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Defining the Chondrocyte "Mechanome"...

Palmer, Daniel R.,

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Defining the Chondrocyte "Mechanome": How Mechanosensitive Ion Channels TRPV4 and PIEZO1 Drive Changes in Gene Expression to Affect Cell Behavior and Cartilage Health /

紀錄類型:	書目-電子資源 : Monograph/item
正題名/作者:	Defining the Chondrocyte "Mechanome": How Mechanosensitive Ion Channels TRPV4 and PIEZO1 Drive Changes in Gene Expression to Affect Cell Behavior and Cartilage Health // Daniel R Palmer.
作者:	Palmer, Daniel R.,
面頁冊數:	1 electronic resource (184 pages)
附註:	Source: Dissertations Abstracts International, Volume: 86-06, Section: B.
Contained By:	Dissertations Abstracts International86-06B.
標題:	Biomedical engineering. -
電子資源:	https://pqdd.sinica.edu.tw/twdaoapp/servlet/advanced?query=31764338
ISBN:	9798346865513

Defining the Chondrocyte "Mechanome": How Mechanosensitive Ion Channels TRPV4 and PIEZO1 Drive Changes in Gene Expression to Affect Cell Behavior and Cartilage Health /
Palmer, Daniel R.,

Defining the Chondrocyte "Mechanome": How Mechanosensitive Ion Channels TRPV4 and PIEZO1 Drive Changes in Gene Expression to Affect Cell Behavior and Cartilage Health /Daniel R Palmer. - 1 electronic resource (184 pages)

Source: Dissertations Abstracts International, Volume: 86-06, Section: B.

Chondrocytes, the only native cell population of cartilage, utilize mechanosensitive transmembrane ion channels to sense mechanical forces. Transient Receptor Potential Vanilloid 4 (TRPV4) is activated by physiologic levels of load (resulting in ~10% tissue deformation) while PIEZO1 is activated by supraphysiologic levels of load (resulting in >50% tissue deformation). TRPV4 activation promotes the expression of a limited number of chondrogenic genes and the production of vital cartilaginous matrix proteins, while PIEZO1 activation drives cell death and senescence, cytoskeletal weakening, and production of catabolic mediators, which contribute to the development of osteoarthritis (OA). However, the path connecting activation of these channels to these large changes in cell behavior and cell fate is not fully characterized. A more complete understanding of which genes are up- or down-regulated by activation of TRPV4 and/or PIEZO1 would begin to close the gap between mechano-transduction and resulting changes in chondrocyte behavior.Towards this end, we set out to map the full transcriptome, i.e. all changes in gene expression at the mRNA level, in response to activation of either TRPV4 or PIEZO1 in the chondrocyte. Furthermore, we strove to compare these mechanosensitive transcriptomes, or "mechanomes," to the transcriptome driven by exposure to inflammatory mediator Interleukin-1 (IL-1). IL-1 plays a prominent role in OA-related cartilage degradation and is known to interact with mechanotransduction. To achieve this, we loaded porcine chondrocytes seeded in tissue-engineered hydrogel constructs to activate either TRPV4 or PIEZO1, or treated with IL-1, isolated mRNA, and used bulk RNA-Sequencing to quantify resultant transcriptomic changes. We split our analysis into two portions: upregulated transcriptomes, and downregulated transcriptomes. In our analysis of upregulated transcriptomes, we discovered that activation of PIEZO1 through supraphysiologic deformation induced a transient inflammatory profile that overlapped with the IL-1-responsive transcriptome and contained genes associated with cartilage degradation and OA progression. However, PIEZO1 expression also promoted a pro-chondrogenic transcriptome under unloaded conditions, and daily treatment with PIEZO1 agonist Yoda1 significantly increased sulfated glycosaminoglycan deposition in vitro. Our analysis of downregulated transcriptomes revealed that the TRPV4 activation exhibited a notable overlap with genes downregulated by treatment with IL-1. PIEZO1 activation downregulated genes associated with the G2/M cell cycle checkpoint, a system which checks cells for DNA damage prior to entry into mitosis.These findings emphasize the presence of a broad "mechanome" with distinct effects of TRPV4 and PIEZO1 activation in chondrocytes, and suggest complex roles for PIEZO1 in both the physiologic and pathologic responses of chondrocytes. The identification of transcriptomic profiles unique to or shared by PIEZO1 and TRPV4 (distinct from IL-1-induced inflammation) could inform future therapeutic designs targeting these channels for the management and treatment of OA.

English

ISBN: 9798346865513Subjects--Topical Terms:

535387
Biomedical engineering.
Subjects--Index Terms:

Cartilage

Defining the Chondrocyte "Mechanome": How Mechanosensitive Ion Channels TRPV4 and PIEZO1 Drive Changes in Gene Expression to Affect Cell Behavior and Cartilage Health /
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520 $a Chondrocytes, the only native cell population of cartilage, utilize mechanosensitive transmembrane ion channels to sense mechanical forces. Transient Receptor Potential Vanilloid 4 (TRPV4) is activated by physiologic levels of load (resulting in ~10% tissue deformation) while PIEZO1 is activated by supraphysiologic levels of load (resulting in >50% tissue deformation). TRPV4 activation promotes the expression of a limited number of chondrogenic genes and the production of vital cartilaginous matrix proteins, while PIEZO1 activation drives cell death and senescence, cytoskeletal weakening, and production of catabolic mediators, which contribute to the development of osteoarthritis (OA). However, the path connecting activation of these channels to these large changes in cell behavior and cell fate is not fully characterized. A more complete understanding of which genes are up- or down-regulated by activation of TRPV4 and/or PIEZO1 would begin to close the gap between mechano-transduction and resulting changes in chondrocyte behavior.Towards this end, we set out to map the full transcriptome, i.e. all changes in gene expression at the mRNA level, in response to activation of either TRPV4 or PIEZO1 in the chondrocyte. Furthermore, we strove to compare these mechanosensitive transcriptomes, or "mechanomes," to the transcriptome driven by exposure to inflammatory mediator Interleukin-1 (IL-1). IL-1 plays a prominent role in OA-related cartilage degradation and is known to interact with mechanotransduction. To achieve this, we loaded porcine chondrocytes seeded in tissue-engineered hydrogel constructs to activate either TRPV4 or PIEZO1, or treated with IL-1, isolated mRNA, and used bulk RNA-Sequencing to quantify resultant transcriptomic changes. We split our analysis into two portions: upregulated transcriptomes, and downregulated transcriptomes. In our analysis of upregulated transcriptomes, we discovered that activation of PIEZO1 through supraphysiologic deformation induced a transient inflammatory profile that overlapped with the IL-1-responsive transcriptome and contained genes associated with cartilage degradation and OA progression. However, PIEZO1 expression also promoted a pro-chondrogenic transcriptome under unloaded conditions, and daily treatment with PIEZO1 agonist Yoda1 significantly increased sulfated glycosaminoglycan deposition in vitro. Our analysis of downregulated transcriptomes revealed that the TRPV4 activation exhibited a notable overlap with genes downregulated by treatment with IL-1. PIEZO1 activation downregulated genes associated with the G2/M cell cycle checkpoint, a system which checks cells for DNA damage prior to entry into mitosis.These findings emphasize the presence of a broad "mechanome" with distinct effects of TRPV4 and PIEZO1 activation in chondrocytes, and suggest complex roles for PIEZO1 in both the physiologic and pathologic responses of chondrocytes. The identification of transcriptomic profiles unique to or shared by PIEZO1 and TRPV4 (distinct from IL-1-induced inflammation) could inform future therapeutic designs targeting these channels for the management and treatment of OA.
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