Biology subjects

Hirota, Y.

Publications and source records attributed to Hirota, Y..

5 recordsLinked to original sources

bioRxiv2026

A stress-responsive morphogenetic program of the uterine epithelium safeguards the establishment of early pregnancy

Successful embryo implantation requires coordinated interactions among the endometrial epithelium, stroma, and the embryo, yet the underlying mechanisms have not been fully understood. Using three-dimensional histological reconstruction combined with single-cell and spatial transcriptomics, we identify a previously unrecognized phase of luminal architectural reorganization preceding embryo attachment. Within a narrow peri-implantation window, the luminal epithelium rapidly remodels from a highly folded structure into a flattened, organized architecture that provides a scaffold for embryo positioning. This morphogenetic transition is accompanied by activation of stress-responsive signaling across the epithelial and stromal compartments. Functional analyses show that uterine-specific deletion of the stress-responsive MAP kinase p38 disrupts luminal remodeling, leading to persistent epithelial folding, failed embryo attachment, and infertility despite normal hormone levels and embryo development. Although combined progesterone and leukemia inhibitory factor supplementation rescues embryo attachment in p38-deficient uteri, luminal disorganization, abnormal stromal responses, and impaired pregnancy progression persist. These findings identify a p38-dependent, stress-responsive morphogenetic program that coordinates epithelial dynamics and epithelial-stromal communication to establish implantation-competent luminal architecture.

developmental biology↗

bioRxiv2026

The REFLEX system enables in vivo identification of perivascular angiogenic macrophages in the heart

Direct identification of physically interacting cells in vivo remains challenging because conventional interactome analyses infer signaling partners from transcriptomes and cannot reveal which cells are in direct contact. In pressure-overload induced cardiac remodeling, VEGF-A plays a central role in the maintenance of vascular integrity and cardiac function. However, the cell type which produces VEGF-A and how the VEGF-A peptide is delivered to vascular endothelial cells remains unclear. Here, we developed a genetically encoded platform that combines REFLEX mice with HUNTERuni-seq, enabling unbiased detection and transcriptional profiling of the cells that physically interact with vascular endothelial cells. The REFLEX and HUNTERuni-seq approach identified subpopulations of Vegfa positive macrophages which we named perivascular angiogenic macrophages (PVAMs). Although the amount of VEGF-A in PVAMs is small, loss of VEGF-A in PVAMs impaired angiogenesis and systolic function during pressure overload. We additionally show that direct contact between PVAMs and endothelial cells is critical for the delivery of VEGF-A to endothelial cells. Conventional interactome analysis predicted that cardiomyocytes as dominant sources of VEGF-A in the heart. However, cardiomyocyte Vegfa deletion had no effect on capillary density nor systolic function in a model of heart failure. These results suggest that VEGF-A signaling does not rely on free diffusion through the interstitium and that cellular proximity and physical contact between PVAMs and endothelial cells are the key determinants of effective signal delivery. Together, these findings establish REFLEX and HUNTERuni-seq as a versatile platform for uncovering biologically critical cell-to-cell interactions and provide new insight into intercellular communication in pathological tissue contexts.

cell biology↗

bioRxiv2025

Microglia-astrocyte interaction underlies aquaporin-4 dysregulation in the mouse cortex

Brain water homeostasis relies on the coordinated actions of glial cells. In particular, astrocytes play an essential role in facilitating perivascular water exchange between cerebrospinal fluid and interstitial fluid through aquaporin-4 (AQP4), a water channel highly concentrated at astrocytic endfeet. Dysregulation of AQP4 localization is implicated in various neuropathologies, but its underlying mechanisms are unclear. Although astrocytes and microglia both express {beta}-adrenergic receptors ({beta}-AdRs), whether {beta}-AdR signaling modulates astrocytic AQP4 polarization through microglial activation has not yet been investigated. Here, we hypothesized that microglial activation mediates the {beta}-AdR-induced loss of astrocytic AQP4 polarization. To test this hypothesis, we topically applied the {beta}-AdR agonist, isoproterenol, to the primary visual cortex of anesthetized mice and evaluated AQP4 polarization using double immunohistochemistry. Acute {beta}-AdR activation (3 h) significantly reduced perivascular AQP4 polarization and enhanced local microglial reactivity. Both pharmacological inhibition of microglial activity with minocycline and microglial depletion via dietary administration of the CSF1R antagonist, PLX5622, prevented AQP4 dysregulation induced by isoproterenol. These findings demonstrate that microglial activation is required for {beta}-AdR agonist-induced AQP4 dysregulation in the mouse cortex, revealing a previously unrecognized microglia-astrocyte interaction linking adrenergic signaling to glial water homeostasis.

neuroscience↗

bioRxiv2018

Eldecalcitol is more effective for promoting osteogenesis than alfacalcidol in Cyp27b1-knockout Mice

Calcium (Ca) absorption from the intestinal tract is promoted by active vitamin D (1,25D3). Vitamin D not only promotes Ca homeostasis, but it also inhibits bone resorption and promotes osteogenesis, thus playing a role in the maintenance of normal bone metabolism. Because 1,25D3 plays an important role in osteogenesis, vitamin D formulations, such as alfacalcidol (ALF) and eldecalcitol (ELD), are used for treating osteoporosis. While it is known that, in contrast to ALF, ELD is an active ligand that directly acts on bone, the reason for its superior osteogenesis effects is unknown. Cyp27b1-knockout mice (Cyp27b1-/- mice) are congenitally deficient in 1,25D3 and exhibit marked hypocalcemia and high parathyroid hormone levels, resulting in osteodystrophy involving bone hypocalcification and growth plate cartilage hypertrophy. However, because the vitamin D receptor is expressed normally in Cyp27b1-/- mice, they respond normally to 1,25D3. Accordingly, in Cyp27b1-/- mice, the pharmacological effects of exogenously administered active vitamin D derivatives can be analyzed without being affected by 1,25D3. We used Cyp27b1-/- mice to characterize and clarify the superior osteogenic effects of ELD on the bone in comparison with ALF. The results indicated that compared to ALF, ELD strongly induces ECaC2, calbindin-D9k, and CYP24A1 in the duodenum, promoting Ca absorption and decreasing the plasma concentration of 1,25D3, resulting in improved osteogenesis. Because bone morphological measurements demonstrated that ELD has stronger effects on bone calcification, trabecular formation, and cancellous bone density than ALF, ELD appears to be a more effective therapeutic agent for treating postmenopausal osteoporosis, in which cancellous bone density decreases markedly. By using Cyp27b1-/- mice, this study was the first to succeed in clarifying the osteogenic effect of ELD without any influence of endogenous 1,25D3. Furthermore, ELD more strongly enhanced bone mineralization, trabecular proliferation, and cancellous bone density than did ALF. Thus, ELD is expected to show an effect on postmenopausal osteoporosis, in which cancellous bone mineral density decreases markedly.

biochemistry↗

bioRxiv2018

A survey of public attitudes towards third-party reproduction in Japan in 2014

Objective: The objective of this study was to examine public attitudes towards third-party reproduction and the disclosure of conception through third-party reproduction.\n\nMethods: We conducted the web-based survey for the public attitude towards third-party reproduction in February 2014. Twenty-five hundred people were recruited with equal segregation of age (20s, 30s, 40s, and 50s) and gender. We analyzed the association between gender, age, infertility, and ethical view using a questionnaire regarding donor sperm, donor oocyte, donor embryo, gestational surrogacy, and disclosure to offspring.\n\nResults: Of the respondents, 36.2% approved and 26.6% disapproved with gamete or embryo donation. The frequency of those who approved was the lowest in females in the 50-59 years age group, and was significantly higher in males or females with infertility. Secondly, 40.9% approved and 21.8% disapproved with gestational surrogacy. The frequency of those who approved gestational surrogacy was higher in males or females with infertility. Thirdly, 46.3% of respondents agreed and 20.4% disagreed with \"offspring have the right to know their origin\". Those who disagreed were primarily in the 50-59 age group of both genders, and disagreement was significantly higher in the infertility group compared with non-infertility group.\n\nConclusion: In this study, public attitudes were affected by gender, age, and experience of infertility. These study findings are important in understanding the attitude towards third-party reproduction and disclosure to the offspring. Respondents having indecisive attitudes were >30%, which might indicate an increased requirement for information and education to enhance the discussion on the ethical consensus on third-party reproduction in Japan.

scientific communication and education↗