Tensile Stress‐Activated and Exosome‐Transferred YAP/TAZ‐Notch Circuit Specifies Type H Endothelial Cell for Segmental Bone Regeneration

Advanced Science, Journal Year: 2024, Volume and Issue: 11(12)

Published: Jan. 15, 2024

The Ilizarov technique has been continuously innovated to utilize tensile stress (TS) for inducing a bone development-like regenerative process, aiming achieve skeletal elongation and reconstruction. However, it remains uncertain whether this distraction osteogenesis (DO) process induced by TS involves the pivotal coupling of angiogenesis mediated type H endothelial cells (THECs). In study, is demonstrated that induces formation metaphysis-like architecture composed THECs, leading segmental regeneration during DO process. Mechanistically, cell-matrix interactions-mediated activation yes-associated protein (YAP)/transcriptional co-activator with PDZ-binding motif (TAZ) transcriptionally upregulates expression Notch1 Delta-like ligand 4, which act as direct positive regulators THECs phenotype, in marrow (BMECs) upon stimulation. Simultaneously, Notch intracellular domain enhances YAP/TAZ activity upregulating YAP stabilizing TAZ protein, thus establishing YAP/TAZ-Notch circuit. Additionally, TS-stimulated BMECs secrete exosomes enriched vital molecules feedback pathway, can be utilized promote defect healing, mimicking therapeutic effects technique. findings advance understanding TS-induced establish foundation innovative biological strategies aimed at activating THECs.

Language: Английский

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Static Topographical Cue Combined with Dynamic Fluid Stimulation Enhances the Macrophage Extracellular Vesicle Yield and Therapeutic Potential for Bone Defects

ACS Nano, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 25, 2025

Extracellular vesicles (EVs) hold promise for tissue regeneration, but their low yield and limited therapeutic efficacy hinder clinical translation. Bioreactors provide a larger culture surface area stable environment large-scale EV production, yet ability to enhance is limited. Physical stimulation, by inducing cell differentiation modulating cargo composition, offers more efficient, cost-effective, reproducible approach compared the loading of EVs biochemical priming parental cells. Herein, effects 3D-printed perfusion bioreactor with topographical cue on macrophage bioactivity were assessed. The results indicate that increased 12.5-fold enhanced in promoting osteogenic angiogenesis via upregulated miR-210-3p. Mechanistically, fluid shear stress activates Piezo1, triggering Ca2+ influx Yes-associated protein (YAP) nuclear translocation, secretion enhancing M2 polarization conjunction morphological changes guided aligned topography. Moreover, porous electrospun membrane-hydrogel composite scaffold loaded bioreactor-derived exhibited outstanding rat cranial defect model. This study presents scalable, platform production EVs, potentially overcoming key challenges translating EV-based therapies clinic.

Language: Английский

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Exosomes: A New Hope for Angiogenesis-Mediated Bone Regeneration

International Journal of Molecular Sciences, Journal Year: 2024, Volume and Issue: 25(10), P. 5204 - 5204

Published: May 10, 2024

Bone is a metabolically dynamic structure that generally remodeled throughout the lifetime of an individual but often causes problems with increasing age. A key player for bone development and homeostasis, also under pathological conditions, vasculature. This complex system arteries, veins, capillaries forms distinct structures where each subset endothelial cells has important functions. Starting basic process angiogenesis bone-specific blood vessel formation, coupled initial importance different vascular highlighted respect to how these are maintained or changed during aging, conditions. After exemplifying current knowledge on vasculature, this review will move exosomes, novel hotspot scientific research. Exosomes be introduced starting from their discovery via isolation procedures state-of-the-art characterization role in development, regeneration repair while summarizing underlying signal transduction pathways. With processes, especially mesenchymal stem cell-derived extracellular vesicles interest, which leads discussion patented applications update ongoing clinical trials. Taken together, provides overview vasculature regeneration, major focus exosomes influence intricate system, as they might useful therapeutic purposes near future.

Language: Английский

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Endothelial cell-derived exosomes trigger a positive feedback loop in osteogenesis-angiogenesis coupling via up-regulating zinc finger and BTB domain containing 16 in bone marrow mesenchymal stem cell

Journal of Nanobiotechnology, Journal Year: 2024, Volume and Issue: 22(1)

Published: Nov. 19, 2024

The close spatial and temporal connection between osteogenesis angiogenesis around type H vasculature is referred as "osteogenesis-angiogenesis coupling", which one of the basic mechanisms osteogenesis. Endothelial cells (ECs), bone marrow mesenchymal stem (BMSCs), their specific lineage constitute important cluster that participate in regulation microenvironment. However, regulatory mechanism osteogenesis-angiogenesis coupling under condition healing has not been unveiled. In this study, we demonstrated exosome derived from ECs (EC-exo) an initiator blood vessels formation, EC-exo acts a mediator orchestrating by enhancing BMSC osteogenic differentiation EC both monolayer stereoscopic co-culture system primary human cells. transcriptome array indicated zinc finger BTB domain containing 16 (ZBTB16) key gene EC-exo-mediated osteogenesis, ZBTB16 indispensable EC-exo-initiated coupling. Mechanistically, up-regulated expression BMSCs, thereby promoting osteoprogenitor phenotype transformation; osteoprogenitors further promote vessel (H-ECs) generation activating HIF-1α pathway; H-ECs conversely promotes BMSCs. crosstalk BMSCs triggered constitutes positive feedback loop enhances This study demonstrates can become effective therapeutic tool to regeneration repair.

Language: Английский

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Exercise ameliorates osteopenia in mice via intestinal microbial-mediated bile acid metabolism pathway

Theranostics, Journal Year: 2025, Volume and Issue: 15(5), P. 1741 - 1759

Published: Jan. 2, 2025

Rationale: Physical exercise is essential for skeletal integrity and bone health. The gut microbiome, as a pivotal modulator of overall physiologic states, closely associated with homeostasis metabolism. However, the potential role intestinal microbiota in exercise-mediated gain remains unclear. Methods: We conducted depletion fecal transplantation (FMT) ovariectomy (OVX) mice aged to investigate whether transfer ecological traits could confer exercise-induced protective effects. study analyzed metabolic profiles via 16S rRNA gene sequencing LC-MS untargeted metabolomics identify key microbial communities metabolites responsible protection. Transcriptome RNA interference were employed explore molecular mechanisms. Results: found that hindered osteogenic benefits exercise, FMT from exercised osteoporotic effectively mitigated osteopenia. Comprehensive profiling microbiome metabolome revealed exercise-matched reshaped microecology landscape. Notably, alterations bile acid metabolism, specifically enrichment taurine ursodeoxycholic acid, mediated effects on mass. Mechanistically, activated apelin signaling pathway restored bone-fat balance recipient MSCs. Conclusion: Our underscored important microbiota-metabolic axis gain, heralding breakthrough treatment osteoporosis.

Language: Английский

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YAP/TAZ-associated cell signaling – at the crossroads of cancer and neurodevelopmental disorders

Frontiers in Cell and Developmental Biology, Journal Year: 2025, Volume and Issue: 13

Published: Jan. 28, 2025

YAP/TAZ (Yes-associated protein/paralog transcriptional co-activator with PDZ-binding domain) are cofactors that the key and major downstream effectors of Hippo signaling pathway. Both known to play a crucial role in defining cellular outcomes, including cell differentiation, proliferation, apoptosis. Aside from canonical cascade components MST1/2 (mammalian STE20-like kinase 1/2), SAV1 (Salvador homologue 1), MOB1A/B (Mps one binder activator 1A/B) LATS1/2 (large tumor suppressor 1/2) upstream YAP/TAZ, activation is also influenced by numerous other pathways. Such non-canonical regulation includes well-known growth factor pathways such as epidermal receptor (EGFR)/ErbB family, Notch, Wnt well cell-cell adhesion, cell-matrix interactions mechanical cues cell’s microenvironment. This puts at center complex network capable regulating developmental processes tissue regeneration. On hand, dysregulation has been implicated diseases various cancers neurodevelopmental disorders. Indeed, recent years, parallels between cancer development disorders have become apparent being these review discusses brain development, special focus on interconnection different conditions.

Language: Английский

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3D printed porous PEEK scaffolds with stable and durable gelatin composite hydrogel coating loaded Yoda1 for in vivo osseointegration

International Journal of Biological Macromolecules, Journal Year: 2025, Volume and Issue: 307, P. 141577 - 141577

Published: March 5, 2025

Language: Английский

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mpECs with high Piezo2 expression promote fracture healing by driving angiogenesis through the Notch signaling pathway

BMC Musculoskeletal Disorders, Journal Year: 2025, Volume and Issue: 26(1)

Published: March 11, 2025

Fractures will impair or disrupt angiogenesis, resulting in delayed union non-union. Exploring angiogenic signaling molecules and related pathways can promote fracture healing. In this study, the roles of different endothelial cell (EC) subsets healing were observed using single-cell RNA sequencing (scRNA-seq). It was found that mpECs did affect repair regeneration sites, could up-regulate genes to Notch signaling, cycle. addition, Piezo2 expression successfully knocked down by transfection shRNA human umbilical vein cells (HUVECs) for vitro assays. The results suggested reduced HUVECs suppress proliferation cycle further activation pathway, inhibiting angiogenesis. Subsequently, intervened with pathway inhibitor DAPT agonist Jagged1. inhibition knockdown more significant presence DAPT, whereas Jagged1 reversed knockdown-caused changes downstream protein pathway. With Jagged1, knockdown-induced decrease HUVEC tube formation disappeared. Moreover, significantly enhanced, a marked increase length. Cell counting kit-8 (CCK-8) assay flow cytometry demonstrated trigger entry. conclusion, affects phenotype ECs modulating promotes thus accelerating

Language: Английский

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Trifunctional Sialylation‐Based SF‐ZIF@NA Hydrogel for Selective Osteoclast Inhibition and Enhanced Bone‐Vessel Regeneration in Osteoporotic Bone Defects

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: March 26, 2025

Osteoporotic bone defects are challenging to repair due imbalances in resorption and formation, coupled with insufficient vascularization. To address these issues, it develops a trifunctional hydrogel (SF-ZIF@NA) designed selectively inhibit osteoclast activity enhance vascularized regeneration. By enzymatically removing sialic acid, SF-ZIF@NA prevents precursor osteoclasts (pOCs) from fusing into bone-resorbing mature (mOCs), thereby preserving pOCs their anabolic functions. Additionally, the releases Zinc ion (Zn2⁺) response acidic conditions, promoting osteogenesis angiogenesis. In vitro results confirmed that impedes fusion, enhances platelet-derived growth factor-BB (PDGF-BB secretion pOCs, activates FAK (focal adhesion kinase) signaling pathway stimulate formation. osteoporotic defect models, accelerated increased density These findings demonstrate offers targeted multifunctional strategy for regeneration by concurrently modulating

Language: Английский

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Microenvironmental Modulation for Therapeutic Efficacy of Extracellular Vesicles

Advanced Science, Journal Year: 2025, Volume and Issue: unknown

Published: March 27, 2025

Abstract Extracellular vesicles (EVs) hold significant promise for the prevention and treatment of various diseases. However, translation EV‐based therapies into clinical practice faces considerable challenges, particularly in terms production yield therapeutic efficacy. Recent studies have emphasized heterogeneity EVs influence parental cell microenvironmental signals on their biogenesis, cargo composition, outcomes. This review offers a comprehensive overview strategies to optimize efficacy through physical, biochemical, mechanical modulation. Additionally, it explores how affect EV cargoes mechanisms by which these can improve The also addresses current challenges potential solutions accelerate therapies. Ultimately, highlights modulation unlocking full capacity EVs, providing key insights use treating

Language: Английский

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