Biology subjects

Zaffryar-Eilot, S.

Publications and source records attributed to Zaffryar-Eilot, S..

5 recordsLinked to original sources

bioRxiv2026

Hypertension-mediated cardiac fibrosis is a mechanical process initiated by smooth muscle cells

Hypertension represents the most prevalent chronic cardiovascular condition, typically culminating in pathological cardiac remodeling characterized by hypertrophy and extensive fibrosis. Although the cellular phenotypes associated with these changes are well-documented, the precise mechanisms by which hypertensive stress is sensed and transduced into a fibrotic program remain poorly defined. To elucidate these mechanisms, we investigated the role of Lysyl oxidase (LOX), an extracellular matrix (ECM)-modifying enzyme that is upregulated during hypertensive stress and associated with cardiovascular diseases. By employing cell-type specific Cre-Lox technology to conditionally delete Lysyl oxidase in either smooth muscle cells (SMCs) or fibroblasts, the primary ECM-secreting cell populations, we demonstrate that fibroblast-specific Lox deletion had no significant impact on the progression of cardiac fibrosis. Conversely, SMC-specific Lox deletion selectively inhibited the fibrotic response without affecting other remodeling parameters, such as cardiac hypertrophy. Notably, in the SMC-specific Lox knockout hearts, fibrosis was restricted to the perivascular niche and failed to propagate into the cardiac interstitium. We find that this transition is a mechanical, ECM-dependent process initiated by SMCs. Our results identify SMCs, rather than fibroblasts, as the primary sensors and initiators of the hypertensive fibrotic response. These findings demonstrate that fibrosis can be uncoupled from other hypertensive manifestations and identify SMC-mediated ECM modification as a potential therapeutic target for treating hypertensive heart disease.

cell biology↗

bioRxiv2024

Fibroblast diversification is an embryonic process dependent on muscle contraction

Fibroblasts are the most common cell type found in connective tissues, known to play major roles in development, homeostasis, regeneration and disease. Although specific fibroblast subpopulations were associated with different biological processes, the mechanisms and unique activities underlying their diversity has not been thoroughly examined. Turning to skeletal muscle development, we set to dissect the variation of muscle-resident fibroblasts (mrFibroblasts). Our results demonstrate mrFibroblasts diversify following the transition from embryonic to fetal myogenesis prior to birth. We find mrFibroblast segregate into two major subpopulations occupying distinct niches, with interstitial fibroblasts residing between the muscle fibers, and delineating fibroblasts sheathing the muscle mass. We further show these subpopulations entail distinct cellular dynamics and transcriptomes. Notably, we find mrFibroblast subpopulations exert distinct regulatory roles on myoblast proliferation and differentiation. Finally, we demonstrate this diversification depends on muscle contraction. Altogether, these findings establish mrFibroblast diversify in a spatio-temporal embryonic process into distinct cell types, entailing different characteristics and roles.

developmental biology↗

bioRxiv2024

Coordination between cytoskeletal organization, cell contraction and extracellular matrix development, is depended on LOX for aneurysm prevention

Distinct, seemingly independent, cellular pathways affecting intracellular machineries or extracellular matrix (ECM) deposition and organization, have been implicated in aneurysm formation. One of the key genes associated with the pathology in both humans and mice is Lysyl oxidase (LOX), a secreted ECM-modifying enzyme, highly expressed in medial vascular smooth muscle cells. To dissect the mechanisms leading to aneurysm development, we conditionally deleted Lox in smooth muscle cells. We find that cytoskeletal organization is lost following Lox deletion. Cell culture assays and in vivo analyses demonstrate a cell-autonomous role for LOX affecting myosin light chain phosphorylation and cytoskeletal assembly resulting in irregular smooth muscle contraction. These results not only highlight new intracellular roles for LOX, but notably they link between multiple processes leading to aneurysm formation suggesting LOX coordinates ECM development, cytoskeletal organization and cell contraction required for media development and function.

cell biology↗

bioRxiv2022

Initiation of fibronectin fibrillogenesis is an enzyme-dependent process

Fibronectin fibrillogenesis and mechanosensing both depend on integrin-mediated force transmission to the extracellular-matrix. However, force transmission is in itself dependent on fibrillogenesis, and fibronectin fibrils are found in soft embryos where high forces cannot be applied, suggesting that force cannot be the sole initiator of fibrillogenesis. Here we identify a nucleation step prior to force transmission, driven by fibronectin oxidation mediated by lysyl-oxidase enzyme family members. This oxidation induces fibronectin clustering that promotes early adhesion, alters cellular response to soft matrices, and enhances force transmission to the matrix. In contrast, absence of fibronectin oxidation abrogates fibrillogenesis, perturbs cell-matrix adhesion, and compromises mechanosensation. Moreover, fibronectin oxidation promotes cancer cells colony formation in soft agar as well as collective and single-cell migration. These results reveal a force-independent enzyme-dependent mechanism that initiates fibronectin fibrillogenesis, establishing a critical step in cell adhesion and mechanosensing.

cell biology↗

bioRxiv2020

Fibroblast fusion to the muscle fiber regulates myotendinous junction formation

Vertebrate muscles and tendons are derived from distinct embryonic origins yet they must interact in order to facilitate muscle contraction and body movements. How robust muscle tendon junctions (MTJs) form to be able to withstand contraction forces is still not understood. Using techniques at a single cell resolution we reexamined the classical view of distinct identities for the tissues composing the musculoskeletal system. We identified fibroblasts that have switched on a myogenic program and demonstrate these dual identity cells fuse into the developing muscle fibers along the MTJs facilitating the introduction of fibroblast-specific transcripts into the elongating myofibers. We suggest this mechanism resulting in a hybrid muscle fiber, primarily along the fiber tips, enables a smooth transition from muscle fiber characteristics towards tendon features essential for forming robust MTJs. We propose that dual characteristics of junctional cells could be a common mechanism for generating stable interactions between tissues throughout the musculoskeletal system.

developmental biology↗