Biology subjects

Baude, J. A.

Publications and source records attributed to Baude, J. A..

3 recordsLinked to original sources

bioRxiv2026

Matrix stiffness and stress relaxation regulate matrix-bound nanovesicle release from alginate hydrogels

Matrix-bound nanovesicles (MBVs) are a recently discovered subclass of small extracellular vesicles (EVs) that reside within the extracellular matrix of non-mineralized tissues throughout the body. Functionally, MBVs exhibit unique immunomodulatory properties that have been leveraged therapeutically to treat various tissue pathologies, including periprosthetic osteolysis, rheumatoid arthritis, and skeletal muscle injury. However, like other EVs, the therapeutic efficacy of MBV applications is limited by delivery methods, namely bolus injections, that offer poor control of EV persistence and bioavailability at the site of administration. We hypothesized that a superior MBV delivery platform could be developed by entrapping MBVs in a tunable, engineered alginate matrix to control retention and release of MBVs on therapeutically relevant timescales. To this end, we encapsulated dermal fibroblast MBVs in bioinert alginate hydrogels of varying stiffness and stress relaxation rates to determine the impact of matrix mechanical properties on MBV release and retention over a 14-day period. We found that stiffer matrices increased MBV release compared to their softer counterparts. Additionally, fast-relaxing matrices exhibited release of MBVs in the first four days of release experiments, in contrast with slow-relaxing matrices, which promoted long-term sequestration of nearly all encapsulated MBVs regardless of differences in matrix stiffness. Our results offer promise that alginate hydrogels can be utilized for more precise control of MBV delivery in the body and may overcome limitations associated with current EV administration methods.

bioengineering↗

bioRxiv2025

Sp1 mechanotransduction regulates breast cancer cell invasion in response to multiple tumor-mimicking extracellular matrix cues

Breast cancer progression is marked by extracellular matrix (ECM) remodeling, including increased stiffness, faster stress relaxation, and elevated collagen levels. In vitro experiments have revealed a role for each of these factors to individually promote malignant behavior, but their combined effects remain unclear. To address this, we developed alginate-collagen hydrogels with independently tunable stiffness, stress relaxation, and collagen density. We show that these combined tumor-mimicking ECM cues reinforced invasive morphologies and promoted spheroid invasion in breast cancer and mammary epithelial cells. High stiffness and low collagen density in slow-relaxing matrices led to the greatest cell migration speed and displacement. RNA-seq revealed Sp1 target gene enrichment in response to both individual and combined ECM cues, with a greater enrichment observed under multiple cues. Notably, high expression of Sp1 target genes upregulated by fast stress relaxation correlated with poor patient survival. Mechanistically, we found that phosphorylated-Sp1 (T453) was increasingly located in the nucleus in stiff and/or fast relaxing matrices, which was regulated by PI3K and ERK1/2 signaling, as well as actomyosin contractility. This study emphasizes how multiple ECM cues in complex microenvironments reinforce malignant traits and supports an emerging role for Sp1 as a mechanoresponsive transcription factor.

bioengineering↗

bioRxiv2025

Engineered basement membrane mimetic hydrogels to study mammary epithelial morphogenesis and invasion

Reconstituted basement membrane (rBM) products like Matrigel are widely used in 3D culture models of epithelial tissues and cancer. However, their utility is hindered by key limitations, including batch variability, xenogenic contaminants, and a lack of tunability. To address these challenges, we engineered a 3D basement membrane (eBM) matrix by conjugating defined extracellular matrix (ECM) adhesion peptides (IKVAV, YIGSR, RGD) to an alginate hydrogel network with precisely tunable stiffness and viscoelasticity. We optimized the mechanical and biochemical properties of the engineered basement membranes (eBMs) to support mammary acinar morphogenesis in MCF10A cells, similar to rBM. We found that IKVAV-modified, fast-relaxing ({tau}1/2 = 30-150 s), and soft (E = 200 Pa) eBMs best promoted polarized acinar structures. Clusters became invasive and lost polarity only when the IKVAV-modified eBM exhibited both similar stiffness to a malignant breast tumor (E = 4000 Pa) and slow stress relaxation ({tau}1/2 = 600-1100 s). Notably, tumor-like stiffness alone was not sufficient to drive invasion in fast stress relaxing matrices modified with IKVAV. In contrast, RGD-modified matrices promoted a malignant phenotype regardless of mechanical properties. We also utilized this system to interrogate the mechanism driving acinar and tumorigenic phenotypes in response to microenvironmental parameters. A balance in activity between {beta}1- and {beta}4-integrins was observed in the context of IKVAV-modified eBMs, prompting further investigation into the downstream mechanisms. We found differences in hemidesmosome formation and production of endogenous laminin in response to peptide type, stress relaxation, and stiffness. We also saw that inhibiting either focal adhesion kinase or hemidesmosome signaling in IKVAV eBMs prevented acinus formation. This eBM matrix is a powerful, reductionist, xenogenic-free system, offering a robust platform for both fundamental research and translational applications in tissue engineering and disease modeling.

bioengineering↗