Biomechanical regulation of cell shapes promotes branching morphogenesis of the ureteric bud epithelium DOI
Kristen Kurtzeborn, Vladislav Iaroshenko, Tomáš Zárybnický

и другие.

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2024, Номер unknown

Опубликована: Март 31, 2024

Abstract Background Branching morphogenesis orchestrates organogenesis in many tissues including kidney, where ureteric bud branching determines kidney size and nephron number. Defects result congenital renal anomalies which manifest as deviations size, function, number thus critically compromising the lifelong functional capacity established during development. Advances genetic molecular understanding of regulation have proved insufficient to improve prognosis defects. Thus, we addressed mechanisms regulating three-dimensional (3D) epithelial cell morphology shape changes novel branch initiation uncover contributions cellular mechanics on functions tissue organization normal branching-compromised tips. Methods We explored behavior at all scales by utilizing a combination mouse genetics custom machine-learning segmentation pipeline MATLAB. Ureteric shapes sizes were quantified 3D wholemount kidneys. A with live imaging fluorescently labelled UB cells, traction force microscopy, primary cells used determine how basic features niche biomechanics contribute complex point determination process that aims gaining optimal growth density limited space. Results Machine learning-based tip epithelia identified geometrical round-to-elliptical transformation key change facilitating shifts direction enable propitious complexity. Cell analyses demonstrated failure condense conformation. Analysis derived disrupted E-CADHERIN PAXILLIN mediated adhesive forces defective cytoskeletal dynamics detected fluorescent labelling actin cells. Branching-compromised showed wrinkled nuclear alterations MYH9-based microtubule organization, suggest stiff disturbed sensing response biomechanical cues. Conclusions Our results indicate within epithelium towards composed progenitors must dynamically fluctuate allow complexity arborization new formation. The data collectively propose model crowding tandem stretching transforms individual into elliptical elongated shapes. This creates local curvatures drive formation ampulla-to-asymmetric ampulla transition bud.

Язык: Английский

Extracellular matrix stiffness activates mechanosensitive signals but limits breast cancer cell spheroid proliferation and invasion DOI Creative Commons

Irina Jahin,

Thomas Phillips,

Stefania Marcotti

и другие.

Frontiers in Cell and Developmental Biology, Год журнала: 2023, Номер 11

Опубликована: Дек. 6, 2023

Breast cancer is characterized by physical changes that occur in the tumor microenvironment throughout growth and metastasis of tumors. Extracellular matrix stiffness increases as tumors develop spread, with stiffer environments thought to correlate poorer disease prognosis. Changes extracellular other characteristics are sensed integrins which integrate these cues intracellular signaling, resulting modulation proliferation invasion. However, co-ordination mechano-sensitive signaling functional groups cells within 3-dimensional remains poorly understood. Here we provide evidence increasing collagen scaffolds results increased activation ERK1/2 YAP human breast cell spheroids. We also show acts upstream this context. further demonstrate YAP, metalloproteinases actomyosin contractility required for remodeling, invasion lower scaffolds. proteins higher gels correlated reduced Our data collectively induce mechano-signaling but contrary from 2-dimensional studies, not sufficient promote pro-tumorigenic effects

Язык: Английский

Процитировано

15
Time-dependent effects of BRAF-V600E on cell cycling, metabolism, and function in engineered myocardium DOI Creative Commons
Nicholas Strash, Sophia DeLuca, Geovanni L. Janer Carattini

и другие.

Science Advances, Год журнала: 2024, Номер 10(4)

Опубликована: Янв. 24, 2024

Candidate cardiomyocyte (CM) mitogens such as those affecting the extracellular signal–regulated kinase (ERK) signaling pathway represent potential targets for functional heart regeneration. We explored whether activating ERK via a constitutively active mutant of B-raf proto-oncogene (BRAF), BRAF-V600E (caBRAF), can induce proproliferative effects in neonatal rat engineered cardiac tissues (ECTs). Sustained CM-specific caBRAF expression induced chronic activation, substantial tissue growth, deficit sarcomeres and contractile function, stiffening, all which persisted at least 4 weeks culture. caBRAF-expressing CMs ECTs exhibited broad transcriptomic changes, shift to glycolytic metabolism, loss connexin-43, promigratory phenotype. Transient, doxycycline-controlled revealed that induction CM cycling is rapid precedes decline, are reversible only with short-lived activation. Together, direct activation BRAF sufficient modulate phenotype, offering mechanistic insights into roles context development

Язык: Английский

Процитировано

6
Biomimetic Fibers Derived from an Equidistant Micropillar Platform Dictate Osteocyte Fate via Mechanoreception DOI
Yang Liu,

Xiaohua Pu,

Mengmeng Duan

и другие.

Nano Letters, Год журнала: 2023, Номер 23(17), С. 7950 - 7960

Опубликована: Июль 7, 2023

It is a big challenge to design biomimetic physical microenvironment with greater similarity in vivo tissue observe real cell behaviors. We established novel culture platform based on patterned equidistant micropillars stiff and soft stiffnesses mimic the changes that happened transition from normal osteoporotic disease. first demonstrated micropillar substrate decreased osteocyte synaptogenesis through synaptogyrin 1 this decrease was accompanied by impairment of mechanoperception cellular cytoskeletal rearrangement. then found reduced mainly via inactivation Erk/MAPK signaling. finally substrate-mediated impacted cell-to-cell communication matrix mineralization osteocytes. Taken together, study provides evidence mechanical responses are much more similar those osteocytes at bone level.

Язык: Английский

Процитировано

13
Optogenetic clustering and membrane translocation of the BcLOV4 photoreceptor DOI Creative Commons
Ayush Aditya Pal, William Benman, Thomas R. Mumford

и другие.

Proceedings of the National Academy of Sciences, Год журнала: 2023, Номер 120(32)

Опубликована: Авг. 1, 2023

Optogenetic tools respond to light through one of a small number behaviors including allosteric changes, dimerization, clustering, or membrane translocation. Here, we describe new class optogenetic actuator that simultaneously clusters and translocates the plasma in response blue light. We demonstrate dual translocation clustering BcLOV4 photoreceptor can be harnessed for novel single-component tools, control entire family epidermal growth factor receptor (ErbB1-4) tyrosine kinases. further find are mechanistically linked. Stronger increased magnitude downstream signaling, sensitivity by ~threefold-to-fourfold, decreased expression levels needed strong signal activation. Thus light-induced provides strategy generate enhance existing ones.

Язык: Английский

Процитировано

13
Piezo1 activates noncanonical EGFR endocytosis and signaling DOI Creative Commons
Carlos Pardo-Pastor, Jody Rosenblatt

Science Advances, Год журнала: 2023, Номер 9(39)

Опубликована: Сен. 27, 2023

EGFR-ERK signaling controls cell cycle progression during development, homeostasis, and disease. While EGF ligand mechanical inputs can activate signaling, the molecules linking force to this axis have remained mysterious. We previously found that stretch promotes mitosis via stretch-activated ion channel Piezo1 ERK signaling. Here, we show provides missing link between signals activation. both EGF- Piezo1-dependent activation trigger clathrin-mediated EGFR endocytosis activation, relies on canonical tyrosine autophosphorylation, whereas involves Src-p38 kinase-dependent serine phosphorylation. In addition, unlike EGF, ex vivo lung slices treated with agonist promoted re-entry nuclear ERK, AP-1 (FOS JUN), YAP accumulation, typical of regenerative malignant Our results suggest Piezo1, Src, p38 may be more relevant controlling repair, regeneration, cancer growth than kinase suggesting an alternative therapeutic approach.

Язык: Английский

Процитировано

12
PI3K signaling through a biochemical systems lens DOI Creative Commons
Ralitsa R. Madsen, Alex Toker

Journal of Biological Chemistry, Год журнала: 2023, Номер 299(10), С. 105224 - 105224

Опубликована: Сен. 9, 2023

Faced with the remarkable complexity of cellular signaling networks, human brain naturally turns to a reductionist approach that seeks characterize smaller units, commonly known as pathways, and their individual components. This has proven essential for understanding pleiotropic physiological processes attributed PI3K well consequences disease-causing aberrations in pathway biochemical molecular discovery resulted identification multiple different catalytic regulatory isoforms PI3K, biosynthetic routes key lipid products second messengers PIP3 PI(3,4)P2, effectors such AKT downstream substrates.

Язык: Английский

Процитировано

11
pYtags enable spatiotemporal measurements of receptor tyrosine kinase signaling in living cells DOI Creative Commons
Payam E. Farahani, Xiaoyu Yang, Emily V. Mesev

и другие.

eLife, Год журнала: 2023, Номер 12

Опубликована: Май 19, 2023

Receptor tyrosine kinases (RTKs) are major signaling hubs in metazoans, playing crucial roles cell proliferation, migration, and differentiation. However, few tools available to measure the activity of a specific RTK individual living cells. Here, we present pYtags, modular approach for monitoring user-defined by live-cell microscopy. pYtags consist an modified with activation motif that, when phosphorylated, recruits fluorescently labeled tandem SH2 domain high specificity. We show that enable on seconds-to-minutes time scales across subcellular multicellular length scales. Using pYtag biosensor epidermal growth factor receptor (EGFR), quantitatively characterize how dynamics vary identity dose activating ligand. orthogonal can be used monitor EGFR ErbB2 same cell, revealing distinct phases each RTK. The specificity modularity open door robust biosensors multiple may engineering synthetic receptors response programs.

Язык: Английский

Процитировано

10
Low-frequency ERK and Akt activity dynamics are predictive of stochastic cell division events DOI Creative Commons
Jamie J. R. Bennett, Alan D. Stern, Xiang Zhang

и другие.

npj Systems Biology and Applications, Год журнала: 2024, Номер 10(1)

Опубликована: Июнь 4, 2024

Abstract Understanding the dynamics of intracellular signaling pathways, such as ERK1/2 (ERK) and Akt1/2 (Akt), in context cell fate decisions is important for advancing our knowledge cellular processes diseases, particularly cancer. While previous studies have established associations between ERK Akt activities proliferative fate, heterogeneity single-cell responses adds complexity to this understanding. This study employed a data-driven approach address challenge, developing machine learning models trained on dataset growth factor-induced activity time courses single cells, predict division events. The most predictive were developed by applying discrete wavelet transforms (DWTs) extract low-frequency features from courses, followed using Ensemble Integration, data integration modeling framework. results demonstrated that these effectively predicted events MCF10A cells (F-measure=0.524, AUC=0.726). found be more than Akt, but combination both measurements further enhanced performance. model`s performance also generalized predicting RPE indicating potential applicability methodology across different biological contexts. Interpretation suggested throughout cycle, rather immediately after factor stimulation, associated with likelihood division. Overall, work contributes insights into power intra-cellular decisions, highlights approaches unraveling complex behaviors.

Язык: Английский

Процитировано

4
Navigating the biophysical landscape: how physical cues steer the journey of bone metastatic tumor cells DOI

Pengrong Ouyang,

Bo Cheng, Xijing He

и другие.

Trends in cancer, Год журнала: 2024, Номер 10(9), С. 792 - 808

Опубликована: Авг. 10, 2024

Язык: Английский

Процитировано

3
Tissue sculpting with light DOI

Romane Petit,

Léo Valon

Cell Systems, Год журнала: 2025, Номер 16(3), С. 101241 - 101241

Опубликована: Март 1, 2025

Язык: Английский

Процитировано

0