Mechanisms of postnatal mammalian skin regeneration
Abstract/Contents
- Abstract
- Scars following trauma, burn, and surgeries cumulatively impose an enormous biomedical burden for hundreds of millions of patients each year. In contrast, skin regeneration, with complete recovery of normal dermal architecture, appendages (hair follicles, glands), and mechanical strength equal to that of unwounded skin, would represent a vastly superior outcome. This dissertation explores skin regeneration through the lens of fibroblast mechanobiology (i.e., how mechanical forces in the wound environment alter fibroblast behavior). Chapter I describes skin regeneration, demonstrated for the first time in postnatal mammalian wounds, following targeted modulation of Engrailed-1 (En-1) lineage-negative fibroblasts with the Yes-associated protein (YAP) inhibitor, verteporfin. Chapter II concerns the specific mechanisms of skin regeneration following YAP inhibition, as compared to scarring (PBS control), studied using single cell RNA-sequencing, timsTOF shotgun proteomics, and a novel AI ultrastructural algorithm (described in detail in Chapter IV) to profile regenerating (verteporfin) and scarring (PBS) wounds at multiple time points of healing (post-operative [POD] days 0, 2, 7, 14, and 30). Chapter III reports the translation of the above work to red Duroc pigs, an animal model featuring human-like skin architecture and mechanical properties. Chapter IV describes an image processing and machine learning pipeline I developed to profile extracellular matrix features in solid organ fibroses, which I then utilize to profile matrix architectures in pancreatic ductal adenocarcinoma (PDAC) desmoplasia. In summary, these studies highlight the central functional role of mechanical forces in skin fibrosis after injury and support mechanotransduction inhibition as a promising translational approach to promote regenerative healing outcomes
Description
| Type of resource | text |
|---|---|
| Form | electronic resource; remote; computer; online resource |
| Extent | 1 online resource |
| Place | California |
| Place | [Stanford, California] |
| Publisher | [Stanford University] |
| Copyright date | 2023; ©2023 |
| Publication date | 2023; 2023 |
| Issuance | monographic |
| Language | English |
Creators/Contributors
| Author | Mascharak, Shamik |
|---|---|
| Degree supervisor | Chan, Charles K. F. (Charles Kwok Fai), 1975-2024 |
| Degree supervisor | Longaker, Michael T |
| Thesis advisor | Chan, Charles K. F. (Charles Kwok Fai), 1975-2024 |
| Thesis advisor | Longaker, Michael T |
| Thesis advisor | Gurtner, Geoffrey |
| Degree committee member | Gurtner, Geoffrey |
| Associated with | Stanford University, School of Medicine |
| Associated with | Stanford University, Stem Cell Biology and Regenerative Medicine Program |
Subjects
| Genre | Theses |
|---|---|
| Genre | Text |
Bibliographic information
| Statement of responsibility | Shamik Mascharak |
|---|---|
| Note | Submitted to the Stem Cell Biology and Regenerative Medicine Program |
| Thesis | Thesis Ph.D. Stanford University 2023 |
| Location | https://purl.stanford.edu/vp805wh3912 |
Access conditions
- Copyright
- © 2023 by Shamik Mascharak
- License
- This work is licensed under a Creative Commons Attribution 3.0 Unported license (CC BY).
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