Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment

Nature Communications, Journal Year: 2022, Volume and Issue: 13(1)

Published: Nov. 4, 2022

Abstract Cancer-associated fibroblasts (CAFs) are the predominant components of tumor microenvironment (TME) and influence cancer hallmarks, but without systematic investigation on their ubiquitous characteristics across different types. Here, we perform pan-cancer analysis 226 samples 10 solid types to profile TME at single-cell resolution, illustrating commonalities/plasticity heterogenous CAFs. Activation trajectory major CAF is divided into three states, exhibiting distinct interactions with other cell components, relating prognosis immunotherapy. Moreover, minor represent alternative origin from (e.g., endothelia macrophages). Particularly, presentation endothelial-to-mesenchymal transition CAF, which may interact proximal SPP 1 + tumor-associated macrophages, implicated in survival stratifications. Our study comprehensively profiles shared dynamics CAFs, highlight heterogeneity plasticity Browser integrated information available https://gist-fgl.github.io/sc-caf-atlas/ .

Language: Английский

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Adipose tissue at single-cell resolution

Cell Metabolism, Journal Year: 2023, Volume and Issue: 35(3), P. 386 - 413

Published: March 1, 2023

Language: Английский

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Mechanical Signal‐Tailored Hydrogel Microspheres Recruit and Train Stem Cells for Precise Differentiation

Advanced Materials, Journal Year: 2023, Volume and Issue: 35(40)

Published: May 25, 2023

The aberrant mechanical microenvironment in degenerated tissues induces misdirection of cell fate, making it challenging to achieve efficient endogenous regeneration. Herein, a hydrogel microsphere-based synthetic niche with integrated recruitment and targeted differentiation properties via mechanotransduction is constructed . Through the incorporation microfluidics photo-polymerization strategies, fibronectin (Fn) modified methacrylated gelatin (GelMA) microspheres are prepared independently tunable elastic modulus (1-10Kpa) ligand density (2 10 µg mL-1 ), allowing wide range cytoskeleton modulation trigger corresponding mechanobiological signaling. combination soft matrix (2Kpa) low ) can support nucleus pulposus (NP)-like intervertebral disc (IVD) progenitor/stem cells by translocating Yes-associated protein (YAP), without addition inducible biochemical factors. Meanwhile, platelet-derived growth factor-BB (PDGF-BB) loaded onto Fn-GelMA (PDGF@Fn-GelMA) heparin-binding domain Fn initiate recruitment. In vivo experiments, microsphere-niche maintained IVD structure stimulated synthesis. Overall, this recruiting training capabilities offered promising strategy for tissue

Language: Английский

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The enhancer landscape predetermines the skeletal regeneration capacity of stromal cells

Science Translational Medicine, Journal Year: 2023, Volume and Issue: 15(688)

Published: March 22, 2023

Multipotent stromal cells are considered attractive sources for cell therapy and tissue engineering. Despite numerous experimental clinical studies, broad application of therapeutics is not yet emerging. A major challenge the functional diversity available sources. Here, we investigated regenerative potential clinically relevant human from bone marrow (BMSCs), white adipose tissue, umbilical cord compared with mature chondrocytes skin fibroblasts in vitro vivo. Although all types could express transcription factors related to endochondral ossification, only BMSCs formed cartilage discs that fully regenerated critical-size femoral defects after transplantation into mice. We identified type–specific epigenetic landscapes as underlying molecular mechanism controlling transcriptional differentiation networks. Binding sites commonly expressed enhancer promoter regions ossification-related genes, including Runt bZIP families, were accessible but extraskeletal cells. This suggests an epigenetically predetermined depending on origin allows common trigger distinct organ-specific programs, facilitating forward selection regeneration-competent Last, demonstrate viable initiated defect healing through secretion osteopontin contributed transient mineralized hard callus formation immunodeficient mice, which was eventually replaced by murine recipient during final remodeling.

Language: Английский

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The molecular classification of cancer‐associated fibroblasts on a pan‐cancer single‐cell transcriptional atlas

Clinical and Translational Medicine, Journal Year: 2023, Volume and Issue: 13(12)

Published: Dec. 1, 2023

Abstract Background Cancer‐associated fibroblasts (CAFs), integral to the tumour microenvironment, are pivotal in cancer progression, exhibiting either pro‐tumourigenic or anti‐tumourigenic functions. Their inherent phenotypic and functional diversity allows for subdivision of CAFs into various subpopulations. While several classification systems have been suggested different types, a unified molecular on single‐cell pan‐cancer scale has yet be established. Methods We employed comprehensive transcriptomic atlas encompassing 12 solid types. Our objective was establish novel elucidate evolutionary trajectories CAFs. investigated profiles each CAF subtype using Single‐Cell Regulatory Network Inference Clustering gene set enrichment analysis. The clinical relevance these subtypes assessed through survival curve Concurrently, we multiplex immunofluorescence staining tissues determine dynamic changes across stages. Additionally, identified small molecule procyanidin C1 (PCC1) as target matrix‐producing (matCAF) docking techniques further validated findings vitro vivo experiments. Results In our investigation tumours, four clusters CAFs: progenitor (proCAF), inflammatory (iCAF), myofibroblastic (myCAF) matCAF, characterised by distinct traits. This consistently applicable all nine studied These displayed unique pathways, roles tumours. Notably, matCAF associated with poorer prognoses targeting molecule, PCC1, demonstrated promising antitumour activity. Conclusions Collectively, CAFs, particularly crucial initiation progression cancer. Focusing therapeutic strategies tumours holds significant potential treatment.

Language: Английский

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Epigenetic regulators controlling osteogenic lineage commitment and bone formation

Bone, Journal Year: 2024, Volume and Issue: 181, P. 117043 - 117043

Published: Feb. 9, 2024

Bone formation and homeostasis are controlled by environmental factors endocrine regulatory cues that initiate intracellular signaling pathways capable of modulating gene expression in the nucleus. Bone-related is nucleosome-based chromatin architecture limits accessibility lineage-specific DNA sequences sequence-specific transcription factors. From a developmental perspective, bone-specific must be suppressed during early stages embryogenesis to prevent premature mineralization skeletal elements fetal growth utero. Hence, bone initially inhibited suppressive epigenetic regulators, while other regulators actively support osteoblast differentiation. Prominent stimulate or attenuate osteogenesis include lysine methyl transferases (e.g., EZH2, SMYD2, SUV420H2), deacetylases HDAC1, HDAC3, HDAC4, HDAC7, SIRT1, SIRT3), arginine PRMT1, PRMT4/CARM1, PRMT5), dioxygenases TET2), bromodomain proteins BRD2, BRD4) chromodomain CBX1, CBX2, CBX5). This narrative review provides broad overview covalent modifications histone involve hundreds enzymes add, read, delete these relevant for self-renewal differentiation mesenchymal stem cells, cells osteoblasts osteogenesis.

Language: Английский

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Delivery of coenzyme Q10 loaded micelle targets mitochondrial ROS and enhances efficiency of mesenchymal stem cell therapy in intervertebral disc degeneration

Bioactive Materials, Journal Year: 2022, Volume and Issue: 23, P. 247 - 260

Published: Nov. 17, 2022

Stem cell transplantation has been proved a promising therapeutic instrument in intervertebral disc degeneration (IVDD). However, the elevation of oxidative stress degenerated region impairs efficiency mesenchymal stem cells (BMSCs) treatment via exaggeration mitochondrial ROS and promotion BMSCs apoptosis. Herein, we applied an emulsion-confined assembly method to encapsulate Coenzyme Q10 (Co-Q10), hydrophobic antioxidant which targets mitochondria ROS, into lecithin micelles, renders insoluble Co-Q10 dispersible water as stable colloids. These micelles are injectable, displayed efficient ability facilitate get vitro, exhibited prolonged release tissue animal models. Compared mere use Co-Q10, loaded micelle possessed better bioactivities, elevated viability, restored structure well function, enhanced production ECM components rat BMSCs. Moreover, it is demonstrated that injection this with retained height alleviated IVDD needle puncture model. Therefore, these play protective role survival differentiation through antagonizing might be potential agent for IVDD.

Language: Английский

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Efferocytosis by bone marrow mesenchymal stromal cells disrupts osteoblastic differentiation via mitochondrial remodeling

Cell Death and Disease, Journal Year: 2023, Volume and Issue: 14(7)

Published: July 14, 2023

Abstract The efficient clearance of dead and dying cells, efferocytosis, is critical to maintain tissue homeostasis. In the bone marrow microenvironment (BMME), this role primarily fulfilled by professional macrophages, but recent work has shown that mesenchymal stromal cells (MSCs) act as a non-professional phagocyte within BMME. However, little known about mechanism impact efferocytosis on MSCs their function. To investigate, we performed flow cytometric analysis neutrophil uptake ST2 murine marrow-derived cell line, in primary cells. Transcriptional showed possess necessary receptors internal processing machinery conduct with Axl Tyro3 serving main receptors, while MerTK was not expressed. Moreover, expression these modulated efferocytic behavior, regardless apoptotic target. derived from human also demonstrated showing MSC conserved. all MSCs, impaired osteoblastic differentiation. functional assays identified downregulation mitochondrial function upon efferocytosis. Experimentally, induced fission MSCs. Pharmacologic inhibition only decreased activity rescued differentiation, demonstrating efferocytosis-mediated remodeling plays regulating This describes novel phagocytes BMME demonstrates key directing Efferocytosis may therefore be dysfunction senescence. Since our data show conserved, consequences behavior skeleton, including loss setting aging, cancer other diseases.

Language: Английский

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Transcriptional control of metabolism by interferon regulatory factors

Nature Reviews Endocrinology, Journal Year: 2024, Volume and Issue: 20(10), P. 573 - 587

Published: May 20, 2024

Language: Английский

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Precision Nanomedicine with Bio-Inspired Nanosystems: Recent Trends and Challenges in Mesenchymal Stem Cells Membrane-Coated Bioengineered Nanocarriers in Targeted Nanotherapeutics

Journal of Xenobiotics, Journal Year: 2024, Volume and Issue: 14(3), P. 827 - 872

Published: June 24, 2024

In the recent past, formulation and development of nanocarriers has been elaborated into broader fields opened various avenues in their preclinical clinical applications. particular, cellular membrane-based nanoformulations have formulated to surpass surmount limitations restrictions associated with naïve or free forms therapeutic compounds circumvent physicochemical immunological barriers including but not limited systemic barriers, microenvironmental roadblocks, other subcellular hinderances-which are quite heterogeneous throughout diseases patient cohorts. These drug delivery overcome through mesenchymal cells precision therapeutics, where these interventions led significant enhancements efficacies. However, still focuses on optimization paradigms a one-size-fits-all resolutions. As stem cell engineered highly diversified fashions, being optimized for delivering payloads more better personalized modes, entering arena as well nanomedicine. this Review, we included some advanced which designed utilized both non-personalized applicability can be employed improvements nanotherapeutics. present report, authors focused aspects advancements nanoparticle conceptions several roadblocks It suggested that well-informed designing will lead appreciable efficacy payload approaches also enable tailored customized designs MSC-based applications, finally amending outcomes.

Language: Английский

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