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Research into Schwann cell (SC)-related diseases has been hampered by the difficulty of obtaining human-derived SCs, which have limited proliferative capacity. This has resulted in a delay in progress in drug discovery and cell therapy targeting SCs. To overcome these limitations, we developed a robust method for inducing the differentiation of human induced pluripotent stem cells (hiPSCs) into SCs. We established hiPSC lines and successfully generated high-purity Schwann cell precursors (SCPs) from size-controlled hiPSC aggregates by precisely timed treatment with our proprietary enzyme solution. Such SCPs were successfully expanded and further differentiated into myelin basic protein (MBP) expressing SC populations when treated with an appropriate medium containing dibutyryl-cAMP (db-cAMP). These differentiated cells secreted factors that induced neurite outgrowth in vitro. Our method allows for the efficient and stable production of SCPs and SCs from hiPSCs. This robust induction and maturation method has the potential to be a valuable tool in drug discovery and cell therapy targeting SC-related diseases., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Polycrystalline Ge thin films have attracted considerable attention as potential materials for use in various electronic and optical devices. We recently developed a low-temperature solid-phase crystallization technology for a doped Ge layer and achieved the highest electron mobility in a polycrystalline Ge thin film. In this study, we investigated the effects of strain on the crystalline and electrical properties of n-type polycrystalline Ge layers. By inserting a GeO x interlayer directly under Ge and selecting substrates with different coefficients of thermal expansion, we modulated the strain in the polycrystalline Ge layer, ranging from approximately 0.6% (tensile) to - 0.8% (compressive). Compressive strain enlarged the grain size to 12 µm, but decreased the electron mobility. The temperature dependence of the electron mobility clarified that changes in the potential barrier height of the grain boundary caused this behavior. Furthermore, we revealed that the behavior of the grain boundary barrier height with respect to strain is opposite for the n- and p-types. This result strongly suggests that this phenomenon is due to the piezoelectric effect. These discoveries will provide guidelines for improving the performance of Ge devices and useful physical knowledge of various polycrystalline semiconductor thin films., (© 2024. The Author(s).)

Mesenchymal cells are necessary for organ development. In the lung, distal tip fibroblasts contribute to alveolar and airway epithelial cell differentiation and homeostasis. Here, we report a method for generating human induced pluripotent stem cell (iPSC)-derived mesenchymal cells (iMESs) that can induce human iPSC-derived alveolar and airway epithelial lineages in organoids via epithelial-mesenchymal interaction, without the use of allogenic fetal lung fibroblasts. Through a transcriptome comparison of dermal and lung fibroblasts with their corresponding reprogrammed iPSC-derived iMESs, we found that iMESs had features of lung mesenchyme with the potential to induce alveolar type 2 (AT2) cells. Particularly, RSPO2 and RSPO3 expressed in iMESs directly contributed to AT2 cell induction during organoid formation. We demonstrated that the total iPSC-derived alveolar organoids were useful for characterizing responses to the influenza A (H1N1) virus and severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, demonstrating their utility for disease modeling., Competing Interests: K.T. and S.G. are inventors of a patent application for generating iPSC-derived lung distal tip mesenchymal cells. S.G. is an inventor of Kyoto University’s patents for generating AOs. M.H. and S.G. are founders and shareholders of HiLung, Inc. K.M. and T.S. were employees and shareholders of Kyorin Pharmaceutical Co., Ltd., (© 2022 The Author(s).)

Despite postpartum depression being a common mental health problem, there is no screening method for it. The only risk assessment used is the Edinburgh Postnatal Depression Scale (EPDS). We investigated the relationship between Brief Scale for Coping Profile (BSCP) subscales performed during pregnancy and EPDS scores. We recruited 353 women with normal pregnancies (160 primiparas, and 193 multiparas) and performed BSCP at 26 weeks of gestation. The EPDS was first performed within one week after delivery (T1), and then after one month (T2). Spearman’s correlation coefficients were calculated for the BSCP and EPDS for the whole and primi/multipara groups. Multiple regression analysis was performed with the EPDS T2 scores as the dependent variable. The EPDS scores were higher in the primipara group compared to the multipara (p < 0.001), and the EPDS T1 scores were higher than the overall T2 score (p < 0.001). In the multiple regression analysis, EPDS T1 and the “seeking help for solution” subscale were selected as significant explanatory variables when analyzed in the whole group; EPDS T1 and “active solution” for the primiparas; and EPDS T1, “changing mood”, and “seeking help for solution” for the multiparas. The BSCP can be used as a screening tool for postpartum depression during pregnancy.

Mucociliary clearance is an essential lung function that facilitates the removal of inhaled pathogens and foreign matter unidirectionally from the airway tract and is innately achieved by coordinated ciliary beating of multiciliated cells. Should ciliary function become disturbed, mucus can accumulate in the airway causing subsequent obstruction and potentially recurrent pneumonia. However, it has been difficult to recapitulate unidirectional mucociliary flow using human-derived induced pluripotent stem cells (iPSCs) in vitro and the mechanism governing the flow has not yet been elucidated, hampering the proper humanized airway disease modeling. Here, we combine human iPSCs and airway-on-a-chip technology, to demonstrate the effectiveness of fluid shear stress (FSS) for regulating the global axis of multicellular planar cell polarity (PCP), as well as inducing ciliogenesis, thereby contributing to quantifiable unidirectional mucociliary flow. Furthermore, we applied the findings to disease modeling of primary ciliary dyskinesia (PCD), a genetic disease characterized by impaired mucociliary clearance. The application of an airway cell sheet derived from patient-derived iPSCs and their gene-edited counterparts, as well as genetic knockout iPSCs of PCD causative genes, made it possible to recapitulate the abnormal ciliary functions in organized PCP using the airway-on-a-chip. These findings suggest that the disease model of PCD developed here is a potential platform for making diagnoses and identifying therapeutic targets and that airway reconstruction therapy using mechanical stress to regulate PCP might have therapeutic value., (Copyright © 2021 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Mental illness often affects and is affected by other diseases, such as cardiovascular disease, cancer, and AIDS/HIV infection, and people living with mental illness require additional common services and resource mobilization efforts. Therefore, we developed a mobile phone intervention and conducted a randomized controlled trial with 45 psychiatric outpatients with mental illnesses. Data from 39 individuals (intervention group: 20, control group: 19; mean [SD] age, 44.64 [14.12] years) were included in the analyses. The intervention involved the promotion of help-seeking behaviors by sending text messages, including information about social welfare services, for 3 months. After the intervention period, no significant differences were found in the proportion of help-seeking behaviors between the intervention and control groups. However, concerning the reason for not using social services, the proportion of participants who answered "I do not know how to use it" in the intervention group was significantly lower compared to the control group. More than 80% of participants in the intervention group reported that the text messaging service was helpful and useful, and they wanted more messages and information. This was the first randomized controlled trial to promote psychiatric patients' help-seeking behavior using text messaging. Moreover, the text messaging intervention was found to be cost-effective., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Nakajo-Nishimura syndrome (NNS) is an immunoproteasome-associated autoinflammatory disorder caused by a mutation of the PSMB8 gene. Although dysfunction of the immunoproteasome causes various cellular stresses attributed to the overproduction of inflammatory cytokines and chemokines in NNS, the underlying mechanisms of the autoinflammation are still largely unknown. To investigate and understand the mechanisms and signal pathways in NNS, we established a panel of isogenic pluripotent stem cell (PSC) lines with PSMB8 mutation. Activity of the immunoproteasome in PSMB8-mutant PSC-derived myeloid cell lines (MT-MLs) was reduced even without stimulation compared with non-mutant-MLs. In addition, MT-MLs showed an overproduction of inflammatory cytokines and chemokines, with elevated reactive oxygen species (ROS) and phosphorylated p38 MAPK levels. Treatment with p38 MAPK inhibitor and antioxidants decreased the abnormal production of cytokines and chemokines. The current PSC model revealed a specific ROS-mediated inflammatory pathway, providing a platform for the discovery of alternative therapeutic options for NNS and related immunoproteasome disorders., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: To investigate the prolonged effects of a 12-month exercise-plus-diet intervention in Japanese adults at risk of impaired glucose or lipid metabolism., Methods and Study Design: A total of 180 participants were randomly divided into an intervention group (n=94), and a control group (n=86). An exercise-plus- diet intervention was conducted on the intervention group for 12 months. The effects were evaluated by questionnaire, physical examinations, and blood tests at baseline, 3 months, 12 months (the end of intervention), and 24 months (one year after the end of intervention). The control group took only the same examinations as the intervention group., Results: At the end of the 12-month intervention, body weight, waist circumference, fasting glucose, HbA1c, triglycerides, and LDL-cholesterol were improved in the intervention group compared to the control group (all p<0.05). One year after the end of the intervention, body weight, waist circumference, fasting glucose, triglycerides, and LDL-cholesterol were still decreased in the intervention group compared to the control group (all p<0.05), especially among non-overweight participants. Among overweight persons, only body weight in the intervention group was lower than the control group. The personal behaviours of physical activity and diet in the intervention group were also improved., Conclusions: The 12-month exercise-plus-diet programs were found to be effective in improving glucose and lipid metabolism, as well as personal behaviour one year after completion of the intervention.

Stem cell-mediated cardiac regeneration is impaired with age. In this study, we identified a novel subpopulation of small juvenile stem cells (SJSCs) isolated from aged bone marrow-derived stem cells (BMSCs) with high proliferation and differentiation potential. SJSCs expressed mesenchymal stem cell markers, CD29(+)/CD44(+)/CD59(+)/CD90(+), but were negative for CD45(-)/CD117(-) as examined by flow cytometry analysis. SJSCs showed higher proliferation, colony formation, and differentiation abilities compared with BMSCs. We also observed that SJSCs significantly expressed cardiac lineage markers (Gata-4 and myocyte-specific enhancer factor 2C) and pluripotency markers (octamer-binding transcription factor 4, sex-determining region Y box 2, stage-specific embryonic antigen 1, and Nanog) as well as antiaging factors such as telomerase reverse transcriptase and sirtuin 1. Interestingly, SJSCs either from young or aged animals showed significantly longer telomere length as well as lower senescence-associated β-galactosidase expression, suggesting that SJSCs possess antiaging properties, whereas aged BMSCs have limited potential for proliferation and differentiation. Furthermore, transplantation of aged SJSCs into the infarcted rat heart significantly reduced the infarction size and improved left ventricular function, whereas transplantation of aged BMSCs was less effective. Moreover, neovascularization as well as cardiomyogenic differentiation in the peri-infarcted area were significantly increased in the SJSC-transplanted group compared with the BMSC-transplated group, as evaluated by immunohistochemical analysis. Taken together, these findings demonstrate that SJSCs possess characteristics of antiaging, pluripotency, and high proliferation and differentiation rates, and, therefore, these cells offer great therapeutic potential for repair of the injured myocardium.

Abstract improved growth characteristics of the aging bone marrow cells subsequent to neuropeptide Y (NPY)/neuropeptide Y Y5 receptor (NPY Y5R) ligand-receptor interaction. Bone marrow cells were isolated from neonatal (2-3 weeks), young (8-12 weeks), and old (24-28 months) rats on the basis of their preferential adherence to plastic surface. After culturing the cells at initial seeding density of 1×10(4) cells/cm(2), we found that the proliferation potential of bone marrow cells declined with age. Real-time polymerase chain reaction (PCR) and Western blotting showed that bone marrow cells in different age groups constitutively expressed NPY and NPY receptor subtypes (Y1R, Y2R, and Y5R). However, NPY and Y5R expression increased by more than 130-fold and decreased by 28-fold, respectively, in old bone marrow cells as compared to young bone marrow cells. NPY (10 nM) stimulated the proliferation of all bone marrow cells age groups, and their proliferation was blocked by Y5R antagonist. However, the pro-proliferative effect of NPY on old bone marrow cells was weaker than other cell groups due to lower Y5R expression. Y5R gene transfection of old bone marrow cells with subsequent NPY(3-36) (10 nM) treatment significantly increased proliferation of old bone marrow cells (>56%) as compared to green fluorescence protein-transfected control old bone marrow cells. Stimulation of old bone marrow cells by NPY treatment rejuvenated the growth characteristics of aging bone marrow cells as a result of Y5R overexpression.

Human umbilical cord blood (CB) is a potential source for mesenchymal stem cells (MSC) capable of forming specific tissues, for example, bone, cartilage, or muscle. However, difficulty isolating MSC from CB (CB-MSC) has impeded their clinical application. Using more than 450 CB units donated to two public CB banks, we found that successful cell recovery fits a hyper-exponential function of time since birth with very high fidelity. Additionally, significant improvement in the isolation of CB-MSC was achieved by selecting cord blood units having a volume ≥90  ml and time ≤2  h after donor's birth. This resulted in 90% success in isolation of CB-MSC by density gradient purification and without a requirement for immunoaffinity methods as previously reported. Using MSC isolated from bone marrow (BM-MSC) and adipose tissue (AT-MSC) as reference controls, we observed that CB-MSC exhibited a higher proliferation rate and expanded to the order of the 1 × 10(9)  cells required for cell therapies. CB-MSC showed karyotype stability after prolonged expansion. Functionally, CB-MSC could be more readily induced to differentiate into chondrocytes than could BM-MSC and AT-MSC. CB-MSC showed immunosuppressive activity equal to that of BM-MSC and AT-MSC. Collectively, our data indicate that viable CB-MSC could be obtained consistently and that CB should be reconsidered as a practical source of MSC for cell therapy and regenerative medicine using the well established CB banking system., (Copyright © 2011 Wiley-Liss, Inc.)

We reported previously that mesenchymal progenitor cells derived from chorionic villi of the human placenta could differentiate into osteoblasts, adipocytes, and chondrocytes under proper induction conditions and that these cells should be useful for allogeneic regenerative medicine, including cartilage tissue engineering. However, similar to human mesenchymal stem cells (hMSCs), though these placental cells can be isolated easily, they are difficult to study in detail because of their limited life span in vitro. To overcome this problem, we attempted to prolong the life span of human placenta-derived mesenchymal cells (hPDMCs) by modifying hTERT and Bmi-1, and investigated whether these modified hPDMCs retained their differentiation capability and multipotency. Our results indicated that the combination of hTERT and Bmi-1 was highly efficient in prolonging the life span of hPDMCs with differentiation capability to osteogenic, adipogenic, and chondrogenic cells in vitro. Clonal cell lines with directional differentiation ability were established from the immortalized parental hPDMC/hTERT+Bmi-1. Interestingly, hPDMC/Bmi-1 showed extended proliferation after long-term growth arrest and telomerase was activated in the immortal hPDMC/Bmi-1 cells. However, the differentiation potential was lost in these cells. This study reports a method to extend the life span of hPDMCs with hTERT and Bmi-1 that should become a useful tool for the study of mesenchymal stem cells.

Human mesenchymal stem cells are currently being studied extensively because of their capability for self-renewal and differentiation to various connective tissues, which makes them attractive as cell sources for regenerative medicine. Herein we report the isolation of human placenta-derived mesenchymal cells (hPDMCs) that have the potential to differentiate into various lineages to explore the possibility of using these cells for regeneration of cartilage. We first evaluated the chondrogenesis of hPDMCs in vitro and then embedded the hPDMCs into an atelocollagen gel to make a cartilage-like tissue with chondrogenic induction media. For in vivo assay, preinduced hPDMCs embedded in collagen sponges were subcutaneously implanted into nude mice and also into nude rats with osteochondral defect. The results of these in vivo and in vitro studies suggested that hPDMCs can be one of the possible allogeneic cell sources for tissue engineering of cartilage.

Recently several strategies to treat ischemic diseases have been proposed but the ideal way has to be determined. We explored whether human placenta-derived mesenchymal cells (hPDMCs) can be used for this purpose because placenta is very rich in vessels. First, production of human vascular endothelial growth factor (hVEGF) from hPDMCs was examined. The amount of hVEGF secreted by hPDMCs was similar to the amount produced by HeLa cells. hVEGF was barely detected in human umbilical vein endothelial cells (hUVECs) or human peripheral blood mononuclear cells. hVEGF secreted from hPDMCs stimulated the proliferation of hUVECs, indicating its biological activity. Transplantation of hPDMCs to the ischemic limbs of NOD/Shi-scid mice significantly improved the blood flow of the affected limbs. Blood vessel formation was more prominently observed in the limbs of treated mice as compared to the control mice. Real-time RT-PCR revealed that hPDMCs produced hVEGF for at least 7 days after transplantation. Thus, transplantation of hPDMCs could potentially be a promising treatment for human ischemic diseases.

To clarify whether the mesenchymal cells derived from human placenta were available for bone regeneration, we investigated the effects of osteogenic induction on mesenchymal cells of fetal and maternal parts of the placenta. The osteogenic-induced mineralization in both types of cells was measured by von Kossa staining, and the calcium concentration and the expression of osteogenic markers were assayed by RT-PCR. In the mesenchymal cells of both parts, osteopontin, osteocalcin, alkaline phosphatase, and collagen type I, which are osteogenic markers, were expressed. Moreover, the mesenchymal cells of the fetal part of the placenta were mineralized for 3 weeks, but those of the maternal part were not. These results showed that the mesenchymal cells derived from human placenta had an osteogenic phenotype and that only the mesenchymal cells of the fetal part were capable of being used as a cell source for bone reconstitution.

Objective: The cause of delayed hematopoietic reconstitution after umbilical cord blood transplantation (UCBT) remains controversial. We hypothesized that hematopoietic stem/progenitor cells (HS/PCs) from UCB have some defects of the homing-related molecules responsible for their slow engraftment., Materials and Methods: A homing-related molecule repertoire expressed on HS/PCs from fresh and cryopreserved UCB, mobilized peripheral blood (mPB), and bone marrow (BM) were compared using sensitive, four-color fluorescence-activated cell sorting analysis. Purified CD34+ cells were subjected to ex vivo transmigration through double-coated transwell filter inserts, and an in vivo homing assay was performed in xenotransplanted NOD/SCID mice., Results: UCB-derived CD34(bright) cells expressed significantly lower levels of CD49e, CD49f, and CXCR-4 than their mPB and BM counterparts. CD34+ cells from UCB (and BM) exhibited significantly lower ex vivo transmigration than those from mPB, which were largely blocked by neutralizing antibodies to CD49e or CD49f. Recombinant human tumor necrosis factor-alpha treatment enhanced ex vivo transmigration of CD34+ cells from UCB and BM by inducing expression of the matrix metalloproteinases MMP-2/MMP-9. Short-term treatment of UCB-derived CD34+ cells with rHu-stem cell factor (rHuSCF) up-regulated levels of the homing-related molecules with their increased ex vivo transmigratory and in vivo homing potential., Conclusion: Our results indicate that disadvantageous transmigratory behavior of HS/PCs from UCB, which might partly explain the delayed reconstitution after UCBT, can be reversed by ex vivo manipulation with rHuSCF.

Mesenchymal cells from various sources are pluripotent and are attractive sources for cell transplantation. In this study, we analyzed recombinant adeno-associated virus (rAAV)-mediated gene expression in human placenta-derived mesenchymal cells (hPDMCs), which reside in placental villi. After transduction of AV-CAG-EGFP, a rAAV expressing enhanced green fluorescence protein (EGFP), hPDMCs showed much higher level of EGFP expression than human umbilical vein endothelial cells or rat aortic smooth muscle cells. The number of EGFP-positive hPDMCs infected by AV-CAG-EGFP alone did not increase significantly by coinfection of adenovirus, which enhanced expression level of the rAAV vector. Moreover, flow cytometric analysis showed discrete positive fraction of EGFP-expressing hPDMCs, which is about 15-20% of the cells infected with AV-CAG-EGFP. Therefore, some cell population in hPDMCs might be highly susceptible to rAAV-mediated gene transduction. In addition, stable EGFP expressions were observed in about 1% of hPDMCs infected with AV-CAG-EGFP at 4 weeks post-infection. Collectively, hPDMCs have characters favorable for rAAV-mediated gene expression.

We have investigated whether tea catechins (EC, ECg, EGC, EGCg) have any inhibitory effects on angiogenesis and which step they affect during the process. The effects of catechins were tested on in vitro models of angiogenesis, namely, growth, migration and tube formation of human umbilical vein endothelial cells. All four catechins inhibited angiogenesis in vitro in the three different bioassays with concentrations ranging from 1.56 to 100 microM. Among the four catechins tested, epigallocatechin gallate (EGCg) was the most effective in inhibiting angiogenesis in all three assays. When these four catechins were tested on VEGF binding assay, only EGCg inhibited the binding of VEGF, a major angiogenesis inducing factor, to endothelial cells in a concentration dependent manner. These results indicate that while all four tea catechins inhibit the process of angiogenesis, EGCg alone can reduce the binding of VEGF to its receptors and thus affects the downstream signaling.