Piezo1 incorporates mechanical force signals into the genetic program that governs lymphatic valve development and maintenance
Open accessAbstract
The lymphatic system plays crucial roles in tissue homeostasis, lipid absorption, and immune cell trafficking. Although lymphatic valves ensure unidirectional lymph flows, the flow itself controls lymphatic valve formation. Here, we demonstrate that a mechanically activated ion channel Piezo1 senses oscillating shear stress (OSS) and incorporates the signal into the genetic program controlling lymphatic valve development and maintenance. Time-controlled deletion of Piezo1 using a pan-endothelial Cre driver ( Cdh5[PAC]-CreER T2 ) or lymphatic-specific Cre driver ( Prox1-CreER T2 ) equally inhibited lymphatic valve formation in newborn mice. Furthermore, Piezo1 deletion in adult lymphatics caused substantial lymphatic valve degeneration. Piezo1 knockdown in cultured lymphatic endothelial cells (LECs) largely abrogated the OSS-induced upregulation of the lymphatic valve signature genes. Conversely, ectopic Piezo1 overexpression upregulated the lymphatic valve genes in the absence of OSS. Remarkably, activation of Piezo1 using chemical agonist Yoda1 not only accelerated lymphatic valve formation in animals, but also triggered upregulation of some lymphatic valve genes in cultured LECs without exposure to OSS. In summary, our studies together demonstrate that Piezo1 is the force sensor in the mechanotransduction pathway controlling lymphatic valve development and maintenance, and Piezo1 activation is a potentially novel therapeutic strategy for congenital and surgery-associated lymphedema.
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Data from ex vivo studies of mice and in vitro studies of cultured LECs suggest that oscillatory shear stress initiates the valve developmental program.
“Data from ex vivo studies of mice (38) and in vitro studies of cultured LECs (38, 39) suggest that oscillatory shear stress (OSS) initiates the valve developmental program.”
From Transport and Immune Functions of the Lymphatic System. (2025) · cites this paper as [39]
The Introduction and Results report that OSS upregulated valve-associated genes in cultured LECs, supporting the in vitro part of the claim. The mouse evidence concerns Piezo1 deletion in living pups and subsequent analysis of valve formation, not ex vivo mouse studies showing that OSS initiates the program. Page numbers were not provided in our copy. (LLM, conf=0.86)
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Self-citation
- Authors
- Choi, D., Park, E., Jung, E., Cha, B., Lee, S., Yu, J., Kim, P. M., Lee, S., Hong, Y. J., Koh, C. J., Cho, C.-W., Wu, Y., Li Jeon, N., Wong, A. K., Shin, L., Kumar, S. R., Bermejo-Moreno, I., Srinivasan, R. S., Cho, I.-T., & Hong, Y.-K.
- Affiliations
- University of Southern California (US)
- Oklahoma Medical Research Foundation (US)
- Seoul National University (KR)
- Baylor College of Medicine (US)
- Korea Food Research Institute (KR)
- Department of Mechanical and Aerospace Engineering, Seoul National University, Seoul, South Korea.
- Department of Surgery, and
- ORCID
- Venue
- JCI Insight
- Published
- 2019-03-07
- Volume
- 4
- Issue
- 5
- ISSN
- 2379-3708 (ISSN-L)
- PMC
- PMC6483520
- OpenAlex
- W2911421449
- Cited by
- 176
- References
- 57
- Citations by year
- 2026: 19 · 2025: 22 · 2024: 25 · 2023: 24 · 2022: 28 · 2021: 32 · 2020: 16 · 2019: 9
- FWCI
- 8.88
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- JCI Insight (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- NIH (EY026260,HL121036,HL141857,DE027891,DK114645, HL131652, HL121191)
- Korean Research Foundation (NRF-2018R1A2A1A05019550)
- Topics
- Health Sciences › Medicine › Oncology › Lymphatic System and Diseases
- Health Sciences › Medicine › Surgery › Lymphatic Disorders and Treatments
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Hippo pathway signaling and YAP/TAZ
- Keywords
- Piezo1, mechanotransduction, lymphatic endothelial cells, Yoda1, lymphedema, lymphatic system, mechanical force sensing
- MeSH terms
- Cadherin 5, Animals, Female, Gene Expression Regulation, Humans, Ion Channels, Stress, Mechanical, Antigens, CD, Cadherins, Up-Regulation, Mice, Knockout, Models, Animal, Mechanotransduction, Cellular, Lymphangiogenesis, Lymphatic Vessels, Endothelial Cells, Mice, Transcriptome
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