Date of Award
5-14-2024
Degree Name
Doctor of Philosophy (PhD)
Degree Type
Dissertation
Abstract
Fibrosis, a pathological condition affecting various organs and contributing significantly to mortality, accounts for up to 45% of deaths in industrialized nations. Understanding the mechanobiological signaling pathways in tissues offers a promising avenue for gaining fresh insights into strategies for controlling or reversing fibrosis-related tissue remodeling. Recent research and clinical studies have focused on the use of Adipose-Derived Stem Cells (ASCs) to treat various forms of tissue fibrosis as well as their role in pathologic conditions. This study aimed to enhance our understanding of how ASCs behave in fibrotic environments, particularly in terms of their response to mechanical cues through the Piezo1 ion channel mechanotransduction pathway. Our findings indicate that Piezo1 may play an important role in fibrosis, and modulating Piezo1 activity can influence collagen regulation in ASCs, both in two-dimensional and three-dimensional in vitro models. Moreover, this effect is influenced by the mechanical properties of the substrate. Mechanistically, we observed that Piezo1 modulation can impact the activity and localization of YAP, a key transcriptional regulator. Notably, the depletion of YAP and TAZ did not significantly alter collagen expression patterns in the context of Piezo1 activation, suggesting the existence of potentially independent pathways. These discoveries provide valuable insights into the mechanobiology of human adipose stem cells, particularly in fibrotic microenvironments, highlighting the critical role of Piezo1 in cellular mechanosensing and its implications for tissue engineering and regenerative medicine.
Language
English (en)
Chair
Farshid Guilak