The development of T cells has been characterized as taking place over three stages: nave (Tn), central memory (Tcm), and effector memory (Tem) cells.
Polarization diversity of human CD4+ stem cell memory T cells.
Sex, AgeView Samples
We established several iPSCs from healthy donors, familial ALS (FALS) patients, and sporadic ALS (SALS) patients. Using our differentiation protocol originally developed, we differentiated these iPSCs toward spinal motor neurons (MNs) and reproduced ALS pathology in a dish.
Modeling sporadic ALS in iPSC-derived motor neurons identifies a potential therapeutic agent.
Specimen part, Disease, Treatment, SubjectView Samples
A huge number of microorganisms are colonized in human gut and the balance of their composition is closely related to human health. Recently, many probiotics such as bifidobacteria or lactobacilli have been introduced in our life as effective agents. However, we have not well understood their beneficial mechanisms including host-bacterial crosstalk. Accordingly, we took advantage of the protective mechanisms of probiotics against lethal infection of enterohemorrhagic Escherichia coli O157:H7 in murine gnotobiote model system
Bifidobacteria can protect from enteropathogenic infection through production of acetate.
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Recent studies indicated that iPSCs retain an epigenetic memory relating to their cell of origin that affected their properties and their functions as PSCs.
Modeling neurological diseases with induced pluripotent cells reprogrammed from immortalized lymphoblastoid cell lines.
Specimen part, SubjectView Samples
The number of elderly patients with spinal cord injury (SCI) is increasing worldwide, representing a serious burden for both the affected patients and the community. Previous studies have demonstrated that neural stem cell (NSC) transplantation is an effective treatment for SCI in young animals. Here we show that NSC transplantation is as effective in aged mice as it is in young mice, even though aged mice exhibit more severe neurological deficits after SCI. NSCs grafted into aged mice exhibited better survival than did those grafted into young mice. Furthermore, we show that the neurotrophic factor HGF plays a key role in the enhanced functional recovery after NSC transplantation observed in aged mice with SCI. The unexpected results of the present study suggest that NSC transplantation is a potential therapeutic modality for SCI, even in elderly patients.
No associated publication
Sex, Specimen partView Samples
The major antioxidant glutathione (GSH) protects cancer cells from oxidative damage leading to ferroptosis, an iron-dependent cell death. Therapy-resistant cancer cells often manifest high expression of the cystine-glutamate antiporter subunit xCT which enhances cystine uptake leading to GSH synthesis and thereby survive oxidative damage and ferroptosis. The use of GSH-depleting agents including xCT inhibitors might thus be expected to enhance the efficacy of cancer therapy. On the other hand, the efficacy of xCT-targeted therapy depends on the cellular metabolism affecting antioxidant system in cancer cells and metabolic reprograming might reduce the efficacy of cancer therapy using xCT inhibitors. Recently, to overcome the resistance to xCT-targeted therapy, we performed a library screening and identified an oral anesthetics dyclonine (DYC) as a sensitizing drug for xCT inhibitor sulfasalazine (SSZ). However, DYC is a local anesthetic and might not suitable for the systemic administration combined with SSZ in a clinical setting. In this study, we identified a vasodilator oxyfedrine (OXY) which is clinically used in systemic administration also acts as a sensitizing drug to GSH-depleting agents in multiple type of cancer cells. OXY and DYC share the motif required for the covalent inhibition of aldehyde dehydrogenases (ALDHs), and combined treatment with OXY and SSZ induced the accumulation of cytotoxic aldehyde 4-hydroxynonenal (4-HNE) and induce cell death in SSZ-resistant cancer cells. Furthermore, we found that OXY sensitizes cancer cells to radiation therapy which decreases intracellular GSH content. Our findings establish a rationale for repurposing of OXY as a sensitizing drug for xCT-targeted cancer therapy.
Vasodilator oxyfedrine inhibits aldehyde metabolism and thereby sensitizes cancer cells to xCT-targeted therapy.
Specimen partView Samples
Recent studies have shown that stem cell memory T (TSCM) cell-like properties are important for the successful adoptive immune therapy by the chimeric antigen receptor-engineered-T (CAR-T) cells. We previously reported that both human and murine activated T cells are converted into stem cell memory-like T (iTSCM) cells by co-culture with stromal OP9 cells expressing the NOTCH-ligand. However, the mechanism of NOTCH-mediated iTSCM reprogramming remains to be elucidated. Here, we report that the NOTCH/OP9 system efficiently converts conventional human CAR-T cells into TSCM-like CAR-T, “CAR-iTSCM” cells, and that the mitochondrial metabolic reprogramming plays a key role in this conversion. The NOTCH signals promote mitochondrial biogenesis and fatty acid synthesis during iTSCM formation, which are essential for the properties of iTSCM cells. We identified fork head box M1 (FOXM1) as a downstream target of NOTCH, which is responsible for these metabolic changes and the subsequent iTSCM differentiation. Like NOTCH-induced CAR-iTSCM cells, FOXM1-induced CAR-iTSCM cells possess superior antitumor potential compared to conventional CAR-T cells. We propose that the NOTCH- or FOXM1-driven CAR-iTSCM formation is an effective strategy for improving cancer immunotherapy.
The NOTCH-FOXM1 Axis Plays a Key Role in Mitochondrial Biogenesis in the Induction of Human Stem Cell Memory-like CAR-T Cells.
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