Biology subjects

Ciccone, G.

Publications and source records attributed to Ciccone, G..

5 recordsLinked to original sources

bioRxiv2026

Stiffness Drives Endothelial Senescence and Inflammation in Aging and Doxorubicin-Induced Vascular Dysfunction

Age-related arterial stiffening affects over [~] 60% of elderly individuals and is a major independent risk factor for cardiovascular mortality. Similarly, doxorubicin-induced cardiotoxicity affects up to [~] 48% of cancer patients, limiting therapeutic options. Here, we demonstrate that vascular stiffness mechanically amplifies endothelial senescence phenotypes, identifying the extracellular matrix as a potential therapeutic target for both cardiovascular aging and chemotherapy-induced vascular dysfunction. Using polyacrylamide (PAAm) hydrogels to mimick soft (3.3 kPa) and physiological (30 kPa) arterial stiffness, and glass to reproduce pathological stiffening, we show that substrate rigidity enhances senescence markers including {beta}-galactosidase activity, DNA damage, and inflammatory cytokine secretion in both therapy-induced and replicative senescence models. Critically, we identify a protective effect at physiological stiffness, where IL-6 and IL-8 secretion is minimized compared to both softer and stiffer conditions, suggesting an optimal mechanical therapeutic window. RNA sequencing reveals stiffness-dependent activation inflammatory pathways including chemotaxis and leukocyte migration. Our findings position vascular stiffening not just as a consequence but as driver of endothelial dysfunction, creating a positive feedback loop amenable to therapeutic intervention. These mechanobiological insights provide rationale for developing mechanical-based therapies in cardiovascular medicine and cardio-oncology, where targeting tissue mechanics alongside conventional approaches could improve clinical outcomes.

bioengineering↗

bioRxiv2024

Piezo1 is a mechanosensor of soft matrix viscoelasticity

Mechanosensitive ion channels have emerged as fundamental proteins in sensing extracellular matrix (ECM) mechanics. Among those, Piezo1 has been proposed as a key mechanosensor in cells. However, whether and how Piezo1 senses time-dependent ECM mechanical properties (i.e., viscoelasticity) remains unknown. To address this question, we combined an immortalised mesenchymal stem cell (MSC) line with adjustable Piezo1 expression with soft (400 Pa) and stiff (25 kPa) viscoelastic hydrogels with independently tuneable Youngs modulus and stress relaxation. We demonstrate that Piezo1 is a mechanosensor of viscoelasticity in soft ECMs, consistent with the molecular clutch model. By performing RNA sequencing (RNA-seq), we identified the transcriptomic phenotype of MSCs response to matrix viscoelasticity and Piezo1 activity, highlighting gene signatures that drive MSCs mechanobiology in soft and stiff viscoelastic hydrogels.

biophysics↗

bioRxiv2024

NaBC1 boron transporter enables myoblast response to substrate rigidity via fibronectin-binding integrins

Cells are sensitive to the physical properties of their microenvironment and transduce them into biochemical cues that trigger gene expression and alter cell behavior. Numerous proteins, including integrins, are involved in these mechanotransductive events. Here, we identify a novel role for the boron transporter NaBC1 as a mechanotransducer. We demonstrate that soluble boron ions activate NaBC1 to enhance cell adhesion and intracellular tension in C2C12 myoblasts seeded on fibronectin-functionalised polyacrylamide (PAAm) hydrogels. Retrograde actin flow and traction forces exerted by these cells are significantly increased in vitro in response to both increased boron concentration and hydrogel stiffness. These effects are fibronectin and NaBC1-mediated as they are abrogated in hydrogels coated with laminin-111 in place of fibronectin and in esiRNA NaBC1-silenced cells. Our findings thus demonstrate that NaBC1 controls boron homeostasis and also functions as a mechanosensor.

bioengineering↗

bioRxiv2024

Matrix viscoelasticity controls epithelial cell mechanobiology through dimensionality

In recent years, matrix viscoelasticity has emerged as a potent regulator of fundamental cellular processes and has been implicated in promoting cancer progression. Alongside viscoelasticity, additional ECM cues have been shown to influence migration decision-making of cancer cells, and spatial confinement is now considered as a potential regulator of metastasis. However, our understanding of these complex processes predominantly relies on purely elastic hydrogels, and the exact relationship between matrix viscoelasticity and spatial confinement in driving epithelial cell mechanotransduction and migration during cancer progression remains unclear. Here, we systematically investigated the interplay between matrix stiffness, viscoelasticity and spatial confinement by engineering soft ([~]0.3 kPa) and stiff ([~]3 kPa) polyacrylamide hydrogels with varying degrees of viscous dissipation, mirroring the mechanical properties of healthy and tumoral conditions in breast tissue. We observed that viscoelasticity modulates cell spreading, focal adhesions and YAP nuclear import in opposite directions on soft and stiff substrates. Strikingly, viscoelasticity enhances migration speed and persistence on soft substrates, while impeding them on stiff substrates via actin retrograde flow regulation. Combining soft micropatterning with viscoelastic hydrogels, we also show that spatial confinement restricts cell migration on soft matrices regardless of matrix viscoelasticity and promotes migration on stiff matrices in a viscoelasticity-dependent fashion. Our findings establish substrate viscoelasticity as a key regulator of epithelial cell functions and unravel the role of the matrix dimensionality in this process. SignificanceWhile matrix elasticity has received significant attention, recent findings underscore the importance of its natural dissipative properties and spatial confinement in regulating cellular processes and tumour invasiveness. However, the intricate interplay between viscoelasticity and spatial confinement in orchestrating epithelial cell behaviour during cancer progression remains elusive. Using micropatterned viscoelastic hydrogels to replicate the mechanical properties encountered during breast tumour progression, we unveil that viscoelasticity modulates cell behaviour and mechanotransduction signals differently on soft and stiff substrates. Increased viscoelasticity enhances migration speed and persistence on soft substrates while impeding them on stiff substrates via actin retrograde flow regulation. Furthermore, spatial confinement restricts cell migration on soft matrices regardless of viscoelasticity, while promoting migration on stiff matrices in a viscoelasticity-dependent manner.

biophysics↗

bioRxiv2023

Mind the viscous modulus: The mechanotransductive response to the viscous nature of isoelastic matrices regulates stem cell chondrogenesis

The design of hydrogels as mimetics of tissues matrices typically disregards the viscous nature of native tissues and focuses only on their elastic properties. In the case of stem cell chondrogenesis, this has led to contradictory results, likely due to unreported changes of the matrices viscous modulus. Here, by employing isoelastic matrices with a Youngs modulus of ~12 kPa, we demonstrate that variations in viscous properties alone (i.e., loss tangent between 0.1-0.25) are sufficient to drive efficient growth factor-free chondrogenesis of human mesenchymal stem cells, both in 2D and 3D cultures. The increase of the viscous component of RGD-functionalised polyacrylamide or polyethylene glycol maleimide hydrogels promotes a phenotype with reduced adhesion, alters mechanosensitive signalling, and boosts cell-cell contacts. In turn, this upregulates the chondrogenic transcription factor SOX9 and supports neocartilage formation, demonstrating that the mechanotransductive response to the viscous nature of the matrix can be harnessed to direct cell fate.

bioengineering↗