In Vivo Reprogramming Dysfunctional Retinal Ganglion Cells and Visual-phototransduction via Wireless Charging Nanogold for Leber's Hereditary Optic Neuropathy.

Gene therapy offers a promising treatment for Leber's hereditary optic neuropathy (LHON), a disease of retinal ganglion cell (RGC) degeneration with severe vision loss caused by mitochondria-NADH dehydrogenase 4 (MT-ND4) mutations. However, optimizing mitochondria-targeted gene delivery to promote RGC regeneration and visual-photoreception recovery remains challenging in LHON. Here, mitochondria-targeted wireless charging gold nanoparticles (WCGs), doubling as a wireless charging-mediated gene-delivery platform and electric stimulus-restored phototransduction, are developed for LHON treatment.

Multimodal single-cell transcriptomics with patient-specific iPSC-derived airway organoids as a drug screening approach for cystic fibrosis with nonsense mutations.

Cystic fibrosis arises from loss-of-function mutations in the CFTR gene, disrupting epithelial ion homeostasis and impairing airway mucus clearance. While missense mutations typically lead to minor conformational alterations that can be rectified with pharmacological interventions, nonsense mutations pose a more significant therapeutic challenge. In this research, we established an in vitro model of cystic fibrosis (CF) employing patient-specific induced pluripotent stem cells (iPSCs) that contain the CFTR-S308X nonsense mutation.

Epitranscriptomic Modulation of TET2 Inhibition Suppressed SARS-CoV-2 Infection and Blocked Viral Nucleocapsid Protein in Induced-Pluripotent-Stem-Cell-Derived Cardiomyocyte Screening Models.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) viral infection has been associated with severe cardiovascular complications. However, the role of epitranscriptional modulation involved in SARS-CoV-2-infected myocarditis is still unclear. Ten-eleven translocation 2 (TET2), a methylcytosine dioxygenase, plays key roles in DNA demethylation during viral infection and host-virus interactions.

Induced pluripotent stem cell-derived conditioned medium, as well as nintedanib, ameliorates bleomycin-induced pulmonary fibrosis via suppressing endothelial-mesenchymal transition.

Background: Pulmonary fibrosis (PF), a debilitating lung disease, is heavily influenced by fibroblasts, which may arise from pulmonary endothelial cells through a process called endothelial-mesenchymal transition (EndoMT). While nintedanib and induced pluripotent stem cell-derived conditioned medium (iPSC-CM) have shown promise in PF treatment, their ability to suppress EndoMT remains uncertain.

Methods: PF was induced in C57BL/6 mice via intratracheal bleomycin (BLM) instillation.

Ophthalmic Tethered Gold Yarnball-Mediated Retained Drug Delivery for Eye Fundus Disease Treatment.

Eye fundus diseases, such as retinal degenerative diseases, which lead to blindness in ≈12% of individuals aged >65 years, cause permanent damage to retinal cells. The antioxidant quercetin (QC) is promising for the effective treatment of eye fundus diseases; however, its poor solubility and low retention rate often limit its clinical application. Herein, an in situ ophthalmic tethered gold yarnball (GY) that doubles as an ocular retention agent and QC reservoir to overcome low fundus drug retention is developed.

Towards a holistic framework for multimodal LLM in 3D brain CT radiology report generation.

Multi-modal large language models (MLLMs) have transformed the landscape of modern healthcare, with automated radiology report generation (RRG) emerging as a cutting-edge application. While 2D MLLM-based RRG has been well established, its utility for 3D medical images remains largely unexplored. In this regard, we curate the 3D-BrainCT dataset (18,885 text-scan pairs) and develop BrainGPT, a clinically visual instruction-tuned (CVIT) model designed for 3D CT RRG.

Reprogramming patient-induced pluripotent stem cell-specific retinal organoids for deciphering epigenetic modifications of RNA methylation.

Background: Induced pluripotent stem cell (iPSC) technology has emerged as a powerful tool for disease modeling, providing an innovative platform for investigating disease mechanisms. iPSC-derived organoids, including retinal organoids, offer patient-specific models that closely replicate in vivo cellular environments, making them ideal for studying retinal neurodegenerative diseases where retinal ganglion cells (RGCs) are impacted. N6-methyladenosine (m6A), a prevalent internal modification in eukaryotic mRNAs, plays a critical role in RNA metabolic processes such as splicing, stability, translation, and transport.

Identifying Multiomic Signatures of X-Linked Retinoschisis-Derived Retinal Organoids and Mice Harboring Patient-Specific Mutation Using Spatiotemporal Single-Cell Transcriptomics.

X-linked retinoschisis (XLRS) is an inherited retinal disorder with severe retinoschisis and visual impairments. Multiomics approaches integrate single-cell RNA-sequencing (scRNA-seq) and spatiotemporal transcriptomics (ST) offering potential for dissecting transcriptional networks and revealing cell-cell interactions involved in biomolecular pathomechanisms. Herein, a multimodal approach is demonstrated combining high-throughput scRNA-seq and ST to elucidate XLRS-specific transcriptomic signatures in two XLRS-like models with retinal splitting phenotypes, including genetically engineered (Rs1) mice and patient-derived retinal organoids harboring the same patient-specific p.

N-methyladenosine and its epitranscriptomic effects on hematopoietic stem cell regulation and leukemogenesis.

N6-methyladenosine (m6A) RNA modification orchestrates cellular epitranscriptome through tuning the homeostasis of transcript stability, translation efficiency, and the transcript affinity toward RNA-binding proteins (RBPs). An aberrant m6A deposition on RNA can lead toward oncogenic expression profile (mRNA), impaired mitochondrial metabolism (mtRNA), and translational suppression (rRNA) of tumor suppressor genes. In addition, non-coding RNAs (ncRNAs), such as X-inactive specific transcript (XIST), miRNAs, and α-ketoglutarate-centric metabolic transcripts are also regulated by the m6A epitranscriptome.

Harnessing the potential of mesenchymal stem cells-derived exosomes in degenerative diseases.

Mesenchymal stem cells (MSCs) have gained attention as a promising therapeutic approach in both preclinical and clinical osteoarthritis (OA) settings. Various joint cell types, such as chondrocytes, synovial fibroblasts, osteoblasts, and tenocytes, can produce and release extracellular vesicles (EVs), which subsequently influence the biological activities of recipient cells. Recently, extracellular vesicles derived from mesenchymal stem cells (MSC-EVs) have shown the potential to modulate various physiological and pathological processes through the modulation of cellular differentiation, immune responses, and tissue repair.

Gradient conducting polymer surfaces with netrin-1-conjugation promote axon guidance and neuron transmission of human iPSC-derived retinal ganglion cells.

Major advances have been made in utilizing human-induced pluripotent stem cells (hiPSCs) for regenerative medicine. Nevertheless, the delivery and integration of hiPSCs into target tissues remain significant challenges, particularly in the context of retinal ganglion cell (RGC) restoration. In this study, we introduce a promising avenue for providing directional guidance to regenerated cells in the retina.

Inhibition of angiogenesis by the secretome from iPSC-derived retinal ganglion cells with Leber's hereditary optic neuropathy-like phenotypes.

The blood supply in the retina ensures photoreceptor function and maintains regular vision. Leber's hereditary optic neuropathy (LHON), caused by the mitochondrial DNA mutations that deteriorate complex I activity, is characterized by progressive vision loss. Although some reports indicated retinal vasculature abnormalities as one of the comorbidities in LHON, the paracrine influence of LHON-affected retinal ganglion cells (RGCs) on vascular endothelial cell physiology remains unclear.

Predicting Risks of Dry Eye Disease Development Using a Genome-Wide Polygenic Risk Score Model.

Purpose: The purpose of this study was to conduct a large-scale genome-wide association study (GWAS) and construct a polygenic risk score (PRS) for risk stratification in patients with dry eye disease (DED) using the Taiwan Biobank (TWB) databases.

Methods: This retrospective case-control study involved 40,112 subjects of Han Chinese ancestry, sourced from the publicly available TWB. Cases were patients with DED (n = 14,185), and controls were individuals without DED (n = 25,927).

Paracrinal regulation of neutrophil functions by coronaviral infection in iPSC-derived alveolar type II epithelial cells.

Coronaviruses (CoVs) are enveloped single-stranded RNA viruses that predominantly attack the human respiratory system. In recent decades, several deadly human CoVs, including SARS-CoV, SARS-CoV-2, and MERS-CoV, have brought great impact on public health and economics. However, their high infectivity and the demand for high biosafety level facilities restrict the pathogenesis research of CoV infection.

Decoding and reconstructing disease relations between dry eye and depression: a multimodal investigation comprising meta-analysis, genetic pathways and Mendelian randomization.

Introduction: The clinical presentations of dry eye disease (DED) and depression (DEP) often comanifest. However, the robustness and the mechanisms underlying this association were undetermined.

Objectives: To this end, we set up a three-segment study that employed multimodality results (meta-analysis, genome-wide association study [GWAS] and Mendelian randomization [MR]) to elucidate the association, common pathways and causality between DED and DEP.

Comparison of the mesodermal differentiation potential between embryonic stem cells and scalable induced pluripotent stem cells.

Background: Mesenchymal stem cells (MSCs) have promising potential in clinical application, whereas their limited amount and sources hinder their bioavailability. Embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) have become prominent options in regenerative medicine as both possess the ability to differentiate into MSCs.

Methods: Recently, our research team has successfully developed human leukocyte antigen (HLA)-homozygous iPSC cell lines with high immune compatibility, covering 13.

Dysregulation of the circRNA_0087207/miR-548c-3p/PLSR1-TGFB2 axis in Leber hereditary optic neuropathy in vitro.

Background: Leber hereditary optic neuropathy (LHON) is mainly the degeneration of retinal ganglion cells (RGCs) associated with high apoptosis and reactive oxygen species (ROS) levels, which is accepted to be caused by the mutations in the subunits of complex I of the mitochondrial electron transport chain. The treatment is still infant while efforts of correcting genes or using antioxidants do not bring good and consistent results. Unaffected carrier carries LHON mutation but shows normal phenotype, suggesting that the disease's pathogenesis is complex, in which secondary factors exist and cooperate with the primary complex I dysfunction.

Manganese-induced neurological pyroptosis: Unveiling the mechanism through the ROS activaed Caspase-3/GSDME signaling pathway.

Manganese (Mn) is an essential micronutrient in maintaining homeostasis in the human body, while excessive Mn exposure can lead to neurological disorders. To investigate whether there is an association between elevated ROS and pyroptosis caused by Mn exposure using both in vitro and in vivo models. We exposed BV2 and N2a, which represent microglial cells and Neuroblastoma cells in the brain, respectively, to different concentrations of Mn for 24 h.

Leber's hereditary optic neuropathy: Update on the novel genes and therapeutic options.

A maternal inheritance disorder called Leber's hereditary optic neuropathy (LHON) is the most common primary mitochondrial deoxyribonucleic acid (DNA) disorder. In most studies, there are more male patients than female patients, which contradicts the usual pattern in mitochondrial hereditary diseases. This suggests that nuclear DNA (nDNA) may influence the degeneration of retinal ganglion cells (RGCs) in LHON.

HLA-Homozygous iPSC-Derived Mesenchymal Stem Cells Rescue Rotenone-Induced Experimental Leber's Hereditary Optic Neuropathy-like Models In Vitro and In Vivo.

Background: Mesenchymal stem cells (MSCs) hold promise for cell-based therapy, yet the sourcing, quality, and invasive methods of MSCs impede their mass production and quality control. Induced pluripotent stem cell (iPSC)-derived MSCs (iMSCs) can be infinitely expanded, providing advantages over conventional MSCs in terms of meeting unmet clinical demands.

Methods: The potential of MSC therapy for Leber's hereditary optic neuropathy (LHON) remains uncertain.

TMEM132D and VIPR2 Polymorphisms as Genetic Risk Loci for Retinal Detachment: A Genome-Wide Association Study and Polygenic Risk Score Analysis.

Purpose: Retinal detachment (RD) is a sight-threatening ocular disease caused by separation of the neurosensory retina from the underlying retinal pigment epithelium layer. Its genetic basis is unclear because of a limited amount of data. In this study, we aimed to identify genetic risk loci associated with RD in participants without diabetes mellitus and to construct a polygenic risk score (PRS) to predict the risk of RD.

Current trends and promising clinical utility of IPSC-derived MSC (iMSC).

Mesenchymal stem cells (MSCs) differentiated from human induced pluripotent stem cells (iPSC) or induced MSC (iMSCs) are expected to address issues of scalability and safety as well as the difficulty in producing homogenous clinical grade MSCs as demonstrated by the promising outcomes from preclinical and clinical trials, currently ongoing. The assessment of iMSCs based in vitro and in vivo studies have thus far showed more superior performance as compared to that of the primary or native human MSCs, in terms of cell proliferation, expansion capacity, immunomodulation properties as well as the influence of paracrine signaling and exosomal influence in cell-cell interaction. In this chapter, an overview of current well-established methods in generating a sustainable source of iMSCs involving well defined culture media is discussed followed by the properties of iMSC as compared to that of MSC and its promising prospects for continuous development into potential clinical grade applications.

Modifications of lipid pathways restrict SARS-CoV-2 propagation in human induced pluripotent stem cell-derived 3D airway organoids.

Background: Modifications of lipid metabolism were closely associated with the manifestations and prognosis of coronavirus disease of 2019 (COVID-19). Pre-existing metabolic conditions exacerbated the severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection while modulations of aberrant lipid metabolisms alleviated the manifestations. To elucidate the underlying mechanisms, an experimental platform that reproduces human respiratory physiology is required.