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Differentiation of mesenchymal stem cells (MSCs) into vascular endothelial cells has been demonstrated for application in cardiovascular regenerative medicine. In this study, we evaluated the effect of the combined mechanical stimuli of wall shear stress (SS) and cyclic strain (CS), mimicking hemodynamic conditions of arteries, on endothelial differentiation of MSCs. Immortalized human adipose-derived MSCs were subjected to a combined stimulations of SS (1 Pa) and CS (4%, 1 Hz) by using a developed cell culture chamber. Endothelial differentiation of MSCs was evaluated by immunofluorescent staining of an endothelial protein maker, fetal liver kinase-1 (Flk-1). Morphological changes in MSCs by the stimulation were also examined from the fluorescent images. As a result, the application of the combined stimulation of SS and CS for 24 h induced an increased expression of Flk-1 in MSCs and cell alignment to the direction of flow, whereas the stimulation of only SS or CS did not change Flk-1 expression and morphology of MSCs compared to statically cultured cells. We also found that inhibition of the activation of extracellular signal-regulated kinase 1/2 (ERK1/2) blocked the increased expression of Flk-1 under the combined mechanical condition. These results indicate that the combination of SS and CS effectively induces MSCs differentiation into endothelial cells via activation of ERK1/2 signaling pathway.

Biomechanical stimuli derived by interstitial flow regulate morphogenesis of multicellular systems including both physiological and pathological cells. For example, hepatocytes construct three-dimensional structures in directional interstitial flow conditions. Protrusions of tumor cells are also induced by interstitial flow, resulting in enhanced tumor cell invasion. Interestingly, the direction of tumor cell invasion in response to directional interstitial flow differs depending on the type of tumor cells. Furthermore, endothelial cells form capillary networks against the direction of interstitial flow in a magnitude-dependent manner. Taken together, interstitial flow is an important factor for regulating morphogenesis of multicellular systems. [ABSTRACT FROM AUTHOR]

Acute phase proteins such as CRP, amyloid protein A, and α1-antitrypsin are produced in the liver and their plasma levels are increased during the acute inflammatory response. In contrast, there are plasma proteins whose dynamics are opposite to acute phase proteins. This group includes histidine-rich glycoprotein (HRG), inter-α-inhibitor proteins, albumin, and transthyretin. HRG binds to a variety of factors and regulates the fundamental processes; the blood coagulation, the clearance of apoptotic cells, and tumor growth. In the present review, we focus on the anti-septic effects of HRG in mice model, the actions of HRG on human blood cells/vascular endothelial cells, and the identification of a novel receptor CLEC1A for HRG, based on our recent findings. HRG appears to maintain the quiescence of neutrophils; a round shape, the low levels of spontaneous release of ROS, the ease passage through artificial microcapillaries, and prevention of adhesion to vascular endothelial cells. HRG also inhibited activation of vascular endothelial cells; the suppression of adhesion molecules and the inhibition of HMGB1 mobilization and cytokine secretion. It was shown that plasma HRG level was an excellent biomarker of septic patients in ICU for the evaluation of severity and prognosis. So far little attention has been paid to HRG in terms of a functional role in sepsis and ARDS, however, it is strongly suggested that HRG may be an important plasma factor that prevents a progress in the septic cascade and maintains the homeostasis of blood cells and vascular endothelial cells.

A 48-year-old man underwent computed tomography for the examination of lower back pain, which incidentally detected a cardiac tumor in the right atrium. On echocardiography, the tumor was identified as a 30 mm round mass with a thin wall and iso- and hyper-echogenic contents that originated from the atrial septum. The tumor was successfully removed under cardiopulmonary bypass, and the patient was discharged in good health. The cyst was filled with old blood, and focal calcification was observed. Pathological examination revealed that the cystic wall was composed of thin-layered fibrous tissue lined with endothelial cells. Regarding a treatment, it is reported that early surgical removal is preferable to avoid embolic complications, however it is controversial. Furthermore, it needs to discuss about the difference between fetal/neonatal and adult cases.

Complement (C) activation occurs via three pathways, namely the classical, lectin, and alternative pathways. Intercommunication occurs between the complement and coagulation systems, which can trigger tissue injury and inflammation. Disseminated intravascular coagulation (DIC) is a life-threatening disease characterized by disordered coagulation and systemic inflammation; here, the intercommunication between the complement and coagulation systems contributes to the development of DIC. Extracellular histones, which are contributors to the damage-associated molecular pattern, induce severe thrombosis. C5 is a key molecule in the intercommunication between the complement and coagulation systems and is associated with the development of lethal histone-induced thrombosis. Heparin and chondroitin sulfate (CS) are negatively charged, allowing them to bind to extracellular histones. As the coagulation system is less affected by CS than heparin, CS shows potential as an effective drug for the treatment of patients with DIC who have a high risk of bleeding. Complement receptor type-1-related gene Y (Crry) inhibits the complement pathway via binding to C3b and C4b. Hence, Crry is a potent inhibitor of the classical and alternative C pathways. The expression of Crry is decreased by the endothelial damage induced by extracellular histones. Crry dysfunction promotes the activation of C on the surface of endothelial cells. The prevention of C3 cleavage on endothelial cells might be a useful therapy targeting acute lung injury.

By carrying a systemic circulation, hematopoietic and vascular systems coordinately govern the functional organ connections in the body. Blood vessels play an important role in the development, regeneration, and maintenance of organs by acting as conduits for environmental factors in the blood to tissues and secreting organ-specific cytokines as angiocrine signals. Recently, it has become clear that vascular endothelial cells, which are the main constituent cells of the blood vessels and play a role in homeostasis, are diverse. It has also been established that the cells of stem cell fraction exist in endothelial cells. The vascular endothelial cells in various organs are functionally different. For example, it has been discovered that sinusoidal blood vessels in the liver produce coagulation factor VIII as an organ-specific vascular function. Determining how such tissue-/organ-specific function of the endothelial cells is induced is a topic of interest in the vascular field of study.

Blood brain barrier (BBB) is strong barrier specific to the brain vasculatures. BBB protects the brain from xenobiotics, while make it difficult to predict toxicokinetics/toxicodynamics, pharmacokinetics/pharmacodynamics, and efficiencies of new drugs in drug development. In this review, we will explain the physiological significance of BBB, the reason why the humanized BBB Micro Physiological System (MPS) is necessary, and the background technologies of BBB MPS. Because BBB MPS is the fusion of the engineering element technologies and the biological element technologies, we will explain the element technologies in both fields, respectively. We will also introduce the recent trends of BBB MPS to improve the human predictability: the shear stress in microfluidic models and the cellular architecture reproduction by three dimensional culture.

Eritoran (E5564) is Eisai's in-house discovered and developed investigational Toll-Like Receptor 4 (TLR4) antagonist created with natural product organic synthesis technology. It is a structural analogue of Lipid A, which is an activator of endotoxins of bacteria. It has been previously observed to be safe in 14 clinical studies including a large Phase 3 randomized trial in severe sepsis. In order to evaluate therapeutic efficacy by eritoran, we are participating in the international network REMAP-CAP-COVID (Randomized, Embedded, Multi-factorial, Adaptive Platform-Community Acquired Pneumonia COVID) which aims for novel coronavirus medicine development through drug repurposing, and began an international collaborative clinical trial in October 2020 which is designated for confirmed novel coronavirus patients who are hospitalized and are in a progressing disease state. It is hoped that through suppressing the most upstream TLR4 activity which controls production of multiple cytokines by eritoran, the cytokine storm in patients can be suppressed and pneumonia can thus be prevented from becoming severe. On the other hand, E6011 is the only humanized anti-fractalkine (FKN) monoclonal antibody in the world created by KAN Research Institute. E6011 inhibits the tight binding of CD16-positive monocytes (a cell population that highly expresses the FKN receptor CX3CR1) to vascular endothelial cells, which are important for the local inflammatory response. This is expected to suppress the formation and exacerbation of vasculopathy in COVID-19.

Recently, a KRAS mutation located in the endothelial cells of the nidus in arteriovenous malformations(AVMs)was reported. The findings indicate the possibility of medical therapy against cerebral AVMs; the blockade of RAS-MAPK signaling cascade may stabilize AVM nidus. As for surgical treatment for AVMs, achievement of low morbidity is the most important objective. To achieve this, assessment of blood flow, usage of non-stick bipolar forceps, and 3D simulation prior to operation are important. Assessment of individual cases for surgical treatment leads to low morbidity in surgeries.

The mortality rate due to coronavirus disease 2019 (COVID-19) reached 5.3 million. However, identifying the novel treatment targets that ultimately reduce or prevent disease aggravation will be possible by understanding the mechanism and pathophysiology underlying the COVID-19 aggravation. Authors of previous studies have identified the "cytokine storm" that constitutes the secretion of inflammatory cytokines driven by the coagulation/fibrinolytic system as an inflammatory cytodynamic control mechanism that contributes to the aggravated COVID-19 pathology and the pathophysiology of related diseases. Vasculature-lining endothelial cells are bioreactors that produce or contribute to the modulation status of cytokines and coagulation and fibrinolytic system factors. The key steps in the pathophysiology of organ damage include the destabilization of the angiocrine system triggered by vascular endothelial damage during severe COVID-19. Overproduced or imbalanced angiocrine factors and inflammatory cytokines contribute to major COVID-19 complications. Within its scope, this study outlines the significance of the fibrinolytic system in the pathophysiology of inflammatory diseases, focusing on the research results. The possibility of molecular that target these angiocrine and fibrinolytic factors for inflammatory diseases as novel treatment approaches for inflammatory diseases, such as COVID-19, was discussed.

Histidine-rich glycoprotein (HRG) is a plasma glycoprotein produced mainly in the liver. We have shown that HRG replacement therapy has a marked therapeutic effect on sepsis, in which high mobility group box 1 (HMGB1), one of the representative damage-associated molecular patterns (DAMPs), is known to play an important role in the disease progression. The mechanisms of action are diverse, including inhibition of immune thrombus formation and inhibition of ROS production. In addition, HRG has been shown to neutralize the toxicity of heme, a type of DAMPs, and neutralize the activity of LPS, a type of pathogen-associated molecular patterns (PAMPs), and to inhibit the translocation of HMGB1 from the nucleus of vascular endothelial cells to the extracellular space. Since DAMPs/PAMPs are known to play a central role in the pathogenesis of not only sepsis but also many inflammatory diseases, HRG has wide therapeutic applications and is considered to be a very promising seed for drug discovery.

An 86-year-old man was admitted for the abrupt onset of right hemiparesis and aphasia. DWI revealed the high intensity legion in the left insular cortex, and MRA demonstrated the left middle cerebral artery occlusion. Recanalization of the artery was not achieved after mechanical thrombectomy. The diagnosis of infective endocarditis was made as Enterococcus faecalis was cultured from the blood, and mobile vegetation was detected at the aortic valve by transthoracic echocardiography. The patient died from multiple organ failure at 19 days. Autopsy findings revealed fibrin-rich thrombus in the left middle cerebral artery containing neutrophils and bacteria. At the occluded site, neutrophils had intensively infiltrated into the vessel wall, and endothelial cells had partially disappeared. Moreover, disrupted internal elastic lamina was discovered. These findings could indicate that the thrombus had adhered to the vessel wall. The adhesion of the thrombus and vessel wall could be associated with unsuccessful recanalization after endovascular thrombectomy in patients with ischemic stroke due to infective endocarditis.

Sinusoidal obstruction syndrome (SOS), also called veno-occlusive disease (VOD) of the liver, is one of the most relevant complications of hepatic sinusoidal endothelial origin that appears early after hematopoietic cell transplantation (HCT). Despite its relatively low incidence and the spontaneous resolution of most SOS/VOD cases, severe SOS/VOD evolved to multi-organ failure with an >80% mortality rate and represents one of the major clinical problems after HCT. The sinusoidal endothelial cells and hepatocytes are damaged by toxic metabolites generated by the conditioning regimen in these patients. Several risk factors have been identified for SOS/VOD development. Although defibrotide is recommended for both prevention and treatment, no satisfactory therapy exists for managing severe SOS/VOD. Thus, this review describes the new definition of SOS/VOD diagnosis and the severity grading of suspected SOS/VOD from the European Society for Blood and Marrow Transplantation. Furthermore, it describes the results of current treatment including the Japanese therapeutic use program, defibrotide treatment protocol.

An 83-year-old man with left lower back pain was found to have a 5 cm mass in contact with the right adrenal gland and a 12 mm left ureteral stone by abdominal plain computed tomography. An abdominal plain magnetic resonance imaging T2-weighted image revealed a heterogeneous high signal mass in the right adrenal gland. Pheochromocytoma, adrenal carcinoma, and retroperitoneal neurogenic tumor were suspected. Tumor markers and endocrine examinations were within standard values. Laparoscopic right adrenalectomy was performed. A 4×3.6 cm, 62 g solid tumor was found in contact with right adrenal gland. Histopathologically, hobnail-like vascular endothelial cells were found in the tumor, but no malignant findings such as multi-layered vascular endothelial cells and nuclear atypia were observed. This tumorwas diagnosed to be an anastomosing hemangioma.

Clostridium perfringens type A causes gas gangrene, which is a serious disease caused by wound infection. α-Toxin produced by C. perfringens is known to be the primary pathogenic factor of gas gangrene. Although it has been proposed to induce tissue damage by impairing the host immune system and peripheral circulation, sufficient findings have not been obtained to explain the high virulence of C. perfringens. For the purpose of elucidating the pathogenic mechanism of this bacterium, I focused on the disease progressions such as the bacterial colonization, muscle tissue destruction and repair, and sepsis. In this review, focusing on the action of α-toxin, it will be explained together with the latest research results that the toxin suppresses the activation of the host immune response, represents toxicity to vascular endothelial cells, induces peripheral circulatory disorders due to hematopoietic disorders, inhibits muscle tissue repair, and induces excessive immune response. These mechanisms suggest that α-toxin acts in multiple steps to disrupt host defense and that C. perfringens attacks the host with a highly sophisticated mechanism. It is expected that the onset mechanism of gas gangrene would be elucidated, and I hope that new therapeutic strategies are developed.

Antiphospholipid syndrome (APS) is an acquired thrombophilia associated with autoimmunity and is a syndrome that should always be considered when examining patients with thrombosis and pregnancy complications. As per the Sydney criteria, a diagnosis can be established with at least one clinical finding, such as arteriovenous thrombosis and the presence of at least one of the antiphospholipid antibodies (aPL), such as anticardiolipin antibodies (aCL). Moreover, phosphatidylserine-dependent anti-prothrombin antibody and anti-b2GPI-domain 1 antibody are correlated with APS manifestations and enable APS diagnosis. In addition to the inhibition of physiological coagulation inhibitors, such as protein C, the activation of vascular endothelial cells and complement activation by aPL is presumed to be the thrombus mechanism of APS. The mainstay of treatment is anticoagulant therapy with warfarin. For treating APS that has developed by arterial thrombosis, antiplatelet agent alone or in combination with warfarin is considered. In the triple positive aPL (aCL, anti-b2GPI antibodies, and lupus anticoagulant are detected at the same time) cases, sufficient anticoagulant therapy is required. Direct oral anticoagulants are not recommended in cases of triple positive aPL or arterial thrombosis. For patients with catastrophic APS, heparin therapy, plasmapheresis, and steroid pulse therapy are recommended.

The ductus arteriosus (DA) maintains the fetal circulation by connecting the aorta and pulmonary arteries. Patent ductus arteriosus (PDA) occurs in >70% extremely-low-birth-weight infants. Patients with PDA exhibit circulatory failure, which is caused by left-to-right shunt. The DA immediately contracts after birth in response to the elevation of blood oxygen tension and to the decline in circulating prostaglandin E 2 (PGE 2 ). Cyclooxygenase inhibitors targeting smooth muscle cell (SMC) contraction represent only pharmacological treatment for PDA. However, it is important for DA anatomical closure that intimal thickening (IT) is appropriately formed between SMC layer and endothelial cells (EC). IT begins to form before the second-trimester and becomes prominent toward the end of third-trimester as an increase in placenta-derived PGE 2 . Immature DAs frequently fail to be close due to poorly formed IT. IT consists of extracellular matrices (ECM) and migrated DA-SMCs from the tunica media. A glycoprotein fibulin-1 is expressed in developing cardiovascular system and binds to multiple ECMs. We found that PGE 2 increased fibulin-1 via EP4 in DA-SMCs, and Fbln1-deficient mice exhibited PDA with poor IT formation. Although EP4 is a Gs-coupled GPCR, fibulin-1 was secreted from DA-SMCs through the phospholipase C-protein kinase C-non-canonical NFκB signaling pathway. Fibulin-1 bound to DA-EC-derived versican which is a binding partner of hyaluronan, which promoted directional DA-SMC migration toward ECs and contributed to IT formation in the DA. Fibulin-1 upregulation by the activation of specific downstream pathway of EP4 may serve a new pharmacological strategy for PDA.

Cerebrovascular disease and vasculitis-related diseases have been reported as systemic complications of coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A proposed underlying mechanism is that SARS-CoV-2 infects vascular endothelial cells via the angiotensin-converting enzyme 2 (ACE2) and causes inflammation. Cerebrovascular disease and vasculitis are often observed in severe COVID-19 cases, and they may be associated with critical systemic conditions, such as the cytokine storm and thrombotic tendencies. Several other mechanisms have been proposed, and diverse pathological conditions may be associated with COVID-19-related cerebrovascular disease and vasculitis. Clarifying the pathophysiology and establishing a better therapeutic regimen will facilitate favorable outcomes.

The recent phase Ⅲ trials REGARD and RAINBOW have shown survival benefits and acceptable safetyprofiles of ramucirumab( RAM)alone and RAM plus paclitaxel. Based on this result, RAM is recommended as a secondarytreatment for advanced and recurrent gastric cancer bythe Japanese Gastric Cancer Association. Although the frequencyis not high, gastrointestinal perforation has been reported as a serious side effect. RAM is a human anti-vascular endothelial growth factor receptor 2(VEGFR-2)monoclonal antibodythat acts on vascular endothelial cells to inhibit angiogenesis. The detailed mechanism has not been elucidated, but it is thought that the ischemic state and delayed wound healing due to the inhibition of vascular endothelial growth factors could be the cause of perforation. Thus, the usage of angiogenesis inhibitors such as RAM while intestinal stents are placed, mayincrease the risk of gastrointestinal perforation. We report a case in which RAM was administrated with no adverse events after multiple gastrointestinal metal stents being inserted.

Pericytes stabilize microvessels by wrapping them with their processes. They are located within the neurovascular unit between endothelial cells, astrocytes, and neurons, and interact with neighboring cells to generate diverse functional responses that are critical for central nerve system (CNS) function in health and disease. Recent evidence suggests that brain pericytes play crucial roles in regulating microvascular functions, such as blood-brain barrier properties, capillary blood flow, angiogenesis, and the entry of leukocytes into the brain. Pericytes also take part in tissue repair after CNS injury and may have stem cell-like properties. In addition, recent reports suggest that peripheral nerve pericytes, forming the blood-nerve barrier (BNB), regulate BNB function and basement membrane maintenance. Microvascular dysfunction due to pericyte degeneration initiates secondary neurodegenerative changes in the nervous system. In this review, we will first describe the origin, heterogeneity, and the physiological characteristics of pericytes. We next review possible pathological mechanisms and consequences of pericyte impairment in nervous system diseases including Alzheimer's diseases, diabetes, vascular dementia, and stroke. Finally, we will discuss how pericytes can be targeted for developing novel therapeutic approaches for treating patients with neurological disorders.

Deep learning technology is rapidly advancing, and is now used to solve complex problems. induced pluripotent stem cells (iPSCs) can be used for several purposes such as regenerative medicine, disease modeling study and drug screening. It is inevitable to identify iPSC-derived differentiated cells in microscopy for any use. Here, we used deep learning to establish an automated method to identify endothelial cells derived from iPSCs, without the need for immunostaining or lineage tracing.

Angiogenesis is the process of new vascular formation from preexisting blood vessels, and the contribution of endothelial stem cell population to this process has been elucidated. Vascular endothelial growth factor (VEGF) promotes not only the proliferation of endothelial cells (ECs) but also the vascular permeability by inducing cell-to-cell dissociation between ECs. Chronic hyper vascular leakage induces intra-tumoral interstitial hypertension resulting in disturbed vascular perfusion. Hypoxia in the nonfunctional vasculatures causes chromosomal instability of cancer cells resulting in the development of malignant cancer cells, such as cancer stem cells. Hypoxia also induces exhaustion of immune cells. Moreover, the blood vessel structures in tumors are abnormal and nonfunctional, and the infiltration of leukocytes are suppressed. Moreover, drug delivery, including anti-cancer drugs and immune checkpoint inhibitors, is limited. A drug inducing normalization or maturation of abnormal blood vessels in tumor is warranted for the improvement of malignant tumor microenvironment.

GATA1-deficient mice die in utero on 12.5 embryonic day (E12.5) due to a complete block of primitive erythropoiesis in the yolk sac, while GATA2-deficient mice die on E10.5 due to severe anemia and hemorrhage, since GATA2 is essential for the development of hemangioblasts, which are common precursor cells of hematopoietic stem cells and endothelial cells. In contrast, GATA3 is critical to the development of Th2 cells. However, GATA3-deficient mice die in utero before the particular phenotype of hematopoietic system emerges, which is caused by a defect in the development of nervous and renal urinary systems. It has been well elucidated that defects in the hematopoietic GATA factors disturb hematopoietic homeostasis. However, details on how GATA factor dysfunction leads to human hematopoietic diseases remain to be clarified. At the end of the twentieth century, several mutations in GATA1 gene were identified as the cause of familial thrombocytopenia. Since then, various types of hematopoietic diseases elicited by GATA1 and GATA2 dysfunctions have been reported. This review summarizes recent topics of GATA factor-related hematopoietic diseases.

Graft-versus-host disease (GVHD) is a potentially fatal complication of allogeneic hematopoietic stem cell transplantation. The gastrointestinal tract is a major target organ of GVHD, and disruption of the barrier function of the intestinal mucosa leads to an influx of danger signals derived from intestinal microbiota, which may further exaggerate GVHD. We have shown that the recombinant human R-spondin1 protects intestinal stem cells against GVHD, improves intestinal dysbiosis, and ameliorates GVHD. However, the endogenous R-spondin-producing cells in the small intestine remained to be studied in greater detail. This study clarified that R-spondin3 is the predominant R-spondin protein produced in the mouse small intestine. We also found that R-spondin3 is predominantly produced by lymphatic endothelial cells. Furthermore, we found that GVHD targets lymphatic endothelial cells in the small intestine, leading to decreased R-spondin3 production. GVHD-induced reduction of endogenous R-spondin3 could delay intestinal epithelial regeneration, possibly resulting in GVHD deterioration.

In normal condition, vasculature transports only small molecules such as nutrients across vascular wall. When inflammation occurs, inflammatory stimuli increase the permeability of vessel, which induces the extravasation of molecules larger than 40 kDa including plasma proteins. These extravasated molecules cause further inflammation by promoting the infiltration of inflammatory cells and the production of inflammatory mediators. Although it is known that vascular hyper-permeability plays an important role in inflammation, the detailed mechanism of vascular permeability regulation is still unclear. It is known that vascular permeability is controlled by two types of cells: endothelial cells and vascular mural cells. Endothelial cells cover the luminal side of vascular wall in a single layer and form endothelial barrier. Vascular mural cells regulate the blood flow volume of the downstream tissue by contracting or relaxing vascular wall. Endothelial barrier enhancement and vasocontraction suppress the vascular permeability, while endothelial barrier disruption and vasorelaxation promote it. Vascular permeability is regulated by the balance between the response of endothelial cells and vascular mural cells. Prostanoids are cell membrane-derived lipid mediators which bind to each specific G protein-coupled receptor (GPCR), prostanoid receptors. Recently, several studies showed that prostanoids regulate vascular permeability by acting on endothelial cells and/or vascular mural cells. In this review, we would like to describe the role of each prostanoid in vascular permeability by focusing on the characteristics of each specific receptor.

It is well known that platelets play a crucial role in hemostasis, but it has recently been revealed that platelets are also necessary for organ development. The platelet activation receptor CLEC-2 activates platelets by binding to the membrane protein, podoplanin, on the surface of lymphatic endothelial cells. This results in the release of TGF-β family from activated platelets to facilitate blood/lymphatic vessel separation. TGF-β also acts on lung mesothelial cells, which leads to their differentiation into alveolar duct myofibroblasts (adMYFs) and their migration into the inside of the lung. adMYFs generate elastin, which gives elasticity to the lung. Therefore, mice deficient in either CLEC-2 or podoplanin exhibit blood/lymphatic vessel misconnection and die just after birth due to respiratory failure. It had been previously surmised that biologically active substances from cells act on neighboring cells, leading to organ development, and the role of blood cells in organ development had not been elucidated. However, it has recently been demonstrated that blood platelets contain biological active substances in their granules, which are released when and where necessary by specific interactions between platelet receptors and their ligands. Now platelets are recognized as a "biological package" that actively facilitates organ development.

Background: Veno-occlusive disease(VOD)is a fatal coagulopathy, which is caused by an endothelial disorder among patients who undergo hematopoietic stem cell transplantation(SCT). Some protective agents, such as administration of fresh frozen plasma(FFP), have been evaluated for both prophylactic and targeted therapy., Purpose: We evaluated the prophylactic efficacy of FFP for VOD in a retrospective study., Methods: We surveyed patients who received SCT in our hospital between January 2011 and December 2011. We reviewed their data and compared those who were administered prophylactic FFP in the early transplantation period(up to day 60)with those who did not receive prophylactic FFP., Results: A total of 14 cases were evaluated: 7 female and 7 male, with a median age of 50 years(range of 24 to 63 years). Fibrinogen significantly increased in the FFP group compared with the non-FFP group(p=0.0125). Although the hemostasis parameters of prothrombin time, activated partial thromboplastin time, and D-dimer were all comparable between the 2 groups, the level of fibrinogen degradation products(FDP)was significantly attenuated in the FFP group compared with the non-FFP group(p= 0.0140). Of note, we observed 2 peaks in the D-dimer/FDP ratio in the engraftment period(around day 18)and postengraftment( around day 35)compared with the non-FFP group. Overall survival did not significantly differ between the 2 groups(502 days for FFP, and 586 days for non-FFP, p=0.777)., Discussion: Prophylactic administration of FFP improved hypofibrinogenemia and FDP accumulation in this retrospective analysis of patients who received SCT. We speculate that prophylactic FFP treatment for dyscoagulopathy is effective due to supplementation of coagulation factors. Further study, including randomized trials, is warranted in order to confirm this hypothesis.

It is important to know the cellular properties of endoneurial microvascular endothelial cells (PnMECs) and microvascular pericytes which constitute blood-nerve barrier (BNB), since this barrier structure in the peripheral nervous system (PNS) may play pivotal pathophysiological roles in various disorders of the PNS including inflammatory neuropathies (i.e. Guillain-Barré syndrome), vasculitic neuropathies, hereditary neuropathies and diabetic neuropathy. However, in contrast to blood-brain barrier (BBB), very few studies have been directed to BNB and no adequate cell lines originating from BNB had been launched. In our laboratory, we successfully established human immortalized cell lines originating from BNB using temperature-sensitive SV40 large T antigen and the cellular properties of human cell lines are presented in this paper. Human PnMEC cell line showed high transendothelial electrical resistance and expressed tight junction components and various types of influx as well as efflux transporters that have been reported to function at BBB. Human pericyte cell line also possessed tight junction proteins except claudin-5 and secrete various cytokines and growth factors including bFGF, VEGF, GDNF, NGF, BDNF and angiopoietin-1. Co-culture with pericytes or pericyte-conditioned media strengthend barrier properties of PnMEC, suggesting that in the PNS, peripheral nerve pericytes support the BNB function and play the same role of astrocytes in the BBB. Future accumulation of the knowledge concerning the cellular properties of BNB-forming cells will open the door to novel therapeutic strategies for intractable peripheral neuropathies.

Hematopoietic stem cells (HSCs) maintain themselves over cell divisions (self-renewal) and produce all kinds of blood cells (multi-potency). Depletion of these cells eventually causes hematopoietic failure, while deregulated HSC division causes development of myeloproliferative disorders and leukemias. HSCs can be prospectively purified to nearly homogeneity in mice, but such a high-level purification has not been achieved in humans. HSCs are localized to an anatomical place called 'niche'. Specialized osteoblasts arrayed on the endosteum of cavernous bone and sinusoidal endothelial cells located at the distant position from the endosteum are the two representative candidates of such an HSC niche. A number of adhesion molecules and signaling molecules are thought to comprise the niche-HSC synapse. HSCs divide only once in 1-2 months. Both environmental signaling from the niche and HSC-autonomous molecular programs contribute to the quiescent state of HSCs, which is essential for the maintenance of HSC self-renewal capacity and homeostasis of blood production.

Erythroid development is influenced by cytokines: erythropoietin (Epo) and stem cell factor (SCF), which works synergistically. Epo is the major regulator of erythropoiesis, which is produced by kidneys with an inverse relation to oxygen availability. The Epo gene expression is controlled by HIF-1alpha. After binding the Epo-receptor, it activates the JAK2-STAT5 pathway, PI3K-AKT pathway and so on. Finally, these signals enhance erythropoiesis. All hematopoietic cells are derived from the hematopoietic stem cells (HSCs). HSCs are localizing in a two different bone-marrow microenvironment: the osteoblastic niche and the vascular niche. The erythroid progenitors are induced from HSCs mainly by the membrane bound SCF derived from the bone-marrow stromal cells and then entrapped in the extracellular matrix.

There is a growing body of evidence that advanced glycation end product-receptor(AGE-RAGE) interaction elicits oxidative stress generation, thus indicating that it is involved in the pathogenesis of diabetic retinopathy. Inhibition of AGE formation or blockade of the downstream RAGE signaling is a promising therapeutic strategy for treatment of patients with diabetic retinopathy.