. Transplantation occurred at 72 h post-TBI with functional readouts of behavioral and histological deficits conducted during the subsequent 3-month period after TBI. We characterized locomotor, neurological, and cognitive performance at baseline (before TBI), then on days 0, 1, 7, 14, 30, 60, and 90 (locomotor and neurological), and on days 28-30, 58-60, and 88-90 (cognitive) after TBI. Following completion of behavioral testing at 3 months post-TBI, animals were euthanized by transcardial perfusion and brains harvested to histologically characterize the extent of brain damage. Neuronal survival was revealed by Nissl staining, and stem cell engraftment and host tissue repair mechanisms such as the anti-inflammatory response in peri-TBI lesion areas were examined by immunohistochemical analyses. Results: We observed that TBI groups given high and moderate doses of ISC-hpNSC had an improved swing bias on an elevated body swing test for motor function, increased scores on forelimb akinesia and paw grasp neurological tests, and committed significantly fewer errors on a radial arm water maze test for cognition. Furthermore, histological analyses indicated that high and moderate doses of stem cells increased the expression of phenotypic markers related to the neural lineage and myelination and decreased reactive gliosis and inflammation in the brain, increased neuronal survival in the peri-impact area of the cortex, and decreased inflammation in the spleen at 90 days post-TBI. Conclusion: These results provide evidence that high and moderate doses of ISC-hpNSC ameliorate TBI-associated histological alterations and motor, neurological, and cognitive deficits.

Management of De Novo Carotid Stenosis and Postintervention Restenosis-Carotid Endarterectomy Versus Carotid Artery Stenting-a Review of Literature.

The current literature indicates carotid endarterectomy (CEA) as the preferred treatment for symptomatic, moderate to severe carotid artery stenosis. However, recommendations for the management of acute tandem stenosis and complete occlusion, as well as postintervention restenosis of the carotid artery, remain controversial. Here, we review the literature evaluating these conditions and provide suggestions for clinical decision-making. Acute tandem stenosis or occlusion of the common and internal carotid arteries may be treated with angioplasty alone, reserving carotid artery stenting (CAS) or CEA for severe and complex cases. Patients who underwent CEA and developed ipsilateral restenosis may be subjected to angioplasty followed by CAS, which carries a lower risk of cranial nerve injury and subsequent restenosis of the artery. For post-CAS restenosis, current evidence recommends angioplasty and CAS for the management of moderate stenosis and CEA for severe stenosis of the carotid artery. Given the lack of level 1 evidence for the management of these conditions, the abovementioned recommendations may assist clinical decision-making; however, each case and its unique risks and benefits need to be assessed individually. Future studies evaluating and defining the risks and benefits of specific treatment strategies, such as CEA and CAS, in patients with acute tandem stenosis, occlusion, and postintervention restenosis of the carotid artery need to be conducted.

Transplanting GABAergic Neurons Differentiated from Neural Stem Cells into Hippocampus Inhibits Seizures and Epileptiform Discharges in Pilocarpine-Induced Temporal Lobe Epilepsy Model.

OBJECTIVE: This study aimed to explore whether intrahippocampal transplantation of GABAergic neurons generated in vitro ameliorated seizures and epileptiform discharges via increasing γ-aminobutyric acid (GABA)-associated inhibition mediated by the addition of new GABAergic neurons. METHODS: Neural stem cells (NSCs) isolated from newborn rats were induced and differentiated into GABAergic neurons. A total of 36 Pilocarpine-induced pharmacoresistant epileptic rats were divided into 3 groups: PBS (phosphate-buffered saline) group, NSCs group, and GABAergic neurons group (GABA group), with an additional 10 normal rats used (normal rat control group). The effects of grafting on spontaneous recurrent seizures (SRS) were examined and hippocampal GABA content was measured after grafting. RESULTS: In the GABA group, the frequency of electroencephalography decreased significantly compared with the PBS group (P < 0.001), but there was no significant difference between the GABA group and NSCs group. Compared with the PBS group, the overall frequency and duration of SRS significantly decreased in the transplantation group, especially in the GABA group (P < 0.01). The number of GABAergic neurons was highest in the GABA group compared with the other groups (P < 0.001). Furthermore, hippocampal GABA concentrations significantly increased in the GABA group. CONCLUSIONS: We show that GABAergic neurons generated in vitro from NSCs and grafted into the hippocampi of chronically epileptic rats can significantly reduce the frequency of electroencephalography and frequency and duration of SRS via increasing GABA-associated inhibition mediated by the addition of new GABAergic neurons.

Complete resolution of a cervical spine aneurysmal bone cyst after single session of endovascular embolization: Case report.

Treatment options for aneurysmal bone cysts include intralesional curettage, segmental excision, en bloc resection and endovascular embolization. The most commonly used treatment is intralesional curettage and selective arterial embolization is normally an adjunctive therapy, not a definitive treatment. We report a case of a C1 lateral mass aneurysmal bone cyst treated with a single session of endovascular embolization. Long-term follow up demonstrated complete resolution of the cyst. A study of aneurysmal bone cyst embolization was conducted and the key points for obtaining maximal devascularization of the cyst along with embolic material and technique are discussed.

Covered Stent to Salvage Iatrogenic Vertebral Artery Injury with Uncontrolled Bleeding in the Operating Room Setting.

BACKGROUND: Iatrogenic vertebral artery injury is an uncommon but well recognized complication during cervical spine surgery. Intraoperative surgical repair is extremely challenging, and options for endovascular repair are limited because of the lack of proper equipment in the operating room setting. CASE DESCRIPTION: A 53-year-old woman who presented with myelopathy underwent anterior cervical diskectomy and fusion of C3-7. A significant laceration injury of the left vertebral artery was encountered during surgery, which was salvaged by intraoperative endovascular repair with a covered stent under portable fluoroscopy guidance. The salvage and repair led to the rest of the surgery being finished as planned preoperatively without any consequences. CONCLUSIONS: Vertebral artery injury is an uncommon but severe complication of cervical spine surgery. For uncontrolled bleeding, intraoperative endovascular repair with portable fluoroscopy is warranted and possible. A covered stent can seal the laceration and stop the bleeding completely which enables completion of the surgery.

Human stem cells transplanted into the rat stroke brain migrate to the spleen via lymphatic and inflammation pathways.

Despite mounting evidence of a massive peripheral inflammatory response accompanying stroke, the ability of intracerebrally transplanted cells to migrate to the periphery and sequester systemic inflammation remains unexamined. Here, we tested the hypothesis that human bone marrow mesenchymal stromal cells intracerebrally transplanted in the brain of adult rats subjected to experimental stroke can migrate to the spleen, a vital organ that confers peripheral inflammation after stroke. Sham or experimental stroke was induced in adult Sprague-Dawley rats by a 1 hour middle cerebral artery occlusion model. One hour after surgery, rats were intracerebrally injected with human bone marrow mesenchymal stromal cells (3×105/9 µL), then euthanized on day 1, 3, or 7 for immunohistochemical assays. Cell migration assays were performed for human bone marrow mesenchymal stromal cells using Boyden chambers with the bottom plate consisting of microglia, lymphatic endothelial cells, or both, and treated with different doses of tumor necrosis factor-α. Plates were processed in a fluorescence reader at different time points. Immunofluorescence microscopy on different days after the stroke revealed that stem cells engrafted in the stroke brain but, interestingly, homed to the spleen via lymphatic vessels, and were propelled by inflammatory signals. Experiments using human bone marrow mesenchymal stromal cells co-cultured with lymphatic endothelial cells or microglia, and treated with tumor necrosis factor-α, further indicated the key roles of the lymphatic system and inflammation in directing stem cell migration. This study is the first to demonstrate brain-to-periphery migration of stem cells, advancing the novel concept of harnessing the lymphatic system in mobilizing stem cells to sequester peripheral inflammation as a brain repair strategy.

May the force be with you: Transfer of healthy mitochondria from stem cells to stroke cells.

Stroke is a major cause of death and disability in the United States and around the world with limited therapeutic option. Here, we discuss the critical role of mitochondria in stem cell-mediated rescue of stroke brain by highlighting the concept that deleting the mitochondria from stem cells abolishes the cells' regenerative potency. The application of innovative approaches entailing generation of mitochondria-voided stem cells as well as pharmacological inhibition of mitochondrial function may elucidate the mechanism underlying transfer of healthy mitochondria to ischemic cells, thereby providing key insights in the pathology and treatment of stroke and other brain disorders plagued with mitochondrial dysfunctions.

Influence of hippocampal low-frequency stimulation on GABAA R α1, ICER and BNDF expression level in brain tissues of amygdala-kindled drug-resistant temporal lobe epileptic rats.

This study investigated the therapeutic effect of hippocampal low-frequency stimulation (Hip-LFS) and its influence on the type A γ-aminobutyric acid receptor α1 subunit (GABAA R α1 subunit), inducible cAMP early repressor (ICER) and brain-derived neurotrophic factors (BNDF). The model of epilepsy was induced by chronic electrical stimulation in amygdala. Drug-resistant and drug-sensitive epileptic rats were selected by testing their seizure response to phenytoin and phenobarbital. The changes of GABAA R α1 subunit, ICER and BDNF expression were detected via immunohistochemistry and western blot. The expression levels of ICER and BDNF were increased remarkably but the GABAA R α1 subunit decreased significantly in the drug-resistant epileptic rats. However, the expression levels of ICER, BDNF were decreased and the expression of the GABAA R α1 subunit increased significantly in the drug-resistant epileptic rats after two weeks of Hip-LFS. Meanwhile, the seizure degree was reduced and the electroencephalograms were improved. The present study demonstrated thatincreased ICER and BDNF might be associated with the development of drug-resistance. The effect of Hip-LFS in the treatment of drug-resistant epileptic rats might be associated with increasing the levels of the ICER and the BDNF.

An update on intracerebral stem cell grafts.

INTRODUCTION: Primary neurological disorders are notoriously debilitating and deadly, and over the past four decades stem cell therapy has emerged as a promising treatment. Translation of stem cell therapies from the bench to the clinic requires a better understanding of delivery protocols, safety profile, and efficacy in each disease. Areas covered: In this review, benefits and risks of intracerebral stem cell transplantation are presented for consideration. Milestone discoveries in stem cell applications are reviewed to examine the efficacy and safety of intracerebral stem cell transplant therapy for disorders of the central nervous system and inform design of translatable protocols for clinically feasible stem cell-based treatments. Expert commentary: Intracerebral administration, compared to peripheral delivery, is more invasive and carries the risk of open brain surgery. However, direct cell implantation bypasses the blood-brain barrier and reduces the first-pass effect, effectively increasing the therapeutic cell deposition at its intended site of action. These benefits must be weighed with the risk of graft-versus-host immune response. Rigorous clinical trials are underway to assess the safety and efficacy of intracerebral transplants, and if successful will lead to widely available stem cell therapies for neurologic diseases in the coming years.

Suppressed acoustic startle response in traumatic brain injury masks post-traumatic stress disorder hyper-responsivity.

An exaggerated acoustic startle reflex (ASR) is a clinical indicator of anxiety disorders, such as post-traumatic stress disorder (PTSD). Given the prevalence of PTSD following traumatic brain injury (TBI), we studied the effects of TBI on ASR. Adult Sprague Dawley rats exposed to moderate controlled cortical impact injury model of TBI displayed suppression of ASR intensity and sensitivity. As patients with PTSD have been shown to display hyperactive startle responses, the present discrepant observation of TBI-induced suppression of ASR has clinical implications, in that the reduced, instead of elevated, startle response in patients with comorbid TBI/PTSD could be owing to a masking effect of TBI.

A novel approach to glioma therapy using an oncolytic adenovirus with two specific promoters.

Gliomas are the most common type of primary brain tumor in adults, where more than half of the cases are malignant, and the prognosis is poor. The early viral 1A (E1A) protein has been widely recognized to be essential for adenoviral replication and production of progeny virions in human cells, a process that is regulated by human telomerase reverse transcriptase. The p53 gene, as a tumor suppressor, regulates diverse cellular processes, including cell cycle arrest, cell autophagy, senescence and apoptosis. Dysfunction of the p53 pathways is common in malignant gliomas. Exogenous expression of p53 during adenovirus replication in human cancer cells may accelerate cell death and improve the release of early virus progeny. In the present study, a conditionally replicative adenovirus (CRAd) Ad-Tp-E1A-Gp-p53, which expressed functional p53 protein when replicating in cancer cells, was constructed. Next, the level of p53 expression in U251 cells was determined by western blot analysis, and the inhibitory effect of Ad-Tp-E1A-Gp-p53 on U251 cells was detected via an MTT assay. The results indicated that p53 expression was upregulated with an increase in the multiplicity of infection (MOI) of Ad-Tp-E1A-Gp-p53. Additionally, the inhibitory effects of Ad-Tp-E1A-Gp-p53 in different groups were significantly different (P<0.05), with the inhibition ratio of the experimental groups being higher, compared with the control group (P<0.05). Furthermore, the inhibition ratio increased with increases in the MOI of Ad-Tp-E1A-Gp-p53. Therefore, the expression of functional p53 and that of E1A may increase the potency of CRAd, and overexpression of p53 through CRAd is a promising approach to more effective treatments in a number of human cancer types.

The working road map in a neurosurgical Hybrid Angio-Surgical suite------ development and practice of a neurosurgical Hybrid Angio-Surgical suite.

BACKGROUND: The concept of a Hybrid Angio-Surgical Suite (HASS) has emerged as a solution to the complexity of cerebrovascular surgery and the need for immediate intraoperative feedback. When to use it, what cases are suitable for its use, who can use it and how to use it remain debatable. OBJECTIVE: Provide the information regarding the application of the HASS for hospital, neurosurgeon and interventionalist. METHODS: We review the literatures of case reports and studies on the use of the hybrid angio-sugical suite along with application of HASS in our own practice. RESULTS: Indications for using HASS on different types of cerebral vascular disease, including cerebral aneurysm, AVM, DAVF, carotid and vertebral stenosis/occlusion, are addressed. The application of HASS for other non-cerebral vascular diseases, such as trauma, spine and skullbase cases, is reviewed and discussed. CONCLUSION: HASS has made many surgical procedures safer and many difficult or previously untreatable conditions much more tractable and cost-effective. Other than used in cerebral vascular disease, HASS has much more applications, such as trauma, spine and other neurosurgical diseases.

Multifaceted Effects of Delta Opioid Receptors and DADLE in Diseases of the Nervous System.

BACKGROUND: The opioid system is considered a potential therapeutic target in a variety of neurological disorders. Delta opioid receptors (DORs) are broadly expressed in the brain, and their activation protects cells from hypoxic/ischemic insults by counteracting disruptions of ionic homeostasis and initiating neuroprotective pathways. The DOR agonist D-Ala2-D-Leu2-Enkephalin (DADLE) promotes neuronal survival, mitigates apoptotic pathways, and protects neurons and glial cells from ischemia-induced cell death, thus making DADLE a promising therapeutic option for stroke. The significant amount of research regarding DORs and DADLE in the last decades also suggests their potential in treating other neurological disorders. METHODS: This review compiled relevant literature detailing the role of DORs and agonists in central nervous system function and neuropathologies. RESULTS: Several studies demonstrate potential mechanisms implicating a key interaction between DORs and DADLE in conferring neuroprotective benefits. A better understanding of DOR function in disease-specific contexts is critical to transitioning DOR agonists into the clinic as a therapy for stroke and other neurological diseases. CONCLUSION: Evidence-based studies support the potential of the delta-opioid family of receptors and its ligands in developing novel therapeutic strategies for stroke and other brain disorders.

Stem Cell-Induced Biobridges as Possible Tools to Aid Neuroreconstruction after CNS Injury.

Notch-induced mesenchymal stromal cells (MSCs) mediate a distinct mechanism of repair after brain injury by forming a biobridge that facilitates biodistribution of host cells from a neurogenic niche to the area of injury. We have observed the biobridge in an area between the subventricular zone and the injured cortex using immunohistochemistry and laser capture. Cells in the biobridge express high levels of extracellular matrix metalloproteinases (MMPs), specifically MMP-9, which co-localized with a trail of MSCs graft. The transplanted stem cells then become almost undetectable, being replaced by newly recruited host cells. This stem cell-paved biobridge provides support for distal migration of host cells from the subventricular zone to the site of injury. Biobridge formation by transplanted stem cells seems to have a fundamental role in initiating endogenous repair processes. Two major stem cell-mediated repair mechanisms have been proposed thus far: direct cell replacement by transplanted grafts and bystander effects through the secretion of trophic factors including fibroblast growth factor 2 (FGF-2), epidermal growth factor (EGF), stem cell factor (SCF), erythropoietin, and brain-derived neurotrophic factor (BDNF) among others. This groundbreaking observation of biobridge formation by transplanted stem cells represents a novel mechanism for stem cell mediated brain repair. Future studies on graft-host interaction will likely establish biobridge formation as a fundamental mechanism underlying therapeutic effects of stem cells and contribute to the scientific pursuit of developing safe and efficient therapies not only for traumatic brain injury but also for other neurological disorders. The aim of this review is to hypothetically extend concepts related to the formation of biobridges in other central nervous system disorders.