Biology subjects

Fukuhara, S.

Publications and source records attributed to Fukuhara, S..

6 recordsLinked to original sources

bioRxiv2026

Age-associated erosion of organ-specific endothelial programs compromises tissue function and resilience

Endothelial cells (ECs) express organ-specific gene programs supporting tissue homeostasis and resilience. However, the mechanisms by which aging reshapes these organ-specific endothelial programs and how the resulting changes affect tissue homeostasis, resilience, and disease susceptibility remain largely unknown. Herein, we performed single-cell RNA sequencing of ECs harvested from five organs across the lifespan and found that aging progressively erodes organ-specific endothelial programs while inducing shared interferon-responsive and antigen-presentation programs across organs. Although vascular subtype identity and conserved capillary subset identity were mostly preserved, these organ-specific transcriptional programs were broadly attenuated with aging, indicating erosion of organ-specific endothelial identity to be a fundamental feature of endothelial aging. Importantly, these alterations were associated with declines in specialized EC functions, including alveolar barrier maintenance in the lung, scavenging activity in the liver, angiogenic capacity in the heart, and homeostatic programs in the kidneys and the brain, suggesting that age-related EC alterations compromise tissue homeostasis and resilience in multiple organs. Furthermore, we established a single-cell aging index for alveolar capillary ECs in mice and humans, revealing stress-associated endothelial activation to potentially be an intermediate state linking functional deterioration to cellular senescence, and also demonstrating marked heterogeneity in aging states even among ECs from animals of the same chronological age. Notably, alveolar capillary ECs exhibited progressive functional decline before reaching a senescent-like state, suggesting endothelial dysfunction to precede overt cellular senescence as the organism ages. Collectively, our findings establish progressive erosion of organ-specific endothelial programs as a central feature of vascular aging and provide a conceptual framework for elucidating how endothelial aging contributes to tissue dysfunction and reduced resilience across organs.

physiology↗

bioRxiv2022

Coronary artery established through amniote evolution

Coronary arteries are part of the vascular system that nourishes the heart; they are generally considered a synapomorphy of jawed vertebrates. However, the so-called coronary arteries originated from different body parts in amniotes and other groups, and the evolution of these arteries remains unclear. Here we propose that the amniote coronary arteries were newly obtained, overriding the ancestral arterial systems. In mouse (Mus musculus) and quail (Coturnix japonica) embryos, the amniote-type coronary arteries are established by the reconstitution of the transient vascular plexus (aortic subepicardial vessels; ASVs) on the outflow tract and the primitive coronary plexus during the development. In contrast, amphibians (Xenopus laevis, Hyla japonica, Lithobates catesbeianus, and Cynops pyrrhogaster) retain the ASV-like vasculature as extrinsic cardiac arteries throughout their lives and have no primitive coronary plexus. A comparison of zebrafish (Danio rerio) and chondrichthyans (Lamna sp., Narke japonica, and Deania calcea) suggested that their hypobranchial arteries correspond morphologically to the ASVs and also serve as heart-feeding arteries throughout their lives. Thus, the coronary artery of adult amniotes is an evolutionary novelty that has acquired new anatomical connections through the addition of a new developmental process to the ancestral pattern. This change is probably related to the modification of branchial arteries, highlights the drastic morphological changes underlying the physiological transition in amniote evolution.

evolutionary biology↗

bioRxiv2021

Proper migration of lymphatic endothelial cells requires survival and guidance cues from arterial mural cells

The migration of lymphatic endothelial cells (LECs) is key for the development of the complex and vast lymphatic vascular network that pervades most of the tissues in an organism. In zebrafish, arterial intersegmental vessels together with chemokines have been shown to promote lymphatic cell migration from the horizontal myoseptum (HM). Here we found that LECs departure from HM coincides with the emergence of mural cells around the intersegmental arteries, raising the possibility that arterial mural cells promote LEC migration. Our live imaging and cell ablation experiments revealed that LECs migrate slower and fail to establish the lymphatic vascular network in the absence of arterial mural cells. We determined that mural cells are a source for the C-X-C motif chemokine 12 (Cxcl12a and Cxcl12b) and vascular endothelial growth factor C (Vegfc). We showed that ERK, a downstream component of Vegfc-Vegfr3 singling cascade, is activated in migrating LECs and that both chemokine and growth factor signalling is required for the robust migration. Furthermore, Vegfc-Vegfr3 has a pro-survival role in LECs during the migration. Together, the identification of mural cells a source for signals that guide LEC migration and survival will be important in the future design for rebuilding lymphatic vessels in the disease contexts.

developmental biology↗

bioRxiv2021

Conserved and context-dependent roles for Pdgfrb signaling during zebrafish vascular mural cell development

Platelet derived growth factor beta and its receptor, Pdgfrb, play essential roles in the development of vascular mural cells, including pericytes and vascular smooth muscle. To determine if this role was conserved in zebrafish, we analyzed pdgfb and pdgfrb mutant lines. Similar to mouse, pdgfb and pdgfrb mutant zebrafish lack brain pericytes and exhibit anatomically selective loss of vascular smooth muscle coverage. Despite these defects, pdgfrb mutant zebrafish did not otherwise exhibit circulatory defects at larval stages. However, beginning at juvenile stages, we observed severe cranial hemorrhage and vessel dilation associated with loss of pericytes and vascular smooth muscle cells in pdgfrb mutants. Similar to mouse, pdgfrb mutant zebrafish also displayed structural defects in the glomerulus, but normal development of hepatic stellate cells. We also noted defective mural cell investment on coronary vessels with concomitant defects in their development. Together, our studies support a conserved requirement for Pdgfrb signaling in mural cells. In addition, these mutants provide an important model for definitive investigation of mural cells during early embryonic stages without confounding secondary effects from circulatory defects. Summary statementGenetic analysis in zebrafish demonstrates the conserved role of Pdgfb/Pdgfrb signaling in pericyte and vascular smooth muscle cell formation during vascular development in vertebrates.

developmental biology↗

bioRxiv2019

Periosteum-derived Osteocrin regulates bone growth through both endochondral ossification and intramembranous ossification

During development of long bones, two mechanistically distinct processes contribute to long- and short-axis growth. Endochondral ossification in the growth plate leads to the long-axis growth, while intramembranous ossification including apposition in the periosteum regulates the short axis growth. Here, we show that periosteal osteoblast-derived secretory peptide, Osteocrin (OSTN), promotes both types of long bone growth through potentiation of signaling by C-type natriuretic peptide (CNP), because OSTN inhibits the clearance of CNP by binding to natriuretic peptide receptor 3 (NPR3). The mice lacking OSTN showed less bone mass in trabecular and cortical regions than the control mice, suggesting the dual functions of OSTN in long bone growth. We found that OSTN regulated trabecular bone formation by inducing proliferation and maturation of chondrocytes possibly through enhancing CNP-dependent signaling. Besides the contribution of OSTN to long axis growth, we demonstrated that OSTN together with CNP induced osteoblast differentiation of periosteum-derived multipotent progenitor cells expressing NPR3. These data suggest that OSTN induces long bone growth through endochondral ossification and osteoblast specification of multipotent progenitor cells in the periosteum.

developmental biology↗

bioRxiv2019

Dual Role of Jam3b in Early Hematopoietic and Vascular Development

In order to efficiently derive hematopoietic stem cells (HSCs) from pluripotent precursors, it is crucial to understand how mesodermal cells acquire hematopoietic or endothelial identity due to their close developmental connection. Although Npas4 has been recently identified as a conserved master regulator of hemato-vascular development, the molecular mechanisms underlying the cell fate divergence between hematopoietic and vascular endothelial cells are still unclear. Here, we show in zebrafish that the divergence of hematopoietic and vascular endothelial cells in mesodermal cells is regulated by Junctional adhesion molecule 3b (Jam3b) via two independent signaling pathways. Mutation of jam3b led to the reduction of npas4l expression in the posterior lateral plate mesoderm and defect of both hematopoietic and vascular development. Mechanistically, we uncover that Jam3b promotes endothelial specification by regulating npas4l expression through the repression of the Rap1a-Erk signaling cascade. Jam3b subsequently promotes hematopoietic development including HSCs by regulating lrrc15 expression in endothelial precursors through the activation of an integrin-dependent signaling cascade. Our data provide insight into the divergent mechanisms for instructing hematopoietic or vascular fates from mesodermal cells.

developmental biology↗