Aging Brain, Год журнала: 2025, Номер 7, С. 100136 - 100136
Опубликована: Янв. 1, 2025
Язык: Английский
Journal of Human Genetics, Год журнала: 2022, Номер 68(3), С. 131 - 152
Опубликована: Июнь 13, 2022
Abstract Amyotrophic lateral sclerosis (ALS) is an intractable disease that causes respiratory failure leading to mortality. The main locus of ALS motor neurons. success antisense oligonucleotide (ASO) therapy in spinal muscular atrophy (SMA), a neuron disease, has triggered paradigm shift developing therapies. causative genes and disease-modifying genes, including those sporadic ALS, have been identified one after another. Thus, the freedom target choice for gene expanded by ASO strategy, new avenues therapeutic development. Tofersen superoxide dismutase 1 (SOD1) was pioneer ALS. Improving protocols devising early interventions are vital. In this review, we updated knowledge We summarized genetic mutations familial their clinical features, focusing on SOD1 , fused sarcoma (FUS) transacting response DNA-binding protein. frequency C9ORF72 mutation low Japan, unlike Europe United States, while FUS more common, indicating vary ethnicity. A genome-wide association study revealed which could be novel therapy. current status prospects development were discussed, ethical issues. Furthermore, discussed potential axonal pathology as targets from perspective intervention, intra-axonal transcription factors, neuromuscular junction disconnection, dysregulated local translation, abnormal protein degradation, mitochondrial pathology, impaired transport, aberrant cytoskeleton, axon branching. simultaneously discuss important pathological states cell bodies: persistent stress granules, disrupted nucleocytoplasmic cryptic splicing. based elucidation intervention molecular expected become strategy
Язык: Английский
Процитировано
92
Med, Год журнала: 2022, Номер 4(1), С. 51 - 66.e10
Опубликована: Ноя. 16, 2022
BackgroundHuman induced pluripotent stem cells (iPSCs) are expected to be useful for regenerative medicine many diseases. Many researchers have focused on and enabled the generation of differentiated or tissue-like structures, including organoids, which help ameliorate target To promote such cell therapies, we established a clinically applicable iPSC haplobank matching as people possible in Japan.MethodsThrough cooperation with several organizations, recruited donors whose human leukocyte antigens (HLAs) involved immunorejection were homozygous. The peripheral umbilical cord blood collected from was used production by electroporation episomal vectors. These lines then subjected testing, genome analyses sterility, maximize safety.FindingsWe constructed clinical-grade 27 7 according good manufacturing practice regulations. However, reasons avoid using include presence residual vectors genetic mutations cancer-related genes.ConclusionsThis provides HLA-matched approximately 40% Japanese population. Since haplobank's release 2015, these been more than 10 clinical trials. establishment this is an important step toward application iPSCs therapies.FundingThis study supported research center network realization Japan Agency Medical Research Development (AMED) under grant number JP20bm0104001h0108.
Язык: Английский
Процитировано
75
Molecular Cancer, Год журнала: 2023, Номер 22(1)
Опубликована: Ноя. 28, 2023
The advent of iPSCs has brought about a significant transformation in stem cell research, opening up promising avenues for advancing cancer treatment. formation is multifaceted process influenced by genetic, epigenetic, and environmental factors. offer distinctive platform investigating the origin cancer, paving way novel approaches to treatment, drug testing, tailored medical interventions. This review article will provide an overview science behind iPSCs, current limitations challenges iPSC-based therapy, ethical social implications, comparative analysis with other types also discuss applications tumorigenesis, future tumorigenesis highlight successful case studies utilizing research. conclusion summarize advancements made research importance continued investment iPSC unlock full potential these cells.
Язык: Английский
Процитировано
66
Signal Transduction and Targeted Therapy, Год журнала: 2024, Номер 9(1)
Опубликована: Апрель 26, 2024
The induced pluripotent stem cell (iPSC) technology has transformed in vitro research and holds great promise to advance regenerative medicine. iPSCs have the capacity for an almost unlimited expansion, are amenable genetic engineering, can be differentiated into most somatic types. been widely applied model human development diseases, perform drug screening, develop therapies. In this review, we outline key developments iPSC field highlight immense versatility of modeling therapeutic applications. We begin by discussing pivotal discoveries that revealed potential a nucleus reprogramming led successful generation iPSCs. consider molecular mechanisms dynamics as well numerous methods available induce pluripotency. Subsequently, discuss various iPSC-based cellular models, from mono-cultures single type complex three-dimensional organoids, how these models elucidate diseases. use examples neurological disorders, coronavirus disease 2019 (COVID-19), cancer diversity disease-specific phenotypes modeled using iPSC-derived cells. also used high-throughput screening toxicity studies. Finally, process developing autologous allogeneic therapies their alleviate
Язык: Английский
Процитировано
56
Neuron, Год журнала: 2023, Номер 111(8), С. 1191 - 1204.e5
Опубликована: Фев. 9, 2023
Using induced pluripotent stem cells (iPSCs) to understand the mechanisms of neurological disease holds great promise; however, there is a lack well-curated lines from large array participants. Answer ALS has generated over 1,000 iPSC control and amyotrophic lateral sclerosis (ALS) patients along with clinical whole-genome sequencing data. The current report summarizes cell marker gene expression in motor neuron cultures derived 92 healthy 341 participants using 32-day differentiation protocol. This largest set iPSCs be differentiated into neurons, characterization suggests that composition sex are significant sources variability need carefully controlled for future studies. These data reported as resource scientific community will utilize modeling wider omics being made available these samples.
Язык: Английский
Процитировано
52
Journal of Neuroinflammation, Год журнала: 2023, Номер 20(1)
Опубликована: Фев. 12, 2023
In Parkinson's disease (PD), neurotoxic microglia, Th1 cells, and Th17 cells are overactivated. Overactivation of these immune exacerbates the process leads to pathological development pro-inflammatory cytokines, chemokines, contact-killing compounds, causing loss dopaminergic neurons. So far, we have mainly focused on role specific class in PD while neglecting impact interactions among disease. Therefore, this review demonstrates reciprocal interplays between microglia T associated subpopulations through cytokine chemokine production that impair and/or protect PD. Furthermore, potential targets models neuroinflammation highlighted provide new ideas/directions for future research.
Язык: Английский
Процитировано
45
Cell stem cell, Год журнала: 2023, Номер 30(6), С. 766 - 780.e9
Опубликована: Июнь 1, 2023
iPSC-based drug discovery led to a phase 1/2a trial of ropinirole in ALS. 20 participants with sporadic ALS received or placebo for 24 weeks the double-blind period evaluate safety, tolerability, and therapeutic effects. Adverse events were similar both groups. During period, muscle strength daily activity maintained, but decline ALSFRS-R, which assesses functional status patients, was not different from that group. However, open-label extension group showed significant suppression ALSFRS-R an additional 27.9 disease-progression-free survival. iPSC-derived motor neurons dopamine D2 receptor expression potential involvement SREBP2-cholesterol pathway Lipid peroxide represents clinical surrogate marker assess disease progression efficacy. Limitations include small sample sizes high attrition rates requiring further validation.
Язык: Английский
Процитировано
41
Science Advances, Год журнала: 2023, Номер 9(42)
Опубликована: Окт. 20, 2023
Human-induced pluripotent stem cells (hiPSCs) have emerged as a promising in vitro model system for studying neurodevelopment. However, current models remain limited their ability to incorporate tunable biomechanical signaling cues imparted by the extracellular matrix (ECM). The native brain ECM is viscoelastic and stress-relaxing, exhibiting time-dependent response an applied force. To recapitulate remodelability of neural ECM, we developed family protein-engineered hydrogels that exhibit stress relaxation rates. hiPSC-derived progenitor (NPCs) encapsulated within these gels underwent rate-dependent maturation. Specifically, NPCs with faster rates extended longer, more complex neuritic projections, exhibited decreased metabolic activity, expressed higher levels genes associated By inhibiting actin polymerization, observed projections concomitant decrease maturation gene expression. Together, results suggest microenvironmental viscoelasticity sufficient bias human NPC
Язык: Английский
Процитировано
41
Journal of Cellular and Molecular Medicine, Год журнала: 2023, Номер 27(20), С. 3075 - 3089
Опубликована: Июль 24, 2023
Resveratrol is an organic compound widely studied for its therapeutic uses. We investigated whether resveratrol exerts cardioprotective effects by inhibiting ferroptosis via the Sirt1/p53 pathway. A heart failure model was established aortic coarctation in Sirt1 knockout mice. The superoxide dismutase (SOD), glutathione (GSH) levels and mitochondrial morphology murine tissues were assessed at different time points to determine role of progression. cardiac function mice with evaluated determining brain natriuretic peptide (BNP) sST2 concentration conducting echocardiography. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) transfected p53 K382R mutant interference lentiviral vectors. Immunoprecipitation (IP) experiments performed investigate influences K382 acetylation SLC7A11 expression modulation. improved decelerated fibrosis progression failure. However, ability prevent treat lost after silencing Sirt1. reduced diminishing acetylation, reducing degradation SLC7A11, increasing GSH peroxidase 4 (GPX4) cells. In conclusion, activating pathway failure, decreased depletion inhibited ferroptosis, function.
Язык: Английский
Процитировано
36
Journal of Movement Disorders, Год журнала: 2023, Номер 16(1), С. 22 - 41
Опубликована: Янв. 11, 2023
Parkinson’s disease (PD) is the second most common neurodegenerative disorder after Alzheimer’s disease, affecting 1%–2% of population over age 65. As ages, it anticipated that burden on society will significantly escalate. Although symptom reduction by currently available pharmacological and/or surgical treatments improves quality life many PD patients, there are no can slow down, halt, or reverse progression. Because loss a specific cell type, midbrain dopamine neurons in substantia nigra, main cause motor dysfunction PD, considered promising target for replacement therapy. Indeed, numerous preclinical and clinical studies using fetal transplantation have provided proof concept therapy may be viable therapeutic approach PD. However, use human cells remains fraught with controversy due to fundamental ethical, practical, limitations. Groundbreaking work pluripotent stem (hPSCs), including embryonic induced cells, coupled extensive basic research field offers potential hPSC-based become realistic treatment regimen once several major issues successfully addressed. In this review, we discuss prospects challenges
Язык: Английский
Процитировано
26