Biology subjects

Oswald, S.

Publications and source records attributed to Oswald, S..

3 recordsLinked to original sources

bioRxiv2024

PIEZO1-Mediated Mechanotransduction Regulates Collagen Synthesis on Nanostructured 2D and 3D Models of Fibrosis

Progressive fibrosis causes tissue malfunction and organ failure due to the pathologic accumulation of a collagen-rich extracellular matrix. In vitro models provide useful tools for deconstructing the roles of specific biomechanical or biological mechanisms involved in these processes and identifying potential therapeutic targets. In particular, recent studies have implicated cellular mechanosensing of substrate micro- and nanoscale architecture as a regulator of fibrosis. In this study, we investigated how the mechanosensitive ion channel PIEZO1 and intracellular mechanotransduction pathways influence fibrotic gene and protein expression in adipose-derived stem cells (hASCs). Specifically, we examined the role of PIEZO1 and the mechano-sensitive transcription factors YAP/TAZ in sensing aligned or non-aligned substrate architecture to regulate collagen formation. We utilized both 2D microphotopatterned substrates and 3D electrospun polycaprolactone (PCL) substrates to study the role of culture dimensionality. We found that PIEZO1 regulates collagen production in hASCs in a manner that is sensitive to substrate architecture. Activation of PIEZO1 induced significant morphological changes in hASCs, particularly when they were cultured on aligned substrates. While YAP translocated to the cytoplasm following PIEZO1 activation, depleting YAP and TAZ did not change collagen expression significantly downstream of PIEZO1 activation, implying that YAP/TAZ translocation out of the nucleus and increased collagen production may be independent outputs of PIEZO1 activation. Our studies demonstrate a role for PIEZO1 in cellular mechanosensing of substrate architecture and provide targetable pathways for treating fibrosis as well as for enhancing tissue-engineered and regenerative approaches for fibrous tissue repair.

bioengineering↗

bioRxiv2023

Acute targeted induction of gut-microbial metabolism disrupts host circadian rhythm

The gut microbiota and host diurnal rhythm mutually influence each other, and microbiota metabolism has been shown to play a role in regulating host circadian function via secretion of fermentation products. Microbial metabolism is dependent on the availability of nutrients for the microbiota, typically through the hosts food intake, making it challenging to disentangle the effect of host and microbiota metabolism. In this study, we acutely induced gut microbial metabolic activity without inducing host metabolism in mice. We found that increasing microbial metabolism in the gut altered clock gene expression locally. Actuating microbiota metabolism also reduced host food intake beyond the calories provided by the microbiota, suggesting a systemic signaling effect of microbial metabolism on the host.

microbiology↗

bioRxiv2019

Gene Therapy for Follistatin Mitigates Systemic Metabolic Inflammation and Post-Traumatic Osteoarthritis in High-Fat Diet-Induced Obese Mice

Obesity-associated inflammation and loss of muscle function play critical roles in the development of osteoarthritis (OA); thus, therapies that target muscle tissue may provide novel approaches to restoring metabolic and biomechanical dysfunction associated with obesity. Recent studies indicate that follistatin (FST), a protein which binds myostatin and activin, may have the potential to enhance muscle formation while neutralizing inflammation induced by these proteins. Here, we hypothesized that adeno-associated virus (AAV9) delivery of FST will enhance muscle formation and mitigate metabolic inflammation and knee OA caused by a high fat diet in mice. Obese mice receiving AAV-mediated FST delivery exhibited decreased inflammatory adipokines and cytokines systemically in the serum as well as locally in the joint synovial fluid. Regardless of diet, mice receiving FST gene therapy were protected from post-traumatic OA and bone remodeling induced by joint injury. While obesity disrupted the mitochondrial oxidative phosphorylation (OXPHOS) system in adipocytes, gene therapy for FST restored the key proteins involved in mitochondrial biogenesis, such as PPAR{gamma} coactivator 1 and AKT protein kinase 1, leading to the browning of white adipose tissue. Taken together, these findings suggest that FST gene therapy may provide a multifactorial therapeutic approach for injury-induced OA and metabolic inflammation in obesity.

physiology↗