A case of ectopic pancreas of the stomach accompanied by intraductal papillary mucinous neoplasm with GNAS mutation.

BACKGROUND: Ectopic pancreas is basically a benign disease and is not always necessary to be removed. However, all types of neoplasms occurring in the normal pancreas such as ductal adenocarcinomas and intraductal papillary mucinous neoplasms (IPMNs) may develop even within ectopic pancreas. We recently encountered an extremely rare case of ectopic pancreas in the gastric antrum associated with IPMN possessing a GNAS mutation. CASE PRESENTATION: A 71-year-old Japanese woman complained of epigastric pain. Computed tomography and upper gastrointestinal endoscopy showed an intramural cystic mass in the antrum of the stomach. Endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) biopsy did not give a definitive diagnosis, and the patient underwent resection of the lesion. Histology of the resected specimen showed that the gastric intramural lesion was ectopic pancreas. Moreover, the lesion contained dilated duct components with tubulo-villous epithelial proliferation consistent with pancreatic IPMN. Since the covering epithelial cells had highly atypical nuclei, the lesion was diagnosed as IPMN with high grade dysplasia. Immunohistochemistry showed that the IPMN component showed to be MUC2-, MUC5AC-, and CDX2-positive but MUC1- and MUC6-negative. Mutational analyses using genomic DNA revealed that the IPMN component had a mutation of GNAS at exon 8 (Arg201Cys). CONCLUSION: We finally diagnosed this case as gastric ectopic pancreas accompanied by intestinal type IPMN with high grade dysplasia possessing GNAS mutation. Although there were 17 cases of ectopic pancreas with IPMN including 6 cases of gastric ones reported in the English literature, this is the first case of ectopic pancreas with IPMN which was proved to have GNAS mutation. Intimate preoperative examinations including imaging analyses and EUS-FNA biopsy/cytology are recommended to decide whether the lesion has to be resected or not even if they are not effective for getting the right diagnosis.

How Long Are Reperfusion Therapies Beneficial for Patients after Stroke Onset? Lessons from Lethal Ischemia Following Early Reperfusion in a Mouse Model of Stroke.

Ischemic stroke caused by cerebral artery occlusion induces neurological deficits because of cell damage or death in the central nervous system. Given the recent therapeutic advances in reperfusion therapies, some patients can now recover from an ischemic stroke with no sequelae. Currently, reperfusion therapies focus on rescuing neural lineage cells that survive in spite of decreases in cerebral blood flow. However, vascular lineage cells are known to be more resistant to ischemia/hypoxia than neural lineage cells. This indicates that ischemic areas of the brain experience neural cell death but without vascular cell death. Emerging evidence suggests that if a vascular cell-mediated healing system is present within ischemic areas following reperfusion, the therapeutic time window can be extended for patients with stroke. In this review, we present our comments on this subject based upon recent findings from lethal ischemia following reperfusion in a mouse model of stroke.

Itraconazole treatment of primary malignant melanoma of the vagina evaluated using positron emission tomography and tissue cDNA microarray: a case report.

BACKGROUND: Primary malignant melanoma of the vagina is extremely rare, with a poorer prognosis than cutaneous malignant melanoma. Previous studies have explored the repurposing of itraconazole, a common oral anti-fungal agent, for the treatment of various cancers. Here, we describe a patient with metastatic, unresectable vaginal malignant melanoma treated with 200 mg oral itraconazole twice a day in a clinical window-of-opportunity trial. CASE PRESENTATION: A 64-year-old Japanese woman with vaginal and inguinal tumours was referred to our institution. On the basis of an initial diagnosis of vaginal cancer metastatic to the inguinal lymph nodes, we treated her with itraconazole in a clinical trial until the biopsy and imaging study results were obtained. During this period, biopsies were performed three times, and 18F-fluoro-deoxyglucose positron emission tomography (FDG/PET)-computed tomography (CT) was performed twice. Biopsy results confirmed the diagnosis of primary malignant melanoma of the vagina. Imaging studies revealed metastases to multiple sites, including the brain, for which she underwent gamma-knife radiosurgery. During the window period before nivolumab initiation, the patient received itraconazole for 30 days. Within a week of itraconazole initiation, pain in the inguinal nodes was ameliorated. PET-CT on days 6 and 30 showed a reduction in tumour size and FDG uptake, respectively. The biopsied specimens obtained on days 1, 13, and 30 were subjected to cDNA microarray analysis, which revealed a 100-fold downregulation in the transcription of four genes: STATH, EEF1A2, TTR, and CDH2. After 12 weeks of nivolumab administration, she developed progressive disease and grade 3 immune-related hepatitis. Discontinuation of nivolumab resulted in the occurrence of left pelvic and inguinal pain. Following re-challenge with itraconazole, the patient has not reported any pain for 4 months. CONCLUSION: The findings of this case suggest that itraconazole is a potential effective treatment option for primary malignant melanoma of the vagina. Moreover, we identified potential itraconazole target genes, which could help elucidate the mechanism underlying this disease and potentially aid in the development of new therapeutic agents.

[A case of liver and bone metastasis from gastrointestinal stromal tumor treated using imatinib].

A 71-year-old man with an unspecified gastric tumor had undergone gastrectomy 15 years previously, and in 2012, positron emission tomography-computed tomography(PET-CT)showed the presence of a bulky tumor located in the right hepatic liver and multiple bone metastases. Although it was unclear whether the tumor was primary or metastatic, liver biopsy was performed. Immunostaining revealed that the lesions were positive for c-kit, and therefore, these lesions were diagnosed as liver and bone metastases from gastric gastrointestinal stromal tumor(GIST). Chemotherapy with imatinib was initiated. PET-CT performed after 3 months revealed a marked decrease in fluorodeoxyglucose(FDG)accumulation. The patient is alive at present with no recurrence.

[A case of jejunum cancer diagnosed by anemia].

The patient was an 85-year-old woman who was referred to a nearby clinic complaining of shortness of breath. Blood test showed anemia, and she was referred to our hospital for identification of the source of bleeding. Upper and lower endoscopy were performed and revealed no abnormalities. Computed tomography (CT) was performed and showed a >7- cm thickening in the wall of her small intestine. The presence of small bowel cancer was suspected. Oral double-balloon endoscopy was performed and showed a near-circumferential ulcerative lesion in the jejunum that was causing small bowel stenosis. A biopsy yielded a diagnosis of signet-ring cell carcinoma. We performed a partial resection of the patient's jejunum. The histopathological diagnosis of the resected specimen (according to the Union for International Cancer Control [UICC]TNM Classification of Malignant Tumours, seventh edition) was poorly differentiated adenocarcinoma, signet-ring cell carcinoma, mucinous carcinoma, T2 (MP), N0, H0, P0, stage I. 7 months after surgery, the patient is alive without recurrence. The incidence of small intestinal cancer is generally reported to be 1% to 2% of all gastrointestinal malignancies. We report a rare case in which cancer of the small intestine was identified during investigation of anemia.

[Liver damage detected after a hepatectomy for liver metastasis after 12 courses of mFOLFOX6 therapy as an adjuvant chemotherapy for colorectal cancer].

The FOLFOX regimen is approved as an adjuvant therapy for colon cancer in Japan. We report a case of pathological damage in the resected non-cancerous liver after 12 courses of mFOLFOX6 therapy as an adjuvant therapy for stage IIIb colon cancer. A 45-year-old man underwent laparoscopic right hemicolectomy for ascending colon cancer. After completing 12 courses of adjuvant mFOLFOX6 therapy, this patient exhibited liver metastasis. Lateral segment resection was performed, and pathological examination of the resected specimen revealed irregular sinusoidal dilatation and cell apoptosis in the non-tumorous part of the liver. This was probably due to the effects of mFOLFOX6. We stress that when resectable liver metastasis is found after 12 courses of FOLFOX as an adjuvant therapy for colon cancer, careful attention should be paid during surgery and during postsurgical management because there may be damage in the remnant liver.

Bone marrow mononuclear cells promote proliferation of endogenous neural stem cells through vascular niches after cerebral infarction.

Increasing evidence shows that administration of bone marrow mononuclear cells (BMMCs) is a potential treatment for various ischemic diseases, such as ischemic stroke. Although angiogenesis has been considered primarily responsible for the effect of BMMCs, their direct contribution to endothelial cells (ECs) by being a functional elements of vascular niches for neural stem/progenitor cells (NSPCs) has not been considered. Herein, we examine whether BMMCs affected the properties of ECs and NSPCs, and whether they promoted neurogenesis and functional recovery after stroke. We compared i.v. transplantations 1 x 10(6) BMMCs and phosphate-buffered saline in mice 2 days after cortical infarction. Systemically administered BMMCs preferentially accumulated at the postischemic cortex and peri-infarct area in brains; cell proliferation of ECs (angiogenesis) at these regions was significantly increased in BMMCs-treated mice compared with controls. We also found that endogenous NSPCs developed in close proximity to ECs in and around the poststroke cortex and that ECs were essential for proliferation of these ischemia-induced NSPCs. Furthermore, BMMCs enhanced proliferation of NSPCs as well as ECs. Proliferation of NSPCs was suppressed by additional treatment with endostatin (known to inhibit proliferation of ECs) following BMMCs transplantation. Subsequently, neurogenesis and functional recovery were also promoted in BMMCs-treated mice compared with controls. These results suggest that BMMCs can contribute to the proliferation of endogenous ischemia-induced NSPCs through vascular niche regulation, which includes regulation of endothelial proliferation. In addition, these results suggest that BMMCs transplantation has potential as a novel therapeutic option in stroke treatment.

Immunodeficiency reduces neural stem/progenitor cell apoptosis and enhances neurogenesis in the cerebral cortex after stroke.

Acute inflammation in the poststroke period exacerbates neuronal damage and stimulates reparative mechanisms, including neurogenesis. However, only a small fraction of neural stem/progenitor cells survives. In this report, by using a highly reproducible model of cortical infarction in SCID mice, we examined the effects of immunodeficiency on reduction of brain injury, survival of neural stem/progenitor cells, and functional recovery. Subsequently, the contribution of T lymphocytes to neurogenesis was evaluated in mice depleted for each subset of T lymphocyte. SCID mice revealed the reduced apoptosis and enhanced proliferation of neural stem/progenitor cells induced by cerebral cortex after stroke compared with the immunocompetent wild-type mice. Removal of T lymphocytes, especially the CD4(+) T-cell population, enhanced generation of neural stem/progenitor cells, followed by accelerated functional recovery. In contrast, removal of CD25(+) T cells, a cell population including regulatory T lymphocytes, impaired functional recovery through, at least in part, suppression of neurogenesis. Our findings demonstrate a key role of T lymphocytes in regulation of poststroke neurogenesis and indicate a potential novel strategy for cell therapy in repair of the central nervous system.

Endothelial cells support survival, proliferation, and neuronal differentiation of transplanted adult ischemia-induced neural stem/progenitor cells after cerebral infarction.

Transplantation of neural stem cells (NSCs) has been proposed as a therapy for a range of neurological disorders. To realize the potential of this approach, it is essential to control survival, proliferation, migration, and differentiation of NSCs after transplantation. NSCs are regulated in vivo, at least in part, by their specialized microenvironment or "niche." In the adult central nervous system, neurogenic regions, such as the subventricular and subgranular zones, include NSCs residing in a vascular niche with endothelial cells. Although there is accumulating evidence that endothelial cells promote proliferation of NSCs in vitro, there is no description of their impact on transplanted NSCs. In this study, we grafted cortex-derived stroke-induced neural stem/progenitor cells, obtained from adult mice, onto poststroke cortex in the presence or absence of endothelial cells, and compared survival, proliferation, and neuronal differentiation of the neural precursors in vivo. Cotransplantation of endothelial cells and neural stem/progenitor cells increased survival and proliferation of ischemia-induced neural stem/progenitor cells and also accelerated neuronal differentiation compared with transplantation of neural precursors alone. These data indicate that reconstitution of elements in the vascular niche enhances transplantation of adult neural progenitor cells.

Recurrent uterine serous carcinoma with a germline pathogenic BRCA2 variant treated using olaparib: A case report.

A germline pathogenic variant in BRCA2 was secondarily found through genomic sequencing of uterine serous carcinoma. Clinical response to olaparib was observed in recurrent uterine serous carcinoma with a germline BRCA2 mutation. Here, we report, for the first time, a long-term clinical response to olaparib in a patient with uterine serous carcinoma and a germline pathogenic BRCA2 variant.

CD44 expression in stem cells and niche microglia/macrophages following ischemic stroke.

BACKGROUND: CD44, an adhesion molecule in the hyaluronate receptor family, plays diverse and important roles in multiple cell types and organs. Increasing evidence is mounting for CD44 expression in various types of stem cells and niche cells surrounding stem cells. However, the precise phenotypes of CD44+ cells in the brain under pathologic conditions, such as after ischemic stroke, remain unclear. METHODS: In the present study, using a mouse model for cerebral infarction by middle cerebral artery (MCA) occlusion, we examined the localization and traits of CD44+ cells. RESULTS: In sham-mice operations, CD44 was rarely observed in the cortex of MCA regions. Following ischemic stroke, CD44+ cells emerged in ischemic areas of the MCA cortex during the acute phase. Although CD44 at ischemic areas was, in part, expressed in stem cells, it was also expressed in hematopoietic lineages, including activated microglia/macrophages, surrounding the stem cells. CD44 expression in microglia/macrophages persisted through the chronic phase following ischemic stroke. CONCLUSIONS: These data demonstrate that CD44 is expressed in stem cells and cells in the niches surrounding them, including inflammatory cells, suggesting that CD44 may play an important role in reparative processes within ischemic areas under neuroinflammatory conditions; in particular, strokes.

Epithelioid glioblastoma with microglia features: potential for novel therapy.

Epithelioid glioblastoma (E-GBM) was recently designated as a subtype of glioblastoma (GBM) by the World Health Organization (2016). E-GBM is an aggressive and rare variant of GBM that primarily occurs in children and young adults. Although most characterized cases of E-GBM harbor a mutation of the BRAF gene in which valine (V) is substituted by glutamic acid (E) at amino acid 600 (BRAF-V600E), in addition to telomerase reverse transcriptase promoter mutations and homozygous CDKN2A/B deletions, the origins and cellular nature of E-GBM remain uncertain. Here, we present a case of E-GBM that exhibits antigenic and functional traits suggestive of microglia. Although no epithelial [e.g., CKAE1/3, epithelial membrane antigen (EMA)] or glial (e.g., GFAP, Olig2) markers were detected by immunohistochemical staining, the microglial markers CD68 and Iba1 were readily apparent. Furthermore, isolated E-GBM-derived tumor cells expressed microglial/macrophage-related genes including cytokines, chemokines, MHC class II antigens, lysozyme and the critical functional receptor, CSF-1R. Isolated E-GBM-derived tumor cells were also capable of phagocytosis and cytokine production. Treating E-GBM-derived tumor cells with the BRAF-V600E inhibitor, PLX4032 (vemurafenib), resulted in a dose-dependent reduction in cell viability that was amplified by addition of the CSF-1R inhibitor, BLZ945. The present case provides insight into the cellular nature of E-GBM and introduces several possibilities for effective targeted therapy for these patients.

Early Reperfusion Following Ischemic Stroke Provides Beneficial Effects, Even After Lethal Ischemia with Mature Neural Cell Death.

Ischemic stroke is a critical disease caused by cerebral artery occlusion in the central nervous system (CNS). Recent therapeutic advances, such as neuroendovascular intervention and thrombolytic therapy, have allowed recanalization of occluded brain arteries in an increasing number of stroke patients. Although previous studies have focused on rescuing neural cells that still survive despite decreased blood flow, expanding the therapeutic time window may allow more patients to undergo reperfusion in the near future, even after lethal ischemia, which is characterized by death of mature neural cells, such as neurons and glia. However, it remains unclear whether early reperfusion following lethal ischemia results in positive outcomes. The present study used two ischemic mouse models-90-min transient middle cerebral artery occlusion (t-MCAO) paired with reperfusion to induce lethal ischemia and permanent middle cerebral artery occlusion (p-MCAO)-to investigate the effect of early reperfusion up to 8 w following MCAO. Although early reperfusion following 90-min t-MCAO did not rescue mature neural cells, it preserved the vascular cells within the ischemic areas at 1 d following 90-min t-MCAO compared to that following p-MCAO. In addition, early reperfusion facilitated the healing processes, including not only vascular but also neural repair, during acute and chronic periods and improved recovery. Furthermore, compared with p-MCAO, early reperfusion after t-MCAO prevented behavioral symptoms of neurological deficits without increasing negative complications, including hemorrhagic transformation and mortality. These results indicate that early reperfusion provides beneficial effects presumably via cytoprotective and regenerative mechanisms in the CNS, suggesting that it may be useful for stroke patients that experienced lethal ischemia.

Ischemia-Induced Multipotent Stem Cells Isolated from Stroke Patients Exhibit Higher Neurogenic Differentiation Potential than Bone Marrow-Derived Mesenchymal Stem Cells.

Perivascular areas of the brain harbor multipotent stem cells. We recently demonstrated that after a stroke, brain pericytes exhibit features of multipotent stem cells. Moreover, these ischemia-induced multipotent stem cells (iSCs) are present within ischemic areas of the brain of patients diagnosed with stroke. Although increasing evidence shows that iSCs have traits similar to those of mesenchymal stem cells (MSCs), the phenotypic similarities and differences between iSCs and MSCs remain unclear. In this study, we used iSCs extracted from stroke patients (h-iSCs) and compared their neurogenic potential with that of human MSCs (h-MSCs) in vitro. Microarray analysis, fluorescence-activated cell sorting, immunohistochemistry, and multielectrode array were performed to compare the characteristics of h-iSCs and h-MSCs. Although h-iSCs and h-MSCs had similar gene expression profiles, the percentage expressing the neural stem/progenitor cell marker nestin was significantly higher in h-iSCs than in h-MSCs. Consistent with these findings, h-iSCs, but not h-MSCs, differentiated into electrophysiologically functional neurons. In contrast, although both h-iSCs and h-MSCs were able to differentiate into several mesodermal lineages, including adipocytes, osteocytes, and chondrocytes, the potential of h-iSCs to differentiate into adipocytes and osteocytes was relatively low. These results suggest that compared with h-MSCs, h-iSCs predominantly exhibit neural rather than mesenchymal lineages. In addition, these results indicate that h-iSCs have the potential to repair the injured brain of patients with stroke by directly differentiating into neuronal lineages.

Isolation and characterization of neural stem/progenitor cells from post-stroke cerebral cortex in mice.

The CNS has the potential to marshal strong reparative mechanisms, including activation of endogenous neurogenesis, after a brain injury such as stroke. However, the response of neural stem/progenitor cells to stroke is poorly understood. Recently, neural stem/progenitor cells have been identified in the cerebral cortex, as well as previously recognized regions such as the subventricular or subgranular zones of the hippocampus, suggesting that a contribution of cortex-derived neural stem/progenitor cells may repair ischemic lesions of the cerebral cortex. In the present study, using a highly reproducible murine model of cortical infarction, we have found nestin-positive cells in the post-stroke cerebral cortex, but not in the non-ischemic cortex. Cells obtained from the ischemic core of the post-stroke cerebral cortex formed neurosphere-like cell clusters expressing nestin; such cells had the capacity for self-renewal and differentiated into electrophysiologically functional neurons, astrocytes and myelin-producing oligodendrocytes. Nestin-positive cells from the stroke-affected cortex migrated into the peri-infarct area and differentiated into glial cells in vivo. Although we could not detect differentiation of nestin-positive cells into neurons in vivo, our current observations indicate that endogenous neural stem/progenitors with the potential to become neurons can develop within post-stroke cerebral cortex.

Potential of Adult Endogenous Neural Stem/Progenitor Cells in the Spinal Cord to Contribute to Remyelination in Experimental Autoimmune Encephalomyelitis.

Demyelination and remyelination play pivotal roles in the pathological process of multiple sclerosis (MS) and experimental autoimmune encephalomyelitis (EAE), a well-established animal model of MS. Although increasing evidence shows that various stimuli can promote the activation/induction of endogenous neural stem/progenitor cells (NSPCs) in the central nervous system, the potential contributions of these cells to remyelination following inflammatory injury remain to be fully investigated. In the present study, using an adult mouse model of EAE induced by myelin oligodendrocyte glycoprotein (MOG) peptide, we investigated whether adult NSPCs in the spinal cord can lead to remyelination under inflammatory conditions. Immunohistochemistry showed that cells expressing the NSPC marker Nestin appeared after MOG peptide administration, predominantly at the sites of demyelination where abundant inflammatory cells had accumulated, whereas Nestin+ cells were rarely present in the spinal cord of PBS-treated control mice. In vitro, Nestin+ NSPCs obtained from EAE mice spinal cords could differentiate into multiple neural lineages, including neurons, astrocytes, and myelin-producing oligodendrocytes. Using the Cre-LoxP system, we established a mouse strain expressing yellow fluorescent protein (YFP) under the control of the Nestin promoter and investigated the expression patterns of YFP-expressing cells in the spinal cord after EAE induction. At the chronic phase of the disease, immunohistochemistry showed that YFP+ cells in the injured regions expressed markers for various neural lineages, including myelin-forming oligodendrocytes. These results show that adult endogenous NSPCs in the spinal cord can be subject to remyelination under inflammatory conditions, such as after EAE, suggesting that endogenous NSPCs represent a therapeutic target for MS treatment.

Challenges in Managing Patients with Hereditary Cancer at Gynecological Services.

AIM: To reveal current problems and challenges faced by our gynecologic services department in managing patients with hereditary cancers. METHODS: We collected clinical data of patients with hereditary cancers, identified via genetic testing (or clinically diagnosed in cases of Cowden syndrome or Peutz-Jeghers syndrome), and treated in our gynecological department from 2012 to 2018. RESULTS: Fifteen patients had hereditary breast and ovarian cancer (HBOC), 6 had Lynch syndrome, 2 had Cowden syndrome, and 2 had Peutz-Jeghers syndrome. Five patients diagnosed with HBOC were younger than 40 years at diagnosis. Risk-reducing salpingo-oophorectomy (RRSO) was performed on 1 patient with a BRCA1 mutation at age 38 years. Seven patients overall underwent RRSO, and none had malignancies on pathological examinations. Peritoneal washing cytology (PWC) was suspicious for malignancy in one patient; however, subsequent PWC at 6 months after RRSO was negative. A patient with endometrial cancer and Lynch syndrome and a patient with atypical endometrial hyperplasia (AEH) and Cowden syndrome strongly desired fertility preservation. They achieved remission after medroxyprogesterone acetate treatment and multiple dilations and curettages, respectively. One patient with Lynch syndrome developed AEH after 11 years of surveillance. Laparotomy revealed adjacent low-grade and high-grade serous ovarian cancer with positive ascites cytology. She had no recurrence during 7-year follow-up after laparotomy. CONCLUSION: Managing patients with hereditary cancer, positive or false-positive ascites cytology discovered during RRSO, and desired preservation of fertility is highly challenging.

Grading of astrocytomas using the PRESTO (principles of echo-shifting with a train of observations) magnetic resonance imaging sequence.

OBJECTIVE: Changes in brain tissue can be detected sensitively using PRESTO (principles of echo-shifting with a train of observations) magnetic resonance imaging (MRI). The aim of this study was to evaluate the correlation between the proliferative ability of astrocytoma and intratumoral spotty signal voids seen as hypo-intense dots on PRESTO MRI. PATIENTS AND METHODS: Fifty-seven astrocytic tumors, comprising 14 astrocytomas, 12 anaplastic astrocytomas, and 31 glioblastomas, were included in this retrospective study. The tumors were classified independently by blinded radiologists according to the number of spotty signal voids detected on PRESTO-MRI as follows: spot-free (grade 0), less than 3 spots (grade 1), or more than 3 spots or a large spot (grade 2). RESULTS: Thirteen patients (92.9%) with astrocytoma were classified as PRESTO grade 0 and 1 patient (7.1%) was classified as grade 1. Seven patients (58.3%) with anaplastic astrocytoma were classified as PRESTO grade 0, 1 (8.3%) as grade 1, and 4 as grade 2 (33.3%). Three patients (9.7%) with glioblastoma were classified as grade 0, 6 (19.4%) as grade 1, and 22 (70.9%) as grade 2. There was a strong correlation between PRESTO tumor grade and the mean MIB-1 index. CONCLUSIONS: These results indicate that a grading system based on the number of spotty signal voids detected on PRESTO images would be useful for the diagnosis of astrocytic tumors and predicting their proliferative ability.

Leptomeningeal-derived doublecortin-expressing cells in poststroke brain.

Increasing evidence indicates that neural stem/progenitor cells (NSPCs) reside in many regions of the central nervous system (CNS), including the subventricular zone (SVZ) of the lateral ventricle, subgranular zone of the hippocampal dentate gyrus, cortex, striatum, and spinal cord. Using a murine model of cortical infarction, we recently demonstrated that the leptomeninges (pia mater), which cover the entire cortex, also exhibit NSPC activity in response to ischemia. Pial-ischemia-induced NSPCs expressed NSPC markers such as nestin, formed neurosphere-like cell clusters with self-renewal activity, and differentiated into neurons, astrocytes, and oligodendrocytes, although they were not identical to previously reported NSPCs, such as SVZ astrocytes, ependymal cells, oligodendrocyte precursor cells, and reactive astrocytes. In this study, we showed that leptomeningeal cells in the poststroke brain express the immature neuronal marker doublecortin as well as nestin. We also showed that these cells can migrate into the poststroke cortex. Thus, the leptomeninges may participate in CNS repair in response to brain injury.

Ischemia-induced neural stem/progenitor cells in the pia mater following cortical infarction.

Increasing evidence shows that neural stem/progenitor cells (NSPCs) can be activated in the nonconventional neurogenic zones such as the cortex following ischemic stroke. However, the precise origin, identity, and subtypes of the ischemia-induced NSPCs (iNSPCs), which can contribute to cortical neurogenesis, is currently still unclear. In our present study, using an adult mouse cortical infarction model, we found that the leptomeninges (pia mater), which is widely distributed within and closely associated with blood vessels as microvascular pericytes/perivascular cells throughout central nervous system (CNS), have NSPC activity in response to ischemia and can generate neurons. These observations indicate that microvascular pericytes residing near blood vessels that are distributed from the leptomeninges to the cortex are potential sources of iNSPCs for neurogenesis following cortical infarction. In addition, our results propose a novel concept that the leptomeninges, which cover the entire brain, have an important role in CNS restoration following brain injury such as stroke.