Cell transplantation for the treatment of spinal cord injury–bone marrow stromal cells and choroid plexus epithelial cells

Transplantation of bone marrow stromal cells （BMSCs） enhanced the outgrowth of regenerating axons and promoted locomotor improvements of rats with spinal cord injury （SCI）. BMSCs did not survive long-term, disappearing from the spinal cord within 2-3 weeks after transplantation. Astrocyte-devoid areas, in which no astrocytes or oligodendrocytes were found, formed at the epicenter of the lesion. It was remarkable that numerous regenerating axons extended through such astrocyte-devoid areas. Regenerating axons were associated with Schwann cells embedded in extracellular matrices. Transplantation of choroid plexus epithelial cells （CPECs） also enhanced axonal regeneration and locomotor improvements in rats with SCI. Although CPECs disappeared from the spinal cord shortly after transplantation, an extensive outgrowth of regenerating axons occurred through astrocyte-devoid areas, as in the case of BMSC transplantation. These findings suggest that BMSCs and CPECs secret neurotrophic factors that promote tissue repair of the spinal cord, including axonal regeneration and reduced cavity formation. This means that transplantation of BMSCs and CPECs promotes ＂intrinsic＂ ability of the spinal cord to regenerate. The treatment to stimu- late the intrinsic regeneration ability of the spinal cord is the safest method of clinical application for SCI. It should be emphasized that the generally anticipated long-term survival, proliferation and differentiation of transplanted cells are not necessarily desirable from the clinical point of view of safety.

Release of interleukin-10 and neurotrophic factors in the choroid plexus：possible inductors of neurogenesis following copolymer-1 immunization after cerebral ischemia

Copolymer-1（Cop-1） is a peptide with immunomodulatory properties, approved by the Food and Drug Administration of United States in the treatment of multiple sclerosis. Cop-1 has been shown to exert neuroprotective effects and induce neurogenesis in cerebral ischemia models. Nevertheless, the mechanism involved in the neurogenic action of this compound remains unknown. The choroid plexus（CP） is a network of cells that constitute the interphase between the immune and central nervous systems, with the ability to mediate neurogenesis through the release of cytokines and growth factors. Therefore, the CP could play a role in Cop-1-induced neurogenesis. In order to determine the participation of the CP in the induction of neurogenesis after Cop-1 immunization, we evaluated the gene expression of various growth factors（brain-derived neurotrophic factor, insulin-like growth factor 1, neurotrophin-3） and cytokines（tumor necrosis factor alpha, interferon-gamma, interleukin-4（IL-4）, IL-10 and IL-17）, in the CP at 14 days after ischemia. Furthermore, we analyzed the correlation between the expression of these genes and neurogenesis. Our results showed that Cop-1 was capable of stimulating an upregulation in the expression of the genes encoding for brain-derived neurotrophic factor, insulin-like growth factor 1, neurotrophin-3 and IL-10 in the CP, which correlated with an increase in neurogenesis in the subventricular and subgranular zone. As well, we observed a downregulation of IL-17 gene expression. This study demonstrates the effect of Cop-1 on the expression of growth factors and IL-10 in the CP, in the same way, presents a possible mechanism involved in the neurogenic effect of Cop-1.

The expressions of brain-derived neurotrophic factor and nerve growth factor in purified rat choroid plexus epithelial cells in vitro

Objective： To detect the expressions of brain-derived neurotrophic factor （BDNF） and nerve growth factor （NGF） in purified rat choroid plexus epithelial cells in vitro. Methods： Primary and passage choroid plexus epithelial cells were obtained from newborn, one-day Spragne-Dawley rats. The expressions of BDNF and NGF were measured by qRT-PCR and Western blottingting. The secretions of BDNF and NGF were detected by ELISA. Cell supematants of primary cells, purified cells and passage 1 cells were harvested. Results： The expression of BDNF in the purified cells was significantly lower than that in the primary cells （P〈0.05）, and it in the primary cells and the purified cells was significantly higher than that in the passage 1 cells （P〈0.05）. The expression of NGF was significantly higher in the purified cells than in the primary cells and the passage 1 cells （P〈0.05）. It in the passage 1 cells was significantly higher than that in the primary cells （P〈0.05）. Conclusion： The time of CPECs transplantation for central nervous system diseases should be selected based on their secretory function and features,which could lead to better and more effective treatment.

The choroid plexus-cerebrospinal fluid interface in Alzheimer's disease:more than just a barrier

The choroid plexus is a complex structure which hangs inside the ventricles of the brain and consists mainly of choroid plexus epithelial（CPE） cells surrounding fenestrated capillaries.These CPE cells not only form an anatomical barrier,called the blood-cerebrospinal fluid barrier（BCSFB）,but also present an active interface between blood and cerebrospinal fluid（CSF）.CPE cells perform indispensable functions for the development,maintenance and functioning of the brain.Indeed,the primary role of the choroid plexus in the brain is to maintain homeostasis by secreting CSF which contains different molecules,such as nutrients,neurotrophins,and growth factors,as well as by clearing toxic and undesirable molecules from CSF.The choroid plexus also acts as a selective entry gate for leukocytes into the brain.Recent findings have revealed distinct changes in CPE cells that are associated with aging and Alzheimer＇s disease.In this review,we review some recent findings that highlight the importance of the CPE-CSF system in Alzheimer＇s disease and we summarize the recent advances in the regeneration of brain tissue through use of CPE cells as a new therapeutic strategy.

Neural differentiation of choroid plexus epithelial cells:role of human traumatic cerebrospinal fluid

As the key producer of cerebrospinal fluid（CSF）,the choroid plexus（CP） provides a unique protective system in the central nervous system.CSF components are not invariable and they can change based on the pathological conditions of the central nervous system.The purpose of the present study was to assess the effects of non-traumatic and traumatic CSF on the differentiation of multipotent stem-like cells of CP into the neural and/or glial cells.CP epithelial cells were isolated from adult male rats and treated with human non-traumatic and traumatic CSF.Alterations in m RNA expression of Nestin and microtubule-associated protein（MAP2）,as the specific markers of neurogenesis,and astrocyte marker glial fibrillary acidic protein（GFAP） in cultured CP epithelial cells were evaluated using quantitative real-time PCR.The data revealed that treatment with CSF（non-traumatic and traumatic） led to increase in m RNA expression levels of MAP2 and GFAP.Moreover,the expression of Nestin decreased in CP epithelial cells treated with non-traumatic CSF,while treatment with traumatic CSF significantly increased its m RNA level compared to the cells cultured only in DMEM/F12 as control.It seems that CP epithelial cells contain multipotent stem-like cells which are inducible under pathological conditions including exposure to traumatic CSF because of its compositions.

Transplanted choroidal plexus epithelial cells can integrate with organotypic spinal cord slices into a new system

This study aimed to evaluate the integration of transplanted choroidal plexus epithelial cells with organotypic spinal cord slices.Organotypic spinal cord slices,normally cultured for 6 days,were divided into control group(Ctrl)and transplanted group(T).The choroidal plexus epithelial cells were dissociated and primary cultured(C group).The choroidal plexus epithelial cells cultured for 6–7 days were labeled by 1,1’-dioctadecyl-3,3,3’,3’-tetramethylindocarbocyanineperchlorate(CM-Dil),and were identified by transthyretin(TTR)in immunocytochemistry.They were adjusted to the density of 0.5–1×107/ml,then 2μl cells suspension were transplanted to the spinal cord slices in the T group.The same amount of basal medium was dripped on the spinal cord slices in the Ctrl group.After 14 days of transplantation,the differentiations into neurons and astrocytes,and the synapses were identified by immunofluorescence histochemistry.At the same time,the ratios of cell differentiations and synapses in new system,and the changes of MAPK signaling pathway were tested by western blotting.The choroid plexus epithelial cells were well labeled by CM-Dil and were immune-stained by TTR in immunocytochemistry.The choroid plexus epithelial cells bodies were small when transplanted on the spinal cord slices,but big when transplanted on the polyester membrane inserts.The transplanted cells could differentiate into astrocytes,and possibly differentiate into neurons,and there were a large number of synaptophysin positive vesicles between transplanted cells and organotypic spinal cord slices in immunofluorescence histochemistry.The levels of GFAP,TUB-III and synaptophysin in the T group were higher than which in the Ctrl and C groups in western blotting(P<0.05).And the ratios of p-JNK/JNK and p-P38/P38 in the T group were significantly lower than which in the Ctrl and C groups(P<0.05).But the ratio of p-ERK/ERK in the three groups was of no significant difference.The transplanted choroidal plexus epithelial cells can integrate with organotypic spinal cord slices into a new system.

Choroid Plexus Papilloma of the Fourth Ventricle Developing Postoperative Intracranial and Rectal Hemorrhage Three Times： A Case Report

Introduction Choroid plexus papilloma （CPP） is a relatively rare, slow-growing benign tumor （WHO level I）. Recently, an adult patient with fourth ventricle choroid plexus papilloma received surgery via a suboc- cipital midline approach in our hospital. It has been rare in clinical practice to see postoperative hemorrhage occurring in the same patient 3 times. The causes of the hemorrhage were analyzed based on literature regarding postoperative hemorrhage in choroid plexus papilloma and in intracranial tumors. The case involved in our study is described and detailed in the following.

Endoscopic Third Ventriculostomy with or without Choroid Plexus Coagulation for Treatment of Hydrocephalus in Guinea: Analysis of 76 Cases in the Department of Neurosurgery of Kipe, Conakry

In low-income countries, endoscopic third ventriculostomy (ETV) with or without choroid plexus coagulation (CPC) is an increasingly accepted alternative to shunt therapy in adult and pediatric hydrocephalus. The authors report the result of this treatment in Conakry in a mixed population of adult and pediatric patients regardless of the etiology of the hydrocephalus. A retrospective study was conducted on 76 patients undergoing 89 ETV from January 2013 to September 2020. The predominant group of patients was infants less than one year with a mean age of 4.3 months and extremes of 1 - 8 months. The H/F sex ratio was 1.7/1. All patients presented acutely with signs of high intracranial pressure. Post-infectious causes and malformations and tumors were the main etiologies, respectively 21%, 47.3%, and 15.7%. The mean duration of the endoscopic procedures was 49.93 ± 10.9 mm, associated with a choroid plexus coagulation in 42% of cases. The complication rate in the first month was 22%, with CSF leak (5%) and death (11%) accounting for the majority. At three months, the complications rates were 45%, with 14.4% closed stroma, 6% epilepsy, and 24% mortality. The mean follow-up was 28 months (range 2 - 53), and the global success rate of 61%. Our study, with its limitations, shows that ETV with CPC is a safe primary approach for the treatment of hydrocephalus in low-income countries regardless of the etiology and the age of the patients.

High Blood Pressure Effects on the Brain Barriers and Choroid Plexus Secretion

High blood pressure produces ventricular dilation, variations in circumventricular organs and changes in the cerebrospinal fluid compositions. On the other hand, chronic hypertension in spontaneously hypertensive rats can cause changes in the integrity of the brain barriers: blood-cerebrospinal fluid barrier and blood brain barrier. The permeability of the brain barriers can be studied by using transthyretin and S-100β. In the present work we study the integrity of the brain barrier and the choroid plexus function variations in arterial hypertension. Control rats and spontaneously hypertensive rats were used and the choroid plexus were processed by immunohistochemistry with anti-transthyretin and anti-vasopressin. Western blot was also performed in cerebrospinal fluid, serum and choroid plexus using anti-S-100β, anti-transthyretin. The accumulation of transthyretin immunoreactive was bigger in spontaneously hypertensive rats with respect to the control. Vasopressin was also higher in spontaneously hypertensive rats with respect to the control. Western blot showed that transthyretin tetramer was higher in the spontaneously hypertensive rats than in the control rats. The expression of transthyretin monomer was lower in hypertensive rats than the control in the cerebrospinal fluid, the transthyretin monomer reaction in the blood was stronger in hypertensive than in control rats. Western blot for the S-100 β showed an increase in blood and cerebrospinal fluid of hypertensive rats. The high blood pressure produces a disruption of the blood brain barrier and blood to cerebrospinal fluid barrier that allows extravasations from the cerebrospinal fluid to the blood and from the blood to the cerebrospinal fluid.

Clinical analysis of four cases of intracranial choroid plexus cysts

Objective To summarize and report the diagnosis and management of choroid plexus cysts. Methods The clinical data of 4 choroid plexus cysts cases from March 2005 and 2010 March were analyzed retrospectively,and pathology appearances,surgical treatment were evaluated. Results Intracranial cystic lesion

Mechanism of Cu entry into the brain:many unanswered questions

Brain tissue requires high amounts of copper(Cu)for its key physiological processes,such as energy production,neurotransmitter synthesis,maturation of neuropeptides,myelination,synaptic plasticity,and radical scavenging.The requirements for Cu in the brain vary depending on specific brain regions,cell types,organism age,and nutritional status.Cu imbalances cause or contribute to several life-threatening neurologic disorders including Menkes disease,Wilson disease,Alzheimer’s disease,Parkinson’s disease,and others.Despite the well-established role of Cu homeostasis in brain development and function,the mechanisms that govern Cu delivery to the brain are not well defined.This review summarizes available information on Cu transfer through the brain barriers and discusses issues that require further research.

Choroid plexus CCL2‒CCR2 signaling orchestrates macrophage recruitment and cerebrospinal fluid hypersecretion in hydrocephalus

The choroid plexus(ChP)serves as the principal origin of cerebrospinal fluid(CSF).CSF hypersecretion due to ChP inflammation has emerged as an important pathogenesis of hydrocephalus recently.Nevertheless,the precise mechanisms of ChP inflammation and the ensuing CSF hypersecretion in hydrocephalus remain ill-defined.In the present study,we elucidate the critical role of macrophages in the pathogenesis of ChP inflammation.Specifically,we identify the chemokine CCL2,released by ChP epithelial cells,recruits CCR2+monocytes to the ChP thereby inciting hydrocephalus pathogenesis.The accumulated ChP macrophages increase the inflammation in ChP epithelial cells through TNF-α/TNFR1/NF-κB signaling cascade,thereby leading to CSF hypersecretion.Strikingly,augmentation of ChP‒CCL2 using an adeno-associated viral approach(AAV)exacerbates macrophage recruitment,activation,and ventriculomegaly in rat PHH models.Systemic application of Bindarit,a specific CCL2 inhibitor,significantly inhibits ChP macrophage infiltration and activation and reduces CSF secretion rate.Furthermore,the administration of CCR2 antagonist(INCB 3284)reduces ChP macrophage accumulation and ventriculomegaly.This study not only unveils the ChP CCL2‒CCR2 signaling in the pathophysiology of hydrocephalus but also unveils Bindarit as a promising therapeutic choice for the management of posthemorrhagic hydrocephalus.

In situ staining of the primo vascular system in the ventricles and subarachnoid space of the brain by trypan blue injection into the lateral ventricle

We examined a new method for visualization of the primo vascular system in the rat brain involving lateral ventricle injection of trypan blue. Results showed that the primo vascular system in the lateral ventricles and arachnoid mater of the brain were preferentially stained relative to blood vessels and fascia. The primo-vessels along blood vessels in the brain were clearly exhibited. In addition, the primo vascular system was evident between the fourth ventricle and the quadrigeminal cistern. Our experimental findings indicate that this new technique of lateral ventricle injection of trypan blue can visualize the primo vascular system in lateral ventricles and arachnoid mater of rats in situ.

The brain as a source and a target of prolactin in mammals

Prolactin is a polypeptide hormone associated with an extensive variety of biological functions.Among the roles of prolactin in vertebrates,some were preserved throughout evolution.This is the case of its function in the brain,where prolactin receptors,are expressed in different structures of the central nervous system.In the brain,prolactin actions are principally associated with reproduction and parental behavior,and involves the modulation of adult neurogenesis,neuroprotection,and neuroplasticity,especially during pregnancy,thereby preparing the brain to parenthood.Prolactin is mainly produced by specialized cells in the anterior pituitary gland.However,during vertebrate evolution many other extrapituitary tissues do also produce prolactin,like the immune system,endothelial cells,reproductive structures and in several regions of the brain.This review summarizes the relevance of prolactin for brain function,the sources of prolactin in the central nervous system,as well as its local production and secretion.A highlight on the impact of prolactin in human neurological diseases is also provided.

Choroid plexus trophic factors in the developing and adult brain

The choroid plexus （CP）, localized in brain ventricles, is the major source of cerebrospinal fluid （CSF） and participates in the blood-CSF barrier. It is essential for brain immunosurveillance and the clearance of toxics, and for brain development and activity. Indeed, the CP secretes a large variety of trophic factors in the CSF that impact the entire brain. These factors are mainly implicated in neurogenesis, but also in the maintenance of brain functions and the vasculature. In this mini-review, we provide an overview of the various trophic factors secreted by the CP in the CSF, and describe their roles in the developing, adult and diseased brain.

Danshen-Chuanxiongqin Injection attenuates cerebral ischemic stroke by inhibiting neuroinflammation via the TLR2/ TLR4-MyD88-NF-κB Pathway in tMCAO mice

Danshen-Chuanxiongqin Injection(DCI)is a commonly used traditional Chinese medicine for the treatment of cerebral ischemic stroke in China.However,its underlying mechanisms remain completely understood.The current study was designed to explore the protective mechanisms of DCI against cerebral ischemic stroke through integrating whole-transcriptome sequencing coupled with network pharmacology analysis.First,using a mouse model of cerebral ischemic stroke by transient middle cerebral artery occlusion(tMCAO),we found that DCI(4.10 mL·kg−1)significantly alleviated cerebral ischemic infarction,neurological deficits,and the pathological injury of hippocampal and cortical neurons in mice.Next,the whole-transcriptome sequencing was performed on brain tissues.The cerebral ischemia disease(CID)network was constructed by integrating transcriptome sequencing data and cerebrovascular disease-related genes.The results showed CID network was imbalanced due to tMCAO,but a recovery regulation was observed after DCI treatment.Pathway analysis of the key genes with recovery efficiency showed that the neuroinflammation signaling pathway was highly enriched,while the TLR2/TLR4-MyD88-NF-κB pathway was predicted to be affected.Consistently,the in vivo validation experiments confirmed that DCI exhibited protective effects against cerebral ischemic stroke by inhibiting neuroinflammation via the TLR2/TLR4-MyD88-NF-κB pathway.More interestingly,DCI markedly suppressed the neutrophils infiltrated into the brain parenchyma via the choroid plexus route and showed anti-neuroinflammation effects.In conclusion,our results provide dependable evidence that inhibiting neuroinflammation via the TLR2/TLR4-MyD88-NF-κB pathway is the main mechanism of DCI against cerebral ischemic stroke in mice.