Dynamically stiffening biomaterials reveal age- and sex-specific differences in pulmonary arterial adventitial fibroblast activation.

Respiratory diseases like pulmonary arterial hypertension (PAH) frequently exhibit sexual dimorphism. Female PAH patients are more susceptible to the disease but have increased survival rates. This phenomenon is known as the estrogen paradox, and the underlying mechanisms are not fully understood. During PAH progression in vivo, human pulmonary arterial adventitial fibroblasts (hPAAFs) differentiate into an activated phenotype. These cells produce excess, aberrant extracellular matrix proteins that stiffen the surrounding pulmonary arterial tissues. Here, we employed dynamic poly(ethylene glycol)-alpha methacrylate (PEGαMA)-based biomaterials to study how the age and sex of human serum influenced hPAAF activation in response to microenvironmental stiffening in vitro . Results showed female and male cells responded differently to increases in microenvironmental stiffness and serum composition. Male hPAAFs were less activated than female cells on soft hydrogels and more responsive to increases in microenvironmental stiffness regardless of serum composition. Female hPAAF activation followed this pattern only when cultured in younger (age < 50) female serum or when older (age ≥ 50) female serum was supplemented with estradiol. Otherwise, female hPAAF activation was relatively high on both soft and stiffened hydrogels, with little difference in activation between the two conditions. Collectively, these results suggest that it may be possible to model the estrogen paradox observed in PAH in vitro and that it is critical for researchers to report cell sex and serum source when conducting in vitro experimentation.
Competing Interests: The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Chelsea M. Magin reports financial support was provided by University of Colorado Anschutz Medical Campus Ludeman Family Center for Women’s Health Research. Chelsea M. Magin reports financial support was provided by Rose Community Foundation. Chelsea M. Magin reports financial support was provided by National Heart Lung and Blood Institute. Chelsea M. Magin reports financial support was provided by National Science Foundation. Chelsea M. Magin reports financial support was provided by Colorado Pulmonary Vascular Disease Research Award. Mikala C. Mueller reports financial support was provided by National Center for Advancing Translational Sciences Clinical and Translational Science Awards Program. Chelsea M. Magin reports a relationship with Colorado Bioscience Institute that includes: board membership. Chelsea M. Magin reports a relationship with Boulder IQ that includes: consulting or advisory. Chelsea M. Magin has patent #PCT/US2019/012722 pending to University of Colorado. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(© 2024 The Author(s).)