Biology subjects

Ichinohe, T.

Publications and source records attributed to Ichinohe, T..

7 recordsLinked to original sources

bioRxiv2024

JMJD3 mediated senescence is required to overcome stress induced hematopoietic defects.

Cellular senescence in stem cells compromises regenerative capacity, promotes chronic inflammation, and is implicated in aging. Hematopoietic stem and progenitor cells (HSPCs) are responsible for producing mature blood cells, however, how cellular senescence influences their function is largely unknown. Here, we show that JMJD3, a histone demethylase, activates cellular senescence via p16Ink4a upregulation in competition with Polycomb group proteins, and reprograms HSPC integrity to overcome hematopoietic defects induced by replicative and oncogenic stresses. JMJD3 deficiency impaired stem cell potential, proper cell cycle regulation, and WNT pathway activation in HSPCs under stress conditions. These impaired phenotypes were rescued through exogenous and retroviral introduction of p16Ink4a. This JMJD3-p16INK4a axis in hematopoiesis is age-dependent and is distinct from cellular senescence. Treatment with a JMJD3 selective inhibitor attenuated leukemic potential during cellular senescence. Taken together, these results demonstrate that JMJD3-p16INK4a mediates cellular senescence and plays critical roles in the functional integrity of HSPCs under stress conditions, suggesting a new link for aging and anti-cancer therapies.

cell biology↗

bioRxiv2023

Propagation of neuronal micronuclei regulates microglial states

Microglia, resident immune cells in the central nervous system, undergo morphological and functional changes in response to signals from the local environment and mature into various homeostatic states. However, niche signals underlying microglial development and maturation remain largely unknown. In this study, we show that neuronal micronuclei propagate microglia, followed by changing microglial states during the postnatal period. We discovered that neurons passing through a dense region of the developing neocortex give rise to micronuclei and release them into the extracellular space. Moreover, neuronal micronuclei were incorporated into microglia and affected morphological changes. Loss of the cGAS gene alleviates effects on micronucleus-dependent morphological changes. Notably, neuronal micronuclei-harboring microglia exhibit unique transcriptome signatures. These results demonstrate that neuronal micronuclei serve as niche signals that produce novel microglial states. Our findings provide a potential mechanism for regulating the microglial state in the early-postnatal neocortex.

neuroscience↗

bioRxiv2023

Partially hydrolyzed guar gum attenuates the symptoms of SARS-CoV-2 infection through gut microbiota modulation in an animal model.

The coronavirus disease 2019 (COVID-19) pandemic has caused worldwide health issues. Although several vaccines have been developed, it is still difficult to prevent and reduce the inflammation caused by the infection. Studies have shown that there are correlations between the gut environment and severity of symptoms caused by SARS-CoV-2 infection. Several gut metabolites produced by the gut microbiota such as SCFAs and the secondary bile acid UDCA are reported to improve the survival rate of the host after viral infection in an animal model through modulation of the host immune system. Therefore, in this study, we attempted to use the prebiotic dietary fiber PHGG to modulate the gut microbiome and intestinal metabolites for improvement of host survival rate after SARS-CoV-2 infection in a Syrian hamster model. We were able to show that PHGG significantly improved the host survival rate and body weight reduction. Analysis of the gut microbiome, serum, and intestinal metabolites revealed that PHGG significantly increased the concentrations of several intestinal SCFAs, fecal secondary bile acids, and serum secondary bile acids. Furthermore, several microbial species and metabolites identified in this study are consistent with reports in humans. Taken together, our data suggest that PHGG is a candidate prebiotic food for reducing the morbidity of COVID-19.

microbiology↗

bioRxiv2022

TLR7/8 stress response drives histiocytosis in SLC29A3 disorders

SLC29A3, also known as ENT3, is a lysosomal transmembrane protein that transports nucleosides from the lysosomes to the cytoplasm1. Loss-of-function mutations in SLC29A3 cause lysosomal nucleoside storage and histiocytosis: phagocyte accumulation in multiple organs2,3. However, little is known about the mechanism through which lysosomal nucleoside storage drives histiocytosis. Herein, histiocytosis in Slc29a3-/- mice was demonstrated to depend on TLR7, which senses a combination of nucleosides and oligoribonucleotides4,5. TLR7 responded to lysosomal nucleoside storage and enhanced proliferation of Ly6Chi CX3CR1low immature monocytes and their maturation into Ly6Clow phagocytes in Slc29a3-/- mice. Because accumulated nucleosides primarily originated from cell corpse phagocytosis, TLR7 in immature monocytes recognized nucleoside storage as lysosomal stress and increased phagocyte numbers. This non-inflammatory compensatory response is referred to as the TLR7 stress response where Syk, GSK3{beta}, {beta}-catenin, and mTORC1 serve as downstream signalling molecules. In SLC29A3 disorders, histiocytosis accompanies inflammation6,7. Nucleoside storage failed to induce pro-inflammatory cytokine production in Slc29a3-/- mice, but enhanced ssRNA-dependent pro-inflammatory cytokine production in Ly6Chi classical monocytes and peripheral macrophages, not proliferating immature monocytes. Patient-derived monocytes harbouring G208R SLC29A3 mutation showed higher survival and proliferation in the presence of M-CSF and produced larger amounts of IL-6 upon ssRNA stimulation than did those derived from healthy subjects. A TLR8 antagonist inhibited the survival/proliferation of patient-derived macrophages. These results demonstrated that TLR7/8 responses to lysosomal nucleoside stress drive SLC29A3 disorders.

immunology↗

bioRxiv2020

Disruption of nasal bacteria enhances protective immune responses to influenza A virus and SARS-CoV-2 infection in mice

Gut microbiota plays a critical role in the induction of adaptive immune responses to influenza virus infection. However, the role of nasal bacteria in the induction of the virus-specific adaptive immunity is less clear. Here we demonstrate that while intranasal administration of influenza virus hemagglutinin vaccine alone was insufficient to induce the vaccine-specific antibody responses, disruption of nasal bacteria by lysozyme or addition of culturable oral bacteria from a healthy human volunteer rescued inability of the nasal bacteria to generate antibody responses to intranasally administered the split-virus vaccine. Myd88-depdnent signaling in the hematopoietic compartment was required for adjuvant activity of intranasally administered oral bacteria. In addition, we found that the oral bacteria-combined intranasal vaccine induced protective antibody response to influenza virus and SARS-CoV-2 infection. Our findings here have identified a previously unappreciated role for nasal bacteria in the induction of the virus-specific adaptive immune responses.

microbiology↗

bioRxiv2019

Nucleosides drive histiocytosis in SLC29A3 disorders by activating TLR7

A lysosomal transmembrane protein SLC29A3 transports nucleosides from lysosomes to the cytoplasm. Loss-of-function mutations of the SLC29A3 gene cause lysosomal nucleoside storage in monocyte/macrophages, leading to their accumulation called histiocytosis in humans and mice. Little is known, however, about a mechanism behind nucleoside-dependent histiocytosis. TLR7, an innate immune sensors for single stranded RNA, bind and respond to nucleosides. We here show that they drive nucleoside-mediated histiocytosis. Patrolling monocyte/macrophages accumulate in the spleen of Slc29a3-/- mice but not Slc29a3-/- Tlr7-/- mice. Accumulated patrolling monocyte/macrophages stored nucleosides derived from cell corpse. TLR7 was recruited to phagosomes and activated as evidenced by TLR7-dependent phagosomal maturation. TLR7 induced hyper-responsiveness to M-CSF in Slc29a3-/- monocyte/macrophages. These results suggest that TLR7 drives histiocytosis in SLC29A3 disorders. One Sentence SummarySLC29A3 disorders are caused by activation of TLR7 with accumulated nucleosides in lysosomes.

immunology↗

bioRxiv2018

Stage-Dependent Differential Gene Expression Profiles of Cranial Neural Crest Cells Derived from Mouse Induced Pluripotent Stem Cells

Cranial neural crest cells (cNCCs) comprise a multipotent population of cells that migrate into the pharyngeal arches of the vertebrate embryo and differentiate into a broad range of derivatives of the craniofacial organs. Consequently, migrating cNCCs are considered as one of the most attractive candidate sources of cells for regenerative medicine. In this study, we analyzed the gene expression profiles of cNCCs at different time points after induction by conducting three independent RNA sequencing experiments. We successfully induced cNCC formation from mouse induced pluripotent stem (miPS) cells by culturing them in neural crest inducing media for 14 days. We found that these cNCCs expressed several neural crest specifier genes but were lacking some previously reported specifiers, such as paired box 3 (Pax3), msh homeobox 1 (Msx1), and Forkhead box D3 (FoxD3), which are presumed to be essential for neural crest development in the embryo. Thus, a distinct molecular network may the control gene expression in miPS-derived cNCCs. We also found that c-Myc, ETS proto-oncogene 1, transcription factor (Ets1), and sex determining region Y-box 10 (Sox10) were only detected at 14 days after induction. Therefore, we assume that these genes would be useful markers for migratory cNCCs induced from miPS cells. Eventually, these cNCCs comprised a broad spectrum of protocadherin (Pcdh) and a disintegrin and metalloproteinase with thrombospondin motifs (Adamts) family proteins, which may be crucial in their migration.

cell biology↗