Prospects of induced pluripotent stem cells in treating advancing Alzheimer's disease: A review.

The World Health Organization has identified Alzheimer's disease (AD), the leading cause of dementia globally, as a public health priority. However, the complex multifactorial pathology of AD means that its etiology remains incompletely understood. Despite being recognized a century ago, incomplete knowledge has hindered the development of effective treatments for AD. Recent scientific advancements, particularly in induced pluripotent stem cell (iPSC) technology, show great promise in elucidating the fundamental mechanisms of AD. iPSCs play a dual role in regenerating damaged cells for therapeutic purposes and creating disease models to understand AD pathology and aid in drug screening. Nevertheless, as an emerging field, iPSC technology requires further technological advancement to develop effective AD treatments in the future. Thus, this review summarizes recent advances in stem cell therapies, specifically iPSCs, aimed at understanding AD pathology and developing treatments.

Guidelines for Manufacturing and Application of Organoids: Skin.

To address the limitations of animal testing, scientific research is increasingly focused on developing alternative testing methods. These alternative tests utilize cells or tissues derived from animals or humans for in vitro testing, as well as artificial tissues and organoids. In western countries, animal testing for cosmetics has been banned, leading to the adoption of artificial skin for toxicity evaluation, such as skin corrosion and irritation assessments. Standard guidelines for skin organoid technology becomes necessary to ensure consistent data and evaluation in replacing animal testing with in vitro methods. These guidelines encompass aspects such as cell sourcing, culture techniques, quality requirements and assessment, storage and preservation, and organoid-based assays.

Impaired Osteogenesis in Human Induced Pluripotent Stem Cells with Acetaldehyde Dehydrogenase 2 Mutations.

Acetaldehyde dehydrogenase 2 (ALDH2) is the second enzyme involved in the breakdown of acetaldehyde into acetic acid during the process of alcohol metabolism. Roughly 40% of East Asians carry one or two ALDH2*2 alleles, and the presence of ALDH2 genetic mutations in individuals may affect the bone remodeling cycle owing to accumulation of acetaldehyde in the body. In this study, we investigated the effects of ALDH2 mutations on bone remodeling. In this study, we examined the effects of ALDH2 polymorphisms on in vitro osteogensis using human induced pluripotent stem cells (hiPSCs). We differentiated wild-type (ALDH2*1/*1-) and ALDH2*1/*2-genotyped hiPSCs into osteoblasts (OBs) and confirmed their OB characteristics. Acetaldehyde was administered to confirm the impact caused by the mutation during OB differentiation. Calcium deposits formed during osteogenesis were significantly decreased in ALDH2*1/*2 OBs. The expression of osteogenic markers were also decreased in acetaldehyde-treated OBs differentiated from the ALDH2*1/*2 hiPSCs. Furthermore, the impact of ALDH2 polymorphism and acetaldehyde-induced stress on inflammatory factors such as 4-hydroxynonenal and tumor necrosis factor α was confirmed. Our findings suggest that individuals with ALDH2 deficiency may face challenges in acetaldehyde breakdown, rendering them susceptible to disturbances in normal bone remodeling therefore, caution should be exercised regarding alcohol consumption. In this proof-of-concept study, we were able to suggest these findings as a result of a disease-in-a-dish concept using hiPSCs derived from individuals bearing a certain mutation. This study also shows the potential of patient-derived hiPSCs for disease modeling with a specific condition.

Stepwise combined cell transplantation using mesenchymal stem cells and induced pluripotent stem cell-derived motor neuron progenitor cells in spinal cord injury.

BACKGROUND: Spinal cord injury (SCI) is an intractable neurological disease in which functions cannot be permanently restored due to nerve damage. Stem cell therapy is a promising strategy for neuroregeneration after SCI. However, experimental evidence of its therapeutic effect in SCI is lacking. This study aimed to investigate the efficacy of transplanted cells using stepwise combined cell therapy with human mesenchymal stem cells (hMSC) and induced pluripotent stem cell (iPSC)-derived motor neuron progenitor cells (iMNP) in a rat model of SCI. METHODS: A contusive SCI model was developed in Sprague-Dawley rats using multicenter animal spinal cord injury study (MASCIS) impactor. Three protocols were designed and conducted as follows: (Subtopic 1) chronic SCI + iMNP, (Subtopic 2) acute SCI + multiple hMSC injections, and (Main topic) chronic SCI + stepwise combined cell therapy using multiple preemptive hMSC and iMNP. Neurite outgrowth was induced by coculturing hMSC and iPSC-derived motor neuron (iMN) on both two-dimensional (2D) and three-dimensional (3D) spheroid platforms during mature iMN differentiation in vitro. RESULTS: Stepwise combined cell therapy promoted mature motor neuron differentiation and axonal regeneration at the lesional site. In addition, stepwise combined cell therapy improved behavioral recovery and was more effective than single cell therapy alone. In vitro results showed that hMSC and iMN act synergistically and play a critical role in the induction of neurite outgrowth during iMN differentiation and maturation. CONCLUSIONS: Our findings show that stepwise combined cell therapy can induce alterations in the microenvironment for effective cell therapy in SCI. The in vitro results suggest that co-culturing hMSC and iMN can synergistically promote induction of MN neurite outgrowth.

Replacing Animal Testing with Stem Cell-Organoids : Advantages and Limitations.

Various groups including animal protection organizations, medical organizations, research centers, and even federal agencies such as the U.S. Food and Drug Administration, are working to minimize animal use in scientific experiments. This movement primarily stems from animal welfare and ethical concerns. However, recent advances in technology and new studies in medicine have contributed to an increase in animal experiments throughout the years. With the rapid increase in animal testing, concerns arise including ethical issues, high cost, complex procedures, and potential inaccuracies.Alternative solutions have recently been investigated to address the problems of animal testing. Some of these technologies are related to stem cell technologies, such as organ-on-a-chip, organoids, and induced pluripotent stem cell models. The aim of the review is to focus on stem cell related methodologies, such as organoids, that can serve as an alternative to animal testing and discuss its advantages and limitations, alongside regulatory considerations.Although stem cell related methodologies has shortcomings, it has potential to replace animal testing. Achieving this requires further research on stem cells, with potential societal and technological benefits.

Etanercept-synthesizing adipose-derived stem cell secretome: A promising therapeutic option for inflammatory bowel disease.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory condition of the gastrointestinal tract, with tumor necrosis factor (TNF)-α playing a key role in its pathogenesis. Etanercept, a decoy receptor for TNF, is used to treat inflammatory conditions. The secretome derived from adipose-derived stem cells (ASCs) has anti-inflammatory effects, making it a promising therapeutic option for IBD. AIM: To investigate the anti-inflammatory effects of the secretome obtained from ASCs synthesizing etanercept on colon cells and in a dextran sulfate sodium (DSS)-induced IBD mouse model. METHODS: ASCs were transfected with etanercept-encoding mini-circle plasmids to create etanercept-producing cells. The secretory material from these cells was then tested for anti-inflammatory effects both in vitro and in a DSS-induced IBD mouse model. RESULTS: This study revealed promising results indicating that the group treated with the secretome derived from etanercept-synthesizing ASCs [Etanercept-Secretome (Et-Sec) group] had significantly lower expression levels of inflammatory mediators, such as interleukin-6, Monocyte Chemoattractant Protein-1, and TNF-α, when compared to the control secretome (Ct-Sec). Moreover, the Et-Sec group exhibited a marked therapeutic effect in terms of preserving the architecture of intestinal tissue compared to the Ct-Sec. CONCLUSION: These results suggest that the secretome derived from ASCs that synthesize etanercept has potential as a therapeutic agent for the treatment of IBD, potentially enhancing treatment efficacy by merging the anti-inflammatory qualities of the ASC secretome with etanercept's targeted approach to better address the multifaceted pathophysiology of IBD.

Predictors of renal relapse in Koreans with lupus nephritis after achieving complete response: a 35-years of experience at a single center.

BACKGROUND/AIMS: Renal relapse has known to be a poor prognostic factor in patients with lupus nephritis (LN), but there were few studies that identified the risk factors of renal relapse in real world. We conducted this study based on 35-years of experience at a single center to find out predictors of renal relapse in Korean patients with LN after achieving complete response (CR). METHODS: We retrospectively analyzed the clinical, laboratory, pathologic and therapeutic parameters in 296 patients of LN who reached CR. The cumulative risk and the independent risk factors for renal relapse were examined by Kaplan-Meier methods and Cox proportional hazards regression analyses, respectively. RESULTS: The median follow-up period from CR was 123 months. Renal relapse had occurred in 157 patients. Renal relapse occurred in 38.2%, 57.6% and 67.9% of patients within 5-, 10-, and 20-year, respectively. The age at diagnosis of SLE and LN were significantly younger, and the proportions of severe proteinuria and serum hypoalbuminemia were higher in patients with renal relapse. Interestingly, the proportion of receiving cytotoxic maintenance treatment was higher in patients with renal relapse. In Cox proportional hazards regression analyses, only young-age onset of LN (by 10 years, HR = 0.779, p = 0.007) was identified to independent predictor of renal relapse. CONCLUSION: Young-age onset of LN was only independent predictor and the patients with severe proteinuria and serum hypoalbuminemia also tended to relapse more, despite of sufficient maintenance treatment. Studies on more effective maintenance treatment regimens and duration are needed to reduce renal relapse.

Effects of stepwise administration of osteoprotegerin and parathyroid hormone-related peptide DNA vectors on bone formation in ovariectomized rat model.

Osteoporosis is a metabolic bone disease that impairs bone mineral density, microarchitecture, and strength. It requires continuous management, and further research into new treatment options is necessary. Osteoprotegerin (OPG) inhibits bone resorption and osteoclast activity. The objective of this study was to investigate the effects of stepwise administration of OPG-encoded minicircles (mcOPG) and a bone formation regulator, parathyroid hormone-related peptide (PTHrP)-encoded minicircles (mcPTHrP) in osteoporosis. The combined treatment with mcOPG and mcPTHrP significantly increased osteogenic marker expression in osteoblast differentiation compared with the single treatment groups. A model of postmenopausal osteoporosis was established in 12-week-old female rats through ovariectomy (OVX). After 8 weeks of OVX, mcOPG (80 µg/kg) was administered via intravenous injection. After 16 weeks of OVX, mcPTHrP (80 µg/kg) was injected once a week for 3 weeks. The bone microstructure in the femur was evaluated 24 weeks after OVX using micro-CT. In a proof-of-concept study, stepwise treatment with mcOPG and mcPTHrP on an OVX rat model significantly improved bone microstructure compared to treatment with mcOPG or mcPTHrP alone. These results suggest that stepwise treatment with mcOPG and mcPTHrP may be a potential treatment for osteoporosis.

A single-centre retrospective study of factors affecting steroid-free remission of immunoglobulin G4-related disease conducted in South Korea: A notable outcome after complete resection.

OBJECTIVES: Few studies have examined factors affecting steroid-free remission (SFR) in patients with immunoglobulin G4-related disease (IgG4-RD). The aim of this study was to investigate clinical factors affecting SFR in IgG4-RD. METHODS: The medical records of 68 patients who met the 2020 revised comprehensive diagnostic criteria for IgG4-RD were reviewed retrospectively. SFR was defined as remission maintained for at least 6 months without corticosteroids. Cox regression analysis was performed to examine the associations between SFR and various clinical factors. The relapse rate after SFR was examined using the log-rank test. RESULTS: After a median follow-up of 36 months, 30.9% (21/68) of patients with IgG4-RD achieved SFR. Multivariate Cox regression analysis revealed that IgG4-RD diagnosed by complete resection rather than by common diagnostic procedures was the only factor positively associated with SFR (hazard ratio, 7.41; 95% confidence interval, 2.23-24.60; P = .001). Furthermore, relapse after attainment of SFR was significantly less common in the group that underwent complete resection than in the group that did not undergo complete resection (log-rank P = .006). CONCLUSIONS: Patients with IgG4-RD diagnosed by complete resection had a higher likelihood of achieving SFR and a lower rate of relapse after attaining SFR.

Characteristics of patients with psoriatic arthritis in Korea: focusing on axial involvement.

BACKGROUND/AIMS: We aimed to clarify the clinical characteristics of psoriatic arthritis (PsA) in Korean patients focusing on PsA with axial involvement. METHODS: A retrospective medical chart review was performed to identify PsA patients at a single tertiary center. Cases of AS patients with psoriasis were recruited from a prospective AS registry of the same center. Demographics, laboratory findings, and radiologic characteristics were assessed. RESULTS: A total of 69 PsA patients were identified. In PsA patients, spondylitis (46.4%) was the most common form. Compared to AS patients with psoriasis, PsA patients with radiographic axial involvement were older (50.9 vs. 32.4 years; p < 0.001) and showed greater peripheral disease activity (peripheral arthritis 78.1 vs. 12.5%, p < 0.001; enthesitis 50.0 vs. 6.3%, p = 0.003). AS patients with psoriasis presented a higher rate of HLA-B*27 positivity (81.3 vs. 17.2%; p < 0.001) and a more frequent history of inflammatory back pain (100.0 vs. 75.0%; p = 0.039) than PsA patients with radiographic axial involvement. Significant proportions of PsA patients with radiographic axial involvement had cervical spine involvement (10/18, 55.6%) and spondylitis without sacroiliitis (10/23, 43.5%). CONCLUSION: We demonstrate that axial involvement is common in Korean PsA patients, and its characteristics can be distinct from those of AS.

Intranasal administration of induced pluripotent stem cell-derived cortical neural stem cell-secretome as a treatment option for Alzheimer's disease.

BACKGROUND: Alzheimer's disease (AD) is the most common neurodegenerative disorder in the elderly, resulting in gradual destruction of cognitive abilities. Research on the development of various AD treatments is underway; however, no definitive treatment has been developed yet. Herein, we present induced pluripotent stem cell (iPSC)-derived cortical neural stem cell secretome (CNSC-SE) as a new treatment candidate for AD and explore its efficacy. METHODS: We first assessed the effects of CNSC-SE treatment on neural maturation and electromagnetic signal during cortical nerve cell differentiation. Then to confirm the efficacy in vivo, CNSC-SE was administered to the 5×FAD mouse model through the nasal cavity (5 µg/g, once a week, 4 weeks). The cell-mediated effects on nerve recovery, amyloid beta (Aß) plaque aggregation, microglial and astrocyte detection in the brain, and neuroinflammatory responses were investigated. Metabolomics analysis of iPSC-derived CNSC-SE revealed that it contained components that could exert neuro-protective effects or amplify cognitive restorative effects. RESULTS: Human iPSC-derived CNSC-SE increased neuronal proliferation and dendritic structure formation in vitro. Furthermore, CNSC-SE-treated iPSC-derived cortical neurons acquired electrical network activity and action potential bursts. The 5×FAD mice treated with CNSC-SE showed memory restoration and reduced Aß plaque accumulation. CONCLUSIONS: Our findings suggest that the iPSC-derived CNSC-SE may serve as a potential, non-invasive therapeutic option for AD in reducing amyloid infiltration and restoring memory.

Predictors for future development of systemic lupus erythematosus in Korean Sjögren's syndrome patients.

OBJECTIVE: This study determined the impact of demographic factors, clinical manifestations, disease activity, and serological tests at baseline on future SLE development in Sjögren's syndrome (SS) patients. METHODS: This retrospective study assessed 1,082 SS patients without other autoimmune diseases at baseline who visited our hospital between January 2012 and March 2021. We analyzed demographic features, extra-glandular manifestations (EGMs), clinical indices, and laboratory values at baseline between the two groups divided per future SLE development (SS/SLE group vs SS group). The probability and predictors of SLE development in SS patients were estimated using the Kaplan-Meier method and Cox proportional hazards models. RESULTS: The median follow-up duration was 1083.5 days. Forty-nine patients (4.5%) developed SLE that met the 2012 Systemic Lupus International Collaborating Clinics or 2019 EULAR/ACR classification criteria. The baseline EULAR SS disease activity index (ESSDAI) score was significantly higher in the SS/SLE group (p < .001). The SS/SLE group had more lymphadenopathy and renal involvement (p = .015 and p = .017, respectively). Shorter SS disease duration (<3 years) (hazard ratio [HR] = 2.12, p = .0328), high ESSDAI (HR = 8.24, p < .0001), leukopenia (HR = 4.17, p = .0005), thrombocytopenia (HR = 3.38, p = .0059), hypocomplementemia (HR = 29.06, p<.0001), and positive for anti-dsDNA (HR = 13.70, p < .0001), anti-ribonucleoprotein (RNP) (HR = 3.82, p = .0027), and anti-ribosomal P (HR = 6.70, p = .0002) at baseline were SLE development predictors in SS patients. CONCLUSION: Shorter disease duration and higher disease activity of SS at baseline may be risk factors for future SLE development. Serologic predictors of SLE development are hypocomplementemia, leukopenia, thrombocytopenia, and positivity for anti-dsDNA, anti-RNP, and anti-ribosomal P antibodies. If the above factors are observed, close monitoring will be necessary during the follow-up period, considering the possibility of future SLE development.

Development of Spondyloarthritis After COVID-19 in HLA-B27-Positive Monozygotic Twins: Case Reports With Single Cell Transcriptome Profiling.

A subset of spondyloarthritis (SpA) called 'reactive arthritis' is triggered by causal pathogens, usually bacteria related to venereal disease or gastrointestinal infection. During the outbreak of coronavirus disease 2019 (COVID-19), there have been case reports about SpA after COVID-19, but the causality is still elusive. We described cases of 23-year-old monozygotic twins both diagnosed with SpA after COVID-19. The probable linkage between SpA and COVID-19 was elaborated with our cases as well as literature reviews. Of note, shared genetic traits by monozygotic twins, particularly HLA-B27 positivity, might have contributed to their susceptibility to COVID-19-induced SpA. Moreover, single-cell transcriptome analysis revealed that the transcriptomic profile of peripheral compartment of SpA after COVID-19 was distinctive from that of typical radiographic axial SpA as shown by differential expression of ribosomal protein S26 (RPS26) and small nucleolar RNA host gene 5 (SNHG5) in nearly all subsets of peripheral blood mononuclear cells.

Prochondrogenic effect of decellularized extracellular matrix secreted from human induced pluripotent stem cell-derived chondrocytes.

Cartilage is mainly composed of chondrocytes and the extracellular matrix (ECM), which transmits important biochemical and biomechanical signals necessary for differentiation and homeostasis. Human articular cartilage has a low ability for regeneration because it lacks blood vessels, nerves, and lymphatic vessels. Currently, cell therapeutics, including stem cells, provide a promising strategy for cartilage regeneration and treatment; however, there are various hurdles to overcome, such as immune rejection and teratoma formation. In this study, we assessed the applicability of stem cell-derived chondrocyte ECM for cartilage regeneration. Human induced pluripotent stem cell (hiPSC)-derived chondrocytes (iChondrocytes) were differentiated, and decellularized ECM (dECM) was successfully isolated from cultured chondrocytes. Isolated dECM enhanced the in vitro chondrogenesis of iPSCs when recellularized. Implanted dECM also restored osteochondral defects in a rat osteoarthritis model. A possible association with the glycogen synthase kinase-3 beta (GSK3ß) pathway demonstrated the fate-determining importance of dECM in regulating cell differentiation. Collectively, we suggest the prochondrogenic effect of hiPSC-derived cartilage-like dECM and offer a promising approach of a noncellular therapeutic for articular cartilage reconstruction without cell transplantation. STATEMENT OF SIGNIFICANCE: Human articular cartilage has low ability for regeneration and cell culture-based therapeutics could aid cartilage regeneration. Yet, the applicability of human induced pluripotent stem cell-derived chondrocyte (iChondrocyte) extracellular matrix (ECM) has not been elucidated. Therefore, we first differentiated iChondrocytes and isolated the secreted ECM by decellularization. Recellularization was performed to confirm the pro-chondrogenic effect of the decellularized ECM (dECM). In addition, we confirmed the possibility of cartilage repair by transplanting the dECM into the cartilage defect in osteochondral defect rat knee joint. We believe that our proof-of-concept study will serve as a basis for investigating the potential of dECM obtained from iPSC-derived differentiated cells as a non-cellular resource for tissue regeneration and other future applications.

Recent updates of stem cell-based erythropoiesis.

Blood transfusions are now an essential part of modern medicine. Transfusable red blood cells (RBCs) are employed in various therapeutic strategies; however, the processes of blood donation, collection, and administration still involve many limitations. Notably, a lack of donors, the risk of transfusion-transmitted disease, and recent pandemics such as COVID-19 have prompted us to search for alternative therapeutics to replace this resource. Originally, RBC production was attempted via the ex vivo differentiation of stem cells. However, a more approachable and effective cell source is now required for broader applications. As a viable alternative, pluripotent stem cells have been actively used in recent research. In this review, we discuss the basic concepts related to erythropoiesis, as well as early research using hematopoietic stem cells ex vivo, and discuss the current trend of in vitro erythropoiesis using human-induced pluripotent stem cells.

Safety and effectiveness of tofacitinib in Korean adult patients with rheumatoid arthritis: A post-marketing surveillance study.

OBJECTIVES: The aim of this article is to assess the safety and effectiveness of tofacitinib in patients with rheumatoid arthritis in routine clinical settings in Korea. METHODS: This is a prospective, multi-centre post-marketing surveillance study. Data were prospectively collected within 6 months after the start of tofacitinib therapy. Safety was evaluated based on the presence of adverse events (AEs) observed in patients who received at least one dose of tofacitinib. Effectiveness was assessed according to the proportion of patients who achieved low disease activity and remission, American College of Rheumatology 20 criteria (ACR20), European League Against Rheumatism (EULAR) response, and change of Disease Activity Score in 28 Joints (DAS28). RESULTS: The incidence rates [patients with events per 100 patient-years (PY)] of AEs and serious AEs were 56.92 and 10.69, respectively. Regarding AEs of special interest, the incidence rates were 4.33 per 100 PY for serious infections and infestations, 5.78 per 100 PY for herpes zoster, no event of tuberculosis, 0.29 per 100 PY for malignancy, 0.29 per 100 PY for venous thromboembolism (one event of deep vein thrombosis and no event of pulmonary embolism), 0.87 per 100 PY for major adverse cardiovascular event, and 0.58 per 100 PY for mortality. Moreover, ∼40.48% and 21.60% of patients achieved low disease activity and remission of DAS28-erythrocyte sedimentation rate. The EULAR response was classified as good responders with 39.12% in the DAS28-erythrocyte sedimentation rate. CONCLUSIONS: The benefit/risk profile of tofacitinib in adult patients with rheumatoid arthritis in routine clinical settings in Korea was similar to long-term clinical trial data.

Differential effects of periodontal microbiome on the rheumatoid factor induction during rheumatoid arthritis pathogenesis.

Association between exposure to periodontal bacteria and development of autoantibodies related to rheumatoid arthritis (RA) has been widely accepted; however, direct causal relationship between periodontal bacteria and rheumatoid factor (RF) is currently not fully understood. We investigated whether periodontal bacteria could affect RF status. Patients with preclinical, new-onset, or chronic RA underwent periodontal examination, and investigation of subgingival microbiome via 16S rRNA sequencing. Degree of arthritis and RF induction was examined in collagen-induced arthritis (CIA) mice that were orally inoculated with different periodontal bacteria species. Subsequently, single-cell RNA sequencing analysis of the mouse spleen cells was performed. Patients with preclinical RA showed an increased abundance of the Porphyromonadacae family in the subgingival microbiome compared to those with new-onset or chronic RA, despite comparable periodontitis severity among them. Notably, a distinct subgingival microbial community was found between patients with high-positive RF and those with negative or low-positive RF (p=0.022). Oral infections with the periodontal pathogens P. gingivalis and Treponema denticola in CIA mice similarly enhanced arthritis score, but resulted in different levels of RF induction. Genes related to B cell receptor signaling, B cell proliferation, activation, and differentiation, and CD4+ T cell costimulation and cytokine production were involved in the differential induction of RF in mice exposed to different bacteria. In summary, periodontal microbiome might shape RF status by affecting the humoral immune response during RA pathogenesis.

Anti-fibrotic effect of a selective estrogen receptor modulator in systemic sclerosis.

BACKGROUND: The rarity of systemic sclerosis (SSc) has hampered the development of therapies for this intractable autoimmune disease. Induced pluripotent stem cell (iPSC) can be differentiated into the key disease-affected cells in vitro. The generation of patient-derived iPSCs has opened up possibilities for rare disease modeling. Since these cells can recapitulate the disease phenotypes of the cell in question, they are useful high-throughput platforms for screening for drugs that can reverse these abnormal phenotypes. METHODS: SSc iPSC was generated from PBMC by Sendai virus. Human iPSC lines from SSc patients were differentiated into dermal fibroblasts and keratinocytes. The iPSC-derived differentiated cells from the SSc patients were used on high-throughput platforms to screen for FDA-approved drugs that could be effective treatments for SSc. RESULTS: Skin organoids were generated from these cells exhibited fibrosis that resembled SSc skin. Screening of the 770-FDA-approved drug library showed that the anti-osteoporotic drug raloxifene reduced SSc iPSC-derived fibroblast proliferation and extracellular matrix production and skin fibrosis in organoids and bleomycin-induced SSc-model mice. CONCLUSIONS: This study reveals that a disease model of systemic sclerosis generated using iPSCs-derived skin organoid is a novel tool for in vitro and in vivo dermatologic research. Since raloxifene and bazedoxifene are well-tolerated anti-osteoporotic drugs, our findings suggest that selective estrogen receptor modulator (SERM)-class drugs could treat SSc fibrosis.

Endotracheal intubation in rabbits using a video laryngoscope with a modified blade.

Rabbits are being increasingly used as companion animals, and in research; thus, the need for proper veterinary care for rabbits has increased. Surgical access is more challenging in rabbits under inhalation anesthesia compared to other animals, such as dogs and cats. Rabbits have a very narrow and deep oral cavity, large incisors, and a large tongue. Moreover, their temporomandibular joint has limited mobility, making it more difficult to approach the larynx. Various methods have been proposed to overcome this difficulty. The video laryngoscope was introduced in 1999 and is useful when airway intubation is unsuccessful using a conventional laryngoscope. We postulated that a video laryngoscope with a modified size 1 Macintosh blade (McGrath MAC Video Laryngoscope, Medtronic, USA) would facilitate the intubation of New Zealand White rabbits. Sixteen specific-pathogen-free male New Zealand White rabbits weighing 3.45-4.70 kg were studied. All rabbits were intubated using the video laryngoscope. Typically, a 3.0 mm endotracheal tube was used for rabbits weighing < 4 kg, while a 3.5 mm tube was used in those weighing > 4 kg. During surgery, anesthesia was well maintained, and there were no major abnormalities in the animals' conditions. No rabbit developed breathing difficulties or anorexia after recovering from anesthesia. We established an intubation method using a video laryngoscope with a modified blade and stylet in the supine (ventrodorsal) position and successfully applied it in 16 rabbits. It is useful for training novices and for treating rabbits in veterinary hospitals with few staff members and animal research facilities where there are insufficient human resources.

Preferential stimulation of melanocytes by M2 macrophages to produce melanin through vascular endothelial growth factor.

Post-inflammatory hyperpigmentation is a skin discoloration process that occurs following an inflammatory response or wound. As the skin begins to heal, macrophages first exhibit a proinflammatory phenotype (M1) during the early stages of tissue repair and then transition to a pro-healing, anti-inflammatory phenotype (M2) in later stages. During this process, M1 macrophages remove invading bacteria and M2 macrophages remodel surrounding tissue; however, the relationship between macrophages and pigmentation is unclear. In this study, we examined the effect of macrophages on melanin pigmentation using human induced pluripotent stem cells. Functional melanocytes were differentiated from human induced pluripotent stem cells and named as hiMels. The generated hiMels were then individually cocultured with M1 and M2 macrophages. Melanin synthesis decreased in hiMels cocultured with M1 macrophages but significantly increased in hiMels cocultured with M2 macrophages. Moreover, the expression of vascular endothelial growth factor was increased in M2 cocultured media. Our findings suggest that M2 macrophages, and not M1 macrophages, induce hyperpigmentation in scarred areas of the skin during tissue repair.