Therapeutic potential of stem cells in subarachnoid hemorrhage

Aneurysm rupture can result in subarachnoid hemorrhage,a condition with potentially severe consequences,such as disability and death.In the acute stage,early brain injury manifests as intracranial pressure elevation,global cerebral ischemia,acute hydrocephalus,and direct blood–brain contact due to aneurysm rupture.This may subsequently cause delayed cerebral infarction,often with cerebral vasospasm,significantly affecting patient outcomes.Chronic complications such as brain volume loss and chronic hydrocephalus can further impact outcomes.Investigating the mechanisms of subarachnoid hemorrhage-induced brain injury is paramount for identifying effective treatments.Stem cell therapy,with its multipotent differentiation capacity and anti-inflammatory effects,has emerged as a promising approach for treating previously deemed incurable conditions.This review focuses on the potential application of stem cells in subarachnoid hemorrhage pathology and explores their role in neurogenesis and as a therapeutic intervention in preclinical and clinical subarachnoid hemorrhage studies.

Health Indicator Bacteria That Is Useful for Risk Assessment of Peri-Implantitis

We established a novel identification method for oral Rothia species using one-step multiplex PCR analysis to investigate whether the monitoring of oral Rothia species levels is useful for peri-implantitis risk assessment, and to examine the oxygen concentration that these organisms need for growth in vitro. The mean number and proportion of Rothia aeria in peri-implant sulcus fluid (PISF) samples was significantly higher in the healthy implant group than in the peri-implantitis group (P < 0.05). Moreover, R. aeria under aerobic conditions vigorously grew compared with those under anaerobic conditions, and this organism grew only at the upper layer where high oxygen concentrations existed in a semi-liquid nutrient medium. Therefore, the monitoring of R. aeria levels may be suitable as an indicator of healthy peri-implant tissue conditions for the prevention of peri-implantitis.

Potential therapeutic molecular targets for blood-brain barrier disruption after subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage remains serious hemorrhagic stroke with high morbidities and mortalities.Aneurysm rupture causes arterial bleeding-induced mechanical brain tissue injuries and elevated intracranial pressure,followed by global cerebral ischemia.Post-subarachnoid hemorrhage ischemia,tissue injuries as well as extravasated blood components and the breakdown products activate microglia,astrocytes and Toll-like receptor 4,and disrupt blood-brain barrier associated with the induction of many inflammatory and other cascades.Once blood-brain barrier is disrupted,brain tissues are directly exposed to harmful blood contents and immune cells,which aggravate brain injuries furthermore.Blood-brain barrier disruption after subarachnoid hemorrhage may be developed by a variety of mechanisms including endothelial cell apoptosis and disruption of tight junction proteins.Many molecules and pathways have been reported to disrupt the blood-brain barrier after subarachnoid hemorrhage,but the exact mechanisms remain unclear.Multiple independent and/or interconnected signaling pathways may be involved in blood-brain barrier disruption after subarachnoid hemorrhage.This review provides recent understandings of the mechanisms and the potential therapeutic targets of blood-brain barrier disruption after subarachnoid hemorrhage.

Lessons from tenascin-C knockout mice and potential clinical application to subarachnoid hemorrhage

Subarachnoid hemorrhage by a ruptured cerebral aneurysmremains the most devastating cerebrovascular disorderswith high morbidity and mortality (Suzuki et al.,2017), which are mainly caused by early brain injury anddelayed cerebral ischemia. Despite many experimentaland clinical research efforts, the mechanisms of earlybrain injury as well as delayed cerebral ischemia remainunclarified. However, recent works have suggested thattenascin-C, which is a special type of secreted extracellularmatrix proteins, is promising as a novel therapeutictarget against post-subarachnoid hemorrhage early braininjury and delayed cerebral ischemia.

Implications of periostin in the development of subarachnoid hemorrhage-induced brain injuries

Target of research in subarachnoid hemorrhage（SAH）：The outcome of aneurysmal SAH remains poor despite advances in the diagnosis and treatment.Although many factors related to patients,aneurysms,and institutions,as well as physiological parameters and medical complications were reported as prognostic factors,

Matricellular proteins as possible biomarkers for early brain injury after aneurysmal subarachnoid hemorrhage

Aneurysmal subarachnoid hemorrhage remains devastating,and the most important determinant of poor outcome is early brain injury（EBI）.In clinical settings,as a surrogate marker of EBI,loss of consciousness at ictus,poor initial clinical grades,and some radiographic findings are used,but these markers are somewhat subjective.Thus,it is imperative to find biomarkers of EBI that have beneficial prognostic and therapeutic implications.In our opinion,an ideal biomarker is a molecule that is implicated in the pathogenesis of both EBI and subsequently developing delayed cerebral ischemia（DCI）,being a therapeutic target,and can be measured easily in the peripheral blood in an acute stage.A good candidate of such a biomarker is a matricellular protein,which is a secreted,inducible and multifunctional extracellular matrix protein.There are many kinds of matricellular proteins reported,but only tenascin-C,osteopontin,galectin-3 and periostin are reported relevant to EBI and DCI.Reliable biomarkers of EBI may stratify aneurysmal subarachnoid hemorrhage patients into categories of risk to develop DCI,and allow objective monitoring of the response to treatment for EBI and earlier diagnosis of DCI.This review emphasizes that further investigation of matricellular proteins as an avenue for biomarker discovery is warranted.

Periostin in cerebrovascular disease

Cerebrovascular diseases,which include ischemic and hemorrhagic strokes,remain serious conditions with high mortality and disability worldwide(He et al.,2018).Ischemic stroke accounts for around 80%of all strokes(He et al.,2018).Hemorrhagic stroke consisting of intracerebral hemorrhage and subarachnoid hemorrhage(SAH)occurs less frequently but may cause poorer outcomes than ischemic stroke(Ji et al.,2017;Luo et al.,2018).It is also well known that aneurysmal SAH may have delayed cerebral ischemia(DCI):thus aneurysmal SAH has both characteristics of hemorrhagic and ischemic strokes(Kanamaru et al.,2019).In spite of enormous efforts to improve outcomes,no conclusive treatment exists thus far,once stroke is completed.

Toll-like receptor 4 as a possible therapeutic target for delayed brain injuries after aneurysmal subarachnoid hemorrhage

Neuroinflammation is a well-recognized consequence of subarachnoid hemorrhage（SAH）, and Toll-like receptor（TLR） 4 may be an important therapeutic target for post-SAH neuroinflammation. Of the TLR family members, TLR4 is expressed in various cell types in the central nervous system, and is unique in that it can signal through both the myeloid differentiation primary-response protein 88-dependent and the toll receptor associated activator of interferon-dependent cascades to coordinate the maximal inflammatory response. TLR4 can be activated by many endogenous ligands having damage-associated molecular patterns including heme and fibrinogen at the rupture of an intracranial aneurysm, and the resultant inflammatory reaction and thereby tissue damages may furthermore activate TLR4. It is widely accepted that the excreted products of TLR4 signaling alter neuronal functions. Previous studies have focused on the pathway through nuclear factor（NF）-κΒ signaling among TLR4 signaling pathways as to the development of early brain injury（EBI） such as neuronal apoptosis and blood-brain barrier disruption, and cerebral vasospasm. However, many findings suggest that both pathways via NF-κΒ and mitogen-activated protein kinases may be involved in EBI and cerebral vasospasm development. To overcome EBI and cerebral vasospasm is important to improve outcomes after SAH, because both EBI and vasopasm are responsible for delayed brain injuries or delayed cerebral ischemia, the most important preventable cause of poor outcomes after SAH. Increasing evidence has shown that TLR4 signaling plays an important role in SAH-induced brain injuries. Better understanding of the roles of TLR4 signaling in SAH will facilitate development of new treatments.

Compression analysis of the gray and white matter of the spinal cord

The spinal cord is composed of gray matter and white matter.It is well known that the properties of these two tissues differ considerably.Spinal diseases often present with symptoms that are caused by spinal cord compression.Understanding the mechanical properties of gray and white matter would allow us to gain a deep understanding of the injuries caused to the spinal cord and provide information on the pathological changes to these distinct tissues in several disorders.Previous studies have reported on the physical properties of gray and white matter,however,these were focused on longitudinal tension tests.Little is known about the differences between gray and white matter in terms of their response to compression.We therefore performed mechanical compression test of the gray and white matter of spinal cords harvested from cows and analyzed the differences between them in response to compression.We conducted compression testing of gray matter and white matter to detect possible differences in the collapse rate.We found that increased compression(especially more than 50%compression)resulted in more severe injuries to both the gray and white matter.The present results on the mechanical differences between gray and white matter in response to compression will be useful when interpreting findings from medical imaging in patients with spinal conditions.

Tensile mechanical analysis of anisotropy and velocity dependence of the spinal cord white matter:a biomechanical study

In spinal cord injuries,external forces from various directions occur at various velocities.Therefore,it is important to physically evaluate whether the spinal cord is susceptible to damage and an increase in internal stress for external forces.We hypothesized that the spinal cord has mechanical features that vary under stress depending on the direction and velocity of injury.However,it is difficult to perform experiment because the spinal cord is very soft.There are no reports on the effects of multiple external forces.In this study,we used bovine spinal cord white matter to test and analyze the anisotropy and velocity dependence of the spinal cord.Tensile-vertical,tensile-parallel,shear-vertical,and shear-parallel tests were performed on the white matter in the fibrous direction(cranial to caudal).Strain rate in the experiment was 0.1,1,10,and 100/s.We calculated the Young’s modulus of the spinal cord.Results of the tensile and shear tests revealed that stress tended to increase when external forces were applied parallel to the direction of axon fibers,such as in tensile-vertical and shear-vertical tests.However,external forces those tear against the fibrous direction and vertically,such as in tensile-parallel and shear-parallel tests,were less likely to increase stress even with increased velocity.We found that the spinal cord was prone to external forces,especially in the direction of the fibers,and to be under increased stress levels when the velocity of external forces increased.From these results,we confirmed that the spinal cord has velocity dependence and anisotropy.The Institutional Animal Care and Use Committee of Yamaguchi University waived the requirement for ethical approval.

Tenascin-C in aneurysmal subarachnoid hemorrhage: deleterious or protective?

Subarachnoid hemorrhage（SAH）caused by the rupture of a cerebral aneurysm is a well-known devastating cerebrovascular disease.Post-SAH brain is vulnerable,associated with early brain injury（EBI;Suzuki,2015）.