A let-7 microRNA-RALB axis links the immune properties of iPSC-derived megakaryocytes with platelet producibility

iPS細胞由来血小板造血における免疫巨核球の制御機構の発見 血小板の大量製造に向けた巨核球マスターセルの品質管理に応用可能. 京都大学プレスリリース. 2024-03-26.Discovering a new microRNA-regulated pathway to boost iPS cell-derived platelet production. 京都大学プレスリリース. 2024-03-26.We recently achieved the first-in-human transfusion of induced pluripotent stem cell-derived platelets (iPSC-PLTs) as an alternative to standard transfusions, which are dependent on donors and therefore variable in supply. However, heterogeneity characterized by thrombopoiesis-biased or immune-biased megakaryocytes (MKs) continues to pose a bottleneck against the standardization of iPSC-PLT manufacturing. To address this problem, here we employ microRNA (miRNA) switch biotechnology to distinguish subpopulations of imMKCLs, the MK cell lines producing iPSC-PLTs. Upon miRNA switch-based screening, we find imMKCLs with lower let-7 activity exhibit an immune-skewed transcriptional signature. Notably, the low activity of let-7a-5p results in the upregulation of RAS like proto-oncogene B (RALB) expression, which is crucial for the lineage determination of immune-biased imMKCL subpopulations and leads to the activation of interferon-dependent signaling. The dysregulation of immune properties/subpopulations, along with the secretion of inflammatory cytokines, contributes to a decline in the quality of the whole imMKCL population

SARS-CoV-2 disrupts respiratory vascular barriers by suppressing Claudin-5 expression

臓器チップ技術を用いて新型コロナウイルスが血管へ侵入するメカニズムを解明 --Claudin-5発現抑制による呼吸器の血管内皮バリア破壊--. 京都大学プレスリリース. 2022-09-22.A study using an organ-on-a-chip reveals a mechanism of SARS-CoV-2 invasion into blood vessels --Disruption of vascular endothelial barrier in respiratory organs by decreasing Claudin-5 expression--. 京都大学プレスリリース. 2022-09-27.In the initial process of coronavirus disease 2019 (COVID-19), severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infects respiratory epithelial cells and then transfers to other organs the blood vessels. It is believed that SARS-CoV-2 can pass the vascular wall by altering the endothelial barrier using an unknown mechanism. In this study, we investigated the effect of SARS-CoV-2 on the endothelial barrier using an airway-on-a-chip that mimics respiratory organs and found that SARS-CoV-2 produced from infected epithelial cells disrupts the barrier by decreasing Claudin-5 (CLDN5), a tight junction protein, and disrupting vascular endothelial cadherin–mediated adherens junctions. Consistently, the gene and protein expression levels of CLDN5 in the lungs of a patient with COVID-19 were decreased. CLDN5 overexpression or Fluvastatin treatment rescued the SARS-CoV-2–induced respiratory endothelial barrier disruption. We concluded that the down-regulation of CLDN5 expression is a pivotal mechanism for SARS-CoV-2–induced endothelial barrier disruption in respiratory organs and that inducing CLDN5 expression is a therapeutic strategy against COVID-19

Numerical Estimation of Limiting Current Density by Focusing on Mass Transfer within Porous Spacers in an Electro-Dialysis

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SELF-EXCITED VIBRATION OF A FLAT PLATE WITH A HOLE FOR WATER FLOW

ABSTRACT In fluid machines such as turbo-pumps and hydro-turbines, self-exited vibrations are among the most serious problems that can cause accidents. However, there have been few reports on the self-excited vibrations, which are treated as a coupled problem between the stiffness of the plate and flow disturbance. Basic studies have been performed to clarify the mechanism of the cover-plate vibration induced in the turbo machinery. In the present study, we employ a water tunnel using a test section comprising a flat plate with a hole and pressure chamber that simulates the passage of impeller of the hydraulic machines, and we discuss the characteristics of the self-excited vibration of a flat plate using a hole for water flow. The results show that the vibration occurs when the natural frequency of the plate corresponds approximately with the specific frequency when the Strouhal number St ≈ 0.5, and the frequency of flat-plate vibration depends on the flow velocity. In addition, we show that the amplitude of the vibration is related to the thickness of the plate, geometry of the hole (circle, square), and flow angle for the square hole

iPSC-Derived Platelets Depleted of HLA Class I Are Inert to Anti-HLA Class I and Natural Killer Cell Immunity

ゲノム編集技術を用いてiPS細胞から「ユニバーサル」な血小板の作製に成功. 京都大学プレスリリース. 2020-01-07.The ex vivo production of platelets depleted of human leukocyte antigen class I (HLA-I) could serve as a universal measure to overcome platelet transfusion refractoriness caused by HLA-I incompatibility. Here, we developed human induced pluripotent cell-derived HLA-I-deficient platelets (HLA-KO iPLATs) in a clinically applicable imMKCL system by genetic manipulation and assessed their immunogenic properties including natural killer (NK) cells, which reject HLA-I downregulated cells. HLA-KO iPLATs were deficient for all HLA-I but did not elicit a cytotoxic response by NK cells in vitro and showed circulation equal to wild-type iPLATs upon transfusion in our newly established Hu-NK-MSTRG mice reconstituted with human NK cells. Additionally, HLA-KO iPLATs successfully circulated in an alloimmune platelet transfusion refractoriness model of Hu-NK-MISTRG mice. Mechanistically, the lack of NK cell-activating ligands on platelets may be responsible for evading the NK cell response. This study revealed the unique non-immunogenic property of platelets and provides a proof of concept for the clinical application of HLA-KO iPLATs