Biology subjects

Oliva, M. A. G.

Publications and source records attributed to Oliva, M. A. G..

3 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

Cryptosporidium Oocyst Wall Proteins are true oocyst wall proteins, with COWP8 functioning to hold the inner and outer layers of the oocyst wall together

Cryptosporidiosis is a significant cause of diarrhoeal disease contributing to substantial morbidity and mortality for the immunocompromised and for young children, especially those who are malnourished. There are no vaccines available and no effective treatments for these patients. Another challenge is that Cryptosporidia are waterborne and resistant to common water treatments including chlorination. Cryptosporidia are transmitted as an oocyst that is made up of a hardy oocyst wall that protects four parasites. Little is understood about how the oocyst is constructed, its composition, and the how it resists chlorination. A family of predicted Cryptosporidium Oocyst Wall Proteins (COWPs) was identified from the genome. Using a genetic approach, we confirm that all members of the COWP family localise to the oocyst wall. Our studies indicate that COWP2, 3 and 4 localise specifically to the oocyst "suture", a zipper-like structure on the oocyst wall from which parasites emerge during infection. In parasites lacking COWP8, we observe that the inner and outer layers of the oocyst wall are no longer associated suggesting a role for COWP8 in oocyst wall morphology. Despite loss of COWP8, these transgenic parasites are viable, unchanged in mechanical strength, and retain resistance to chlorination. This work sets the foundation for future exploration of Cryptosporidium transmission.

microbiology↗

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↗