Biology subjects

Nagasawa, T.

Publications and source records attributed to Nagasawa, T..

9 recordsLinked to original sources

bioRxiv2026

Intermittent parathyroid hormone employs autonomous and non-autonomous mechanisms to drive osteogenesis from Ebf3-expressing skeletal progenitor cells

How systemic hormonal signals coordinate stem cell fate decisions in adult tissues remains incompletely understood. In bone marrow, Cxcl12-abundant reticular (CAR) cells, marked by Early B-cell Factor 3 (Ebf3) expression, are multipotent mesenchymal progenitors that maintain the hematopoietic stem cell niche and serves as a major osteoblast progenitor source during adult bone remodeling. Using inducible lineage tracing coupled with single-cell transcriptomics and conditional genetics in mice, we show that intermittent parathyroid hormone (iPTH; teriparatide) drives osteogenesis from CAR cells by simultaneously engaging cell-intrinsic and cell-extrinsic mechanisms. Directly, iPTH suppresses lineage-enforcing transcription factors Ebf3, Ebf1, and Foxc1, thereby destabilizing progenitor identity and priming CAR cells for osteogenic commitment. Simultaneously, iPTH stimulates osteoclastic bone resorption, releasing TGF{beta} which recruits these primed progenitors to bone surfaces, a process abolished by osteoclast depletion. Preventing CAR cell maturation via Sp7 deletion abrogates iPTH-induced bone gain, establishing these progenitors as essential mediators of bone anabolism. This coupled mechanism, in which intrinsic transcriptional priming converges with extrinsic niche remodeling, is conserved in human CAR cells from teriparatide-treated postmenopausal women, which show concordant suppression of EBF3 and FOXC1 and elevated TGF{beta}-responsive gene signatures. These findings reveal a general principle by which a systemic hormone orchestrates tissue remodeling through simultaneous reprogramming of progenitor identity and remodeling of the niche microenvironment.

physiology↗

bioRxiv2026

A macrocyclic peptide-based fusion inhibitor targeting SARS-CoV-2 Spike S2 subunit

Continuous emergence of SARS-CoV-2 variants carrying mutations in Spike presents a significant challenge for durable antiviral agents. Here we screen for random 13-amino acid non-mimetic macrocyclic peptides that bind to Spike and identify PA-001 that inhibits SARS-CoV-2 infection with high potency at 0.23-2.9 nM as 50% inhibitory concentration (IC50). PA-001 bound to Spike S2 subunit and inhibited the membrane fusion during virus entry. Through drug-resistant selection, we revealed that PA-001 targeted the fusion peptide proximal region (FPPR) in S2, which has not been recognized as a drug target to date. Consistent with its highly conserved amino acid sequences beyond strains, PA-001 exhibited broad antiviral activity against all tested SARS-CoV-2 variants, in contrast to clinically-approved S1-targeting antibodies that lost activity to Omicron variants. PA-001 suppressed SARS-CoV-2 propagation and disease progression in mouse- and hamster-infection models, both by administration prophylactically and therapeutically. Combination therapy with remdesivir further enhanced antiviral profiles. In clinical phase-I trial, PA-001 was well-tolerated and showed high systemic exposure, with 4,300-10,300-fold concentration of IC50 as maximum plasma concentration by single administration to healthy volunteers. These evidence propose FPPR as an unexpected antiviral drug target accessible by macrocyclic peptides and identify PA-001 as a potent anti-SARS-CoV-2 fusion inhibitor.

microbiology↗

bioRxiv2026

Evolutionary trajectories of teleost olfactory signaling genes shaped by long-term redundancy after whole-genome duplication

Whole-genome duplication (WGD) is a major evolutionary event that drives molecular and species diversification. However, few studies have traced how WGD has shaped the long-term functional evolution of individual genes. Here, we investigated the olfactory marker protein (omp) genes duplicated by the teleost-specific WGD ([~]300 million years ago) through phylogenetic, syntenic, expression, and promoter analyses. Our results suggest that the duplicated omp gene pair has retained redundancy over an extended evolutionary period, leading to both non- and sub-functionalization, thereby generating molecular diversity. Moreover, evolutionary analyses of the olfactory signal transduction cascade revealed prolonged redundancy across its components, likely constrained by gene dosage balance. These findings imply that WGD may have introduced unexpected diversity into the entire olfactory signaling machinery of teleosts through dosage-constrained functional divergence. HighlightsO_LITeleost-specific WGD generated duplicated omp genes that persisted for [~]300 million years. C_LIO_LIExtended redundancy in ompa/ompb led to both non- and sub-functionalization. C_LIO_LIOlfactory transduction genes also show long-term redundancy shaped by dosage constraints. C_LIO_LIWGD likely introduced diversification into teleost olfactory signaling via dosage constraints. C_LI

evolutionary biology↗

bioRxiv2025

Niche-targeted therapy via YAP/TAZ activation enhances hematopoietic regeneration

The distinctive milieu of the bone marrow (BM), known as the BM niche, supports hematopoietic stem cells (HSCs) and serves as a foundation for hematopoietic regeneration. Myeloablative stress disrupts not only hematopoietic stem and progenitor cells but also essential BM niche components, including endothelial cells (ECs) and mesenchymal stromal cells (MSCs); disruption of the latter impairs efficient hematopoietic recovery. However, therapeutic strategies targeting niche restoration remain largely underdeveloped. Here, we demonstrate that the Hippo pathway effectors YAP/TAZ are critical for enabling ECs and MSCs to respond to BM injury, and that YAP/TAZ activation accelerates BM niche recovery, thereby promoting hematopoietic regeneration. We found that YAP/TAZ are rapidly activated in both MSCs and ECs following myeloablative stress, maintaining MSC multipotency and orchestrating vascular remodeling. Mechanistically, YAP/TAZ function as transcriptional hubs in MSCs, regulating key transcriptional factors such as Ebf1 and Ebf3. This regulation preserves MSC identity by preventing osteogenic and fibrogenic differentiation while promoting the expression of hematopoietic factors such as Cxcl12 and angiogenic factors. In parallel, YAP/TAZ signaling in ECs facilitates pro-angiogenic responses and drives sinusoidal vessel remodeling after injury. These YAP/TAZ-mediated niche responses are essential for HSC retention and hematopoietic regeneration following diverse myelosuppressive therapies. Notably, pharmacological activation of YAP/TAZ enhances BM niche reorganization and augments hematopoietic regeneration following myeloablative therapies. These findings establish YAP/TAZ as central regulators of BM niche resilience, providing a rationale for niche-targeted therapeutic strategies to enhance hematopoietic regeneration. Key points{blacksquare} YAP/TAZ enable BM niche cells to sense injury and restore their structure and function, thereby promoting hematopoietic regeneration. {blacksquare}Pharmacological activation of YAP/TAZ enhances BM niche resilience and accelerates hematopoietic recovery after myelosuppressive therapies.

cell biology↗

bioRxiv2024

Possible involvement of ghost introgressions in the striking diversity of V1R receptor genes in East African cichlids

Cichlids that have undergone adaptive radiation are genetically close but exhibit extreme ecological and morphological diversity, making them useful for understanding speciation mechanisms. Vomeronasal type 1 receptors (V1R) are highly conserved among teleost fish at the amino acid sequence level and believed to play a fundamental role in reproduction. We previously reported the surprisingly high sequence diversity of V1Rs among certain cichlid species, suggesting a possible role for V1Rs in their speciation. In this study, we investigated the process of evolutionary diversification of all 6 V1Rs (V1R1-6) by using the genome data of 528 cichlid species, encompassing nearly all lineages. In the case of V1R2, two highly divergent alleles (1.17%: variant sites/CDS length) without recombination were preserved and shared among cichlids found in all of the East African Great Lakes. In the case of V1R6, numerous highly variable alleles that could be derived from multiple recombination events between two highly divergent alleles (1.39%: variant sites/CDS length) were found among the Lake Victoria cichlids. Additionally, we identified highly divergent alleles of V1R1 within the tribe Tropheini, and of both V1R3 and V1R6 within Trematocarini and Ectodini. Because one of the two divergent alleles of these V1Rs emerged rapidly during cichlid evolution, they are likely to have been derived from introgression. However, despite extensive investigations, we could not identify the source lineages for these introgressions, implying that they may have become extinct. This study revealed the potential role of introgression in explaining the remarkable diversity of V1Rs in East African cichlids.

evolutionary biology↗

bioRxiv2024

Pronounced expression of extracellular matrix proteoglycans regulated by Wnt pathway underlies the parallel evolution of lip hypertrophy in East African cichlids

Cichlid fishes inhabiting the East African Great Lakes, Victoria, Malawi, and Tanganyika, are textbook examples of parallel evolution, as they have acquired similar traits independently in each of the three lakes during the process of adaptive radiation. In particular, "hypertrophied lip" has been highlighted as a prominent example of parallel evolution. However, the underlying molecular mechanisms remain poorly understood. In this study, we conducted an integrated comparative analysis between the hypertrophied and normal lips of cichlids across three lakes based on histology, proteomics, and transcriptomics. Histological and proteomic analyses revealed that the hypertrophied lips were characterized by enlargement of the proteoglycan-rich layer, in which versican and periostin proteins were abundant. Transcriptome analysis revealed that the expression of extracellular matrix-related genes, including collagens, glycoproteins and proteoglycans, was higher in hypertrophied lips, regardless of their phylogenetic relationships. In addition, the genes in Wnt signaling pathway, which is involved in promoting proteoglycan expression, was highly expressed in both the juvenile and adult stages of hypertrophied lips. Our comprehensive analyses showed that hypertrophied lips of the three different phylogenetic origins can be explained by similar proteomic and transcriptomic profiles, which may provide important clues into the molecular mechanisms underlying phenotypic parallelisms in East African cichlids.

evolutionary biology↗

bioRxiv2023

Tissue-scale dynamic mapping of Hematopoietic Stem Cells and supportive niche cells in the fetal liver

The fetal liver (FL) plays a fundamental role in the ontogeny of the hematopoietic system, by transiently providing a fertile microenvironment for the maturation, proliferation and expansion of fetal hematopoietic progenitors, as well as definitive hematopoietic stem cells (HSCs). Nonetheless, the cellular make up and identity of HSC niches in the FL remain poorly described. Here we employed a combination of 3D quantitative microscopy, bulk mRNA-seq, flow cytometry and cell-specific reporter models, to dissect the spatiotemporal dynamics of putative niche cells and HSCs in the FL microenvironment. We find that at peak stages of FL hematopoiesis, pro-hematopoietic cytokines are promiscuously expressed by endothelial, mesenchymal cells and most prominently by hepatoblasts. These multicellular consortia of parenchymal/stromal cells are spatially predominant in the FL, thus providing unrestricted access to supportive factors throughout the entire tissue. Accordingly, in these early phases HSCs are found scattered across the parenchyma not displaying obvious spatial biases within the broad microanatomy of the FL, but exhibiting clustering behaviors. This highly conducive microenvironment is transient and gets rapidly remodeled through hepatoblast differentiation and sterile inflammatory signaling, leading to the downregulation of hematopoietic factors and the contraction of supportive niches, which temporarily coincide with the exit of HSCs towards emergent BM tissues.

developmental biology↗

bioRxiv2020

CD8 T cells induce destruction of bone marrow stromal niches and hematopoietic stem cell dysfunction in chronic viral infections

Chronic viral infections are associated with hematopoietic suppression and bone marrow (BM) failure, which have been linked to hematopoietic stem cell (HSC) exhaustion. However, how persistent viral infectious challenge and ensuing inflammatory responses target BM tissues and perturb hematopoietic homeostasis remains poorly understood. Here, we combine extensive functional analyses with advanced 3D microscopy to demonstrate that chronic infection with lymphocytic choriomeningitis virus clone 13 results in the long-term impairment of HSC function, concomitant with a persistent destruction of the HSC-supportive stromal networks of mesenchymal CXCL12-abundant reticular cells. During infections, long lasting injuries and aberrant transcriptional programs of the stromal infrastructure diminish the capacity of the BM microenvironment to adequately support HSC maintenance. Mechanistically, BM immunopathology is elicited by virus-specific, activated CD8 T cells, which accumulate in the BM via interferon-dependent mechanisms. Combined inhibition of type I and II IFN pathways completely preempts viral-mediated degeneration of CARc networks and protects HSCs from persistent dysfunction. Hence, viral infections and ensuing immune reactions chronically interfere with BM function by disrupting essential stromal-derived, hematopoietic-supporting cues.

immunology↗

bioRxiv2019

Angiocrine factors from HUVECs amplify erythroid cells

Erythropoiesis is regulated by microenvironmental factors from the vasculature. Enhanced erythropoiesis, which occurs under stress or during development, amplifies erythroid cells to meet the demand of red blood cells. This process uncouples cell division and differentiation, thus the accumulated erythroid cells remain undifferentiated in the vasculature. However, little is known about how vascular endothelial cells (ECs) regulate erythropoiesis. Here we identified that human umbilical vein endothelial cells (HUVECs) keep erythroid cells undifferentiated and amplify their number. We determined that HUVECs amplify erythroid cells via secreted angiocrine factors. The expression profile of these factors suggested that they resemble macrophage-crines for enhanced erythropoiesis. Molecularly, HUVECs mediate the activation of ERK signaling. These data indicate that angiocrine factors from HUVECs enhance erythropoiesis via the amplification of undifferentiated erythroid cells. Our study contributes to the ultimate goal of harnessing erythropoiesis to replace blood transfusions.

developmental biology↗