Bone-derived PDGF-BB drives brain vascular calcification in male mice DOI Creative Commons
Jiekang Wang,

Ching‐Lien Fang,

Kathleen Noller

et al.

Journal of Clinical Investigation, Journal Year: 2023, Volume and Issue: 133(23)

Published: Oct. 10, 2023

Brain vascular calcification is a prevalent age-related condition often accompanying neurodegenerative and neuroinflammatory diseases. The pathogenesis of large-vessel calcifications in peripheral tissue well studied, but microvascular the brain remains poorly understood. Here, we report that elevated platelet-derived growth factor BB (PDGF-BB) from bone preosteoclasts contributed to cerebrovascular male mice. Aged mice had higher serum PDGF-BB levels incidence compared with young mice, mainly thalamus. Transgenic preosteoclast-specific Pdgfb overexpression exhibited recapitulated age-associated thalamic calcification. Conversely, deletion displayed diminished In an ex vivo cerebral culture system, dose-dependently promoted Analysis osteogenic gene array single-cell RNA-Seq (scRNA-Seq) revealed upregulated multiple differentiation genes phosphate transporter Slc20a1 microvessels. Mechanistically, stimulated phosphorylation its receptor PDGFRβ (p-PDGFRβ) ERK (p-ERK), leading activation RUNX2. This activation, turn, induced transcription osteoblast PCs astrocytes. Thus, bone-derived by activating p-PDGFRβ/p-ERK/RUNX2 signaling cascade cells.

Language: Английский

Lymph node stromal cells: cartographers of the immune system DOI
Akshay T. Krishnamurty, Shannon J. Turley

Nature Immunology, Journal Year: 2020, Volume and Issue: 21(4), P. 369 - 380

Published: March 23, 2020

Language: Английский

Citations

256
Identifying disease-critical cell types and cellular processes by integrating single-cell RNA-sequencing and human genetics DOI Open Access
Karthik A. Jagadeesh, Kushal K. Dey, Daniel T. Montoro

et al.

Nature Genetics, Journal Year: 2022, Volume and Issue: 54(10), P. 1479 - 1492

Published: Sept. 29, 2022

Language: Английский

Citations

148
Single-Cell Analysis Identifies NOTCH3-Mediated Interactions between Stromal Cells That Promote Microenvironment Remodeling and Invasion in Lung Adenocarcinoma DOI Creative Commons
Handan Xiang, Yidan Pan, Marc A. Sze

et al.

Cancer Research, Journal Year: 2024, Volume and Issue: 84(9), P. 1410 - 1425

Published: Feb. 9, 2024

Abstract Cancer immunotherapy has revolutionized the treatment of lung adenocarcinoma (LUAD); however, a significant proportion patients do not respond. Recent transcriptomic studies to understand determinants response have pinpointed stromal-mediated resistance mechanisms. To gain better understanding stromal biology at cellular and molecular level in LUAD, we performed single-cell RNA sequencing 256,379 cells, including 13,857 mesenchymal from 9 treatment-naïve patients. Among cell subsets, FAP+PDPN+ cancer-associated fibroblasts (CAF) ACTA2+MCAM+ pericytes were enriched tumors differentiated lung-resident fibroblasts. Imaging mass cytometry revealed that both subsets topographically adjacent perivascular niche had close spatial interactions with endothelial cells (EC). Modeling ligand receptor interactomes between ECs identified NOTCH signaling drives these cell-to-cell tumors, CAFs as signal receivers arterial PLVAPhigh immature neovascular senders. Either pharmacologically blocking or genetically depleting NOTCH3 levels significantly reduced collagen production suppressed invasion. Bulk data demonstrated expression correlated poor survival stroma-rich T cell–inflamed gene signature only predicted low NOTCH3. Collectively, this study provides valuable insights into role regulating tumor stroma biology, warranting further elucidate clinical implications targeting signaling. Significance: activates tumor-associated increases production, augments invasion adenocarcinoma, suggesting its critical remodeling stroma.

Language: Английский

Citations

19
Multi-omics-based mapping of decidualization resistance in patients with a history of severe preeclampsia DOI Creative Commons
Irene Muñoz-Blat, Raúl Pérez-Moraga, Nerea Castillo-Marco

et al.

Nature Medicine, Journal Year: 2025, Volume and Issue: unknown

Published: Jan. 7, 2025

Endometrial decidualization resistance (DR) is implicated in various gynecological and obstetric conditions. Here, using a multi-omic strategy, we unraveled the cellular molecular characteristics of DR patients who have suffered severe preeclampsia (sPE). Morphological analysis unveiled significant glandular anatomical abnormalities, confirmed histologically quantified by digitization hematoxylin eosin-stained tissue sections. Single-cell RNA sequencing (scRNA-seq) endometrial samples from with sPE (n = 11) controls 12) revealed sPE-associated shifts cell composition, manifesting as stromal mosaic state characterized proliferative cells (MMP11 SFRP4) alongside IGFBP1+ decidualized cells, concurrent epithelial mosaicism dearth epithelial–stromal transition associated decidualization. Cell–cell communication network mapping underscored aberrant crosstalk among specific types, implicating crucial pathways such endoglin, WNT SPP1. Spatial transcriptomics replication cohort validated DR-associated features. Laser capture microdissection/mass spectrometry second corroborated several scRNA-seq findings, notably absence to at pathway level, indicating disrupted response steroid hormones, particularly estrogens. These insights shed light on potential mechanisms underpinning pathogenesis context sPE. A multi-omics resistance, which conditions, history defects stroma, epithelium epithelial-to-stromal transition, findings separate cohort.

Language: Английский

Citations

2
Stem Cell Aging in Skeletal Muscle Regeneration and Disease DOI Open Access
Hiroyuki Yamakawa, Dai Kusumoto, Hisayuki Hashimoto

et al.

International Journal of Molecular Sciences, Journal Year: 2020, Volume and Issue: 21(5), P. 1830 - 1830

Published: March 6, 2020

Skeletal muscle comprises 30–40% of the weight a healthy human body and is required for voluntary movements in humans. Mature skeletal formed by multinuclear cells, which are called myofibers. Formation myofibers depends on proliferation, differentiation, fusion progenitor cells during development after injury. Muscle derived from satellite (stem) (MuSCs), reside surface myofiber but beneath basement membrane. MuSCs play central role postnatal maintenance, growth, repair, regeneration muscle. In sedentary adult muscle, mitotically quiescent, promptly activated response to Physiological chronological aging induces MuSC aging, leading an impaired regenerative capability. Importantly, pathological situations, repetitive injury early impairment due stem cell leads ability. this review, we discuss (1) regeneration, (2) under physiological conditions, (3) prospects related clinical applications controlling MuSCs.

Language: Английский

Citations

133
Brain arteriolosclerosis DOI

Brittney L. Blevins,

Harry V. Vinters, Seth Love

et al.

Acta Neuropathologica, Journal Year: 2020, Volume and Issue: 141(1), P. 1 - 24

Published: Oct. 24, 2020

Language: Английский

Citations

131
Tumor vessel co-option probed by single-cell analysis DOI Creative Commons
Laure-Anne Teuwen, Laura de Rooij, Anne Cuypers

et al.

Cell Reports, Journal Year: 2021, Volume and Issue: 35(11), P. 109253 - 109253

Published: June 1, 2021

Tumor vessel co-option is poorly understood, yet it a resistance mechanism against anti-angiogenic therapy (AAT). The heterogeneity of co-opted endothelial cells (ECs) and pericytes, co-opting cancer myeloid in tumors growing via co-option, has not been investigated at the single-cell level. Here, we use murine AAT-resistant lung tumor model, which VEGF-targeting induces for continued growth. Single-cell RNA sequencing (scRNA-seq) 31,964 reveals, unexpectedly, largely similar transcriptome ECs (TECs) pericytes as their healthy counterparts. Notably, identify cell types that might contribute to i.e., an invasive cancer-cell subtype, possibly assisted by matrix-remodeling macrophage population, another M1-like involved keeping or rendering vascular quiescent.

Language: Английский

Citations

74
Dual function of perivascular fibroblasts in vascular stabilization in zebrafish DOI Creative Commons
Arsheen M. Rajan, C. Roger, Katrinka M. Kocha

et al.

PLoS Genetics, Journal Year: 2020, Volume and Issue: 16(10), P. e1008800 - e1008800

Published: Oct. 26, 2020

Blood vessels are vital to sustain life in all vertebrates. While it is known that mural cells (pericytes and smooth muscle cells) regulate vascular integrity, the contribution of other cell types stabilization has been largely unexplored. Using zebrafish, we identified sclerotome-derived perivascular fibroblasts as a novel population blood vessel associated cells. In contrast pericytes, emerge early during development, express extracellular matrix (ECM) genes col1a2 col5a1 , display distinct morphology distribution. Time-lapse imaging reveals serve pericyte precursors. Genetic ablation markedly reduces collagen deposition around endothelial cells, resulting dysmorphic with variable diameters. Strikingly, mutants show spontaneous hemorrhage, penetrance phenotype strongly enhanced by additional loss . Together, our work dual roles where they establish ECM nascent function progenitors.

Language: Английский

Citations

73
Blood–Brain Barrier and Neurodegenerative Diseases—Modeling with iPSC-Derived Brain Cells DOI Open Access
Ying‐Chieh Wu, Tuuli-Maria Sonninen, Sanni Peltonen

et al.

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(14), P. 7710 - 7710

Published: July 19, 2021

The blood-brain barrier (BBB) regulates the delivery of oxygen and important nutrients to brain through active passive transport prevents neurotoxins from entering brain. It also has a clearance function removes carbon dioxide toxic metabolites central nervous system (CNS). Several drugs are unable cross BBB enter CNS, adding complexity drug screens targeting disorders. A well-functioning is essential for maintaining healthy tissue, malfunction BBB, linked its permeability, results in toxins immune cells CNS. This impairment associated with variety neurological diseases, including Alzheimer's disease Parkinson's disease. Here, we summarize current knowledge about neurodegenerative diseases. Furthermore, focus on recent progress using human-induced pluripotent stem cell (iPSC)-derived models study BBB. We review potential novel cell-based platforms modeling address advances key challenges technology human Finally, highlight future directions this area.

Language: Английский

Citations

69
Characteristics of pre-metastatic niche: the landscape of molecular and cellular pathways DOI Creative Commons
Hao Wang, Junjie Pan,

Livnat Barsky

et al.

Molecular Biomedicine, Journal Year: 2021, Volume and Issue: 2(1)

Published: Jan. 30, 2021

Metastasis is a major contributor to cancer-associated deaths. It involves complex interactions between primary tumorigenic sites and future metastatic sites. Accumulation studies have revealed that tumour metastasis not disorderly spontaneous incident but the climax of series sequential dynamic events including development pre-metastatic niche (PMN) suitable for subpopulation cells colonize develop into metastases. A deep understanding formation, characteristics function PMN required developing new therapeutic strategies treat patients. rapidly becoming evident therapies targeting may be successful in averting at an early stage. This review highlights key components main describes potential strategies, providing promising foundation studies.

Language: Английский

Citations

58