Biology subjects

Kakiuchi, M.

Publications and source records attributed to Kakiuchi, M..

4 recordsLinked to original sources

bioRxiv2026

TET2-mutant clonal hematopoiesis prevents T-cell exhaustion and suppresses cancer metastasis

Clonal hematopoiesis (CH) is widely regarded as a risk factor for age-associated disease, yet its influence on solid tumor progression remains poorly understood. Here, we uncover an unexpected tumor-suppressive role for TET2-mutant CH in solid tumors. Through an analysis of over 16,000 cancer patients, we demonstrate that TET2 mutations are associated with a significant reduction in metastatic burden. Mechanistically, we show that Tet2 deficiency prevents terminal exhaustion in CD8+ tumor-infiltrating lymphocytes (CD8+ TILs). This resistance is driven by DNA hypermethylation at regulatory elements of the transcription factor Tox, which prevents the induction of the terminal exhaustion program. Consequently, Tet2-deficient CD8+ TILs maintain stem-like, effector-competent states that mediate durable anti-tumor immunity and suppress metastatic outgrowth. Our findings establish TET2-mutant CH as a natural epigenetic constraint on T-cell exhaustion and uncover a mechanistically defined pathway with translational potential for enhancing anti-tumor immune responses.

immunology↗

bioRxiv2025

Muc6-expressing gastric isthmus progenitors contribute to regeneration and metaplasia supported by myeloid-mesenchymal interactions

Gastric mucosal homeostasis is maintained by tissue-resident stem and progenitor cells residing in the isthmus region. Following mucosal injury, surviving cells contribute to regeneration, coinciding with characteristic pathological changes such as atrophic gastritis and metaplasia. To comprehensively understand the cellular dynamics involved in this process, we performed single-cell and spatial transcriptomics using newly generated transgenic mice. In human samples and mouse models, loss of gastric chief cells precedes, and even induces, loss of parietal cells during the progression of atrophy and metaplasia, validating the causal relationship underlying the decrease of these two lineages. Single-cell analysis confirmed robust stemness and metaplastic changes in the Muc6-expressing neck lineage following either chief or parietal cell ablation, and lineage-tracing experiments revealed that Muc6-expressing isthmus progenitors serve as a source of metaplasia and regeneration. Mechanistically, mucosal injury recruits IL-1-expressing myeloid cells, which stimulates NRG1 production in stromal fibroblasts, leading to mucosal proliferation and regeneration mediated by Myc activation in isthmus progenitors. These findings highlight the injury-responsible stem cell-like function of Muc6-expressing isthmal progenitors, which play a critical role in mucosal homeostasis and disease progression. Visual abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=109 SRC="FIGDIR/small/648856v1_ufig1.gif" ALT="Figure 1"> View larger version (27K): org.highwire.dtl.DTLVardef@10fc2eaorg.highwire.dtl.DTLVardef@1c5b82corg.highwire.dtl.DTLVardef@1be747dorg.highwire.dtl.DTLVardef@d1d722_HPS_FORMAT_FIGEXP M_FIG C_FIG

cell biology↗

bioRxiv2022

A developmental program that regulates mammalian organ size offsets evolutionary distance

Pigs are evolutionarily more distant from humans than mice, but their physiological organs are closest to humans. The molecular program leading to a more than 1,000-fold increase in organ size in pigs and humans over that of mice across evolution has not been elucidated. We generated large-scale transcriptional landscapes throughout swine lung development. Our cross-species single-cell molecular atlas let us discover swine progenitor identities, stage-specific markers, and a core organ-size regulation program (COSRP), well-conserved in swine and humans but less so in mice. Across eight mammalian species, human COSRP promoters showed higher homologies to evolutionary-distant large animals, including pigs, than evolutionary-close small animals. Our study provides a molecular foundation during swine lung development that unveils animal size regulation conserved in the COSRP promoter, independent of genome-wide evolution. COSRP is a critical paradigm for studying thousands-fold changes in biological sizes in evolution, development, cancer, zoology, respirology, organoids, and biotechnology, particularly human-compatible organ generation. One Sentence SummaryA cross-species developmental molecular atlas identified the indicator of lung and animal size beyond evolution

evolutionary biology↗

bioRxiv2022

Single-Cell Transcriptome Analyses Reveal the Cell Diversity and Developmental Features of Human Gastric and Metaplastic Mucosa

The stomach is an important digestive organ with a variety of biological functions. However, due to the complexity of its cellular and glandular composition, the precise cellular biology has yet to be elucidated. In this study, we conducted single-cell RNA sequence analysis of the human stomach and constructed a 137,610-cell dataset, the largest cell atlas reported to date. By integrating this single-cell analysis with spatial cellular distribution analysis, we were able to clarify novel aspects of the developmental and tissue homeostatic ecosystems in the human stomach. We identified LEFTY1+ as a potential stem cell marker in both gastric and intestinal metaplastic glands. We also revealed skewed distribution patterns for PDGFRA+BMP4+WNT5A+ fibroblasts that play pivotal roles in, or even precede, the phenotypic changes from gastric to metaplastic mucosa. Our extensive dataset will function as a fundamental resource in investigations of the stomach, including studies on development, aging, and carcinogenesis.

genomics↗