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조회676

Harvard University, Boston University, Cornell University

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Proc. Natl. Acad. Sci. USA, Oct 10 2023, 120 (41) | https://doi.org/10.1073/pnas.2308941120 A 3D biomimetic model of lymphatics reveals cell-cell junction tightening and lymphedema via a cytokine-induced ROCK2/JAM-A complex

Esak Lee ^{1 2 3 *}, Siu-Lung Chan ⁴, Yang Lee ⁴, William J Polacheck ^{1 2}, Sukyoung Kwak ⁴, Aiyun Wen ⁴, Duc-Huy T Nguyen ^{1 2}, Matthew L Kutys^{1 2}, Stella Alimperti ^{1 2}, Anna M Kolarzyk ³, Tae Joon Kwak ³, Jeroen Eyckmans ^{1 2}, Diane R Bielenberg ⁴, Hong Chen ⁴, Christopher S Chen ^{1 2 *}

¹Wyss Institute for Biologically Inspired Engineering, Harvard University, Boston, MA 02115.
²Department of Biomedical Engineering, Biological Design Center, Boston University, Boston, MA 02215.
³Nancy E. and Peter C. Meinig School of Biomedical Engineering, Cornell University, Ithaca, NY 14853.
⁴Vascular Biology Program, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115.

^*Corresponding authors: correspondence to Esak Lee or Christopher S Chen

Abstract

Impaired lymphatic drainage and lymphedema are major morbidities whose mechanisms have remained obscure. To study lymphatic drainage and its impairment, we engineered a microfluidic culture model of lymphatic vessels draining interstitial fluid. This lymphatic drainage-on-chip revealed that inflammatory cytokines that are known to disrupt blood vessel junctions instead tightened lymphatic cell-cell junctions and impeded lymphatic drainage. This opposing response was further demonstrated when inhibition of rho-associated protein kinase (ROCK) was found to normalize fluid drainage under cytokine challenge by simultaneously loosening lymphatic junctions and tightening blood vessel junctions. Studies also revealed a previously undescribed shift in ROCK isoforms in lymphatic endothelial cells, wherein a ROCK2/junctional adhesion molecule-A (JAM-A) complex emerges that is responsible for the cytokine-induced lymphatic junction zippering. To validate these in vitro findings, we further demonstrated in a genetic mouse model that lymphatic-specific knockout of ROCK2 reversed lymphedema in vivo. These studies provide a unique platform to generate interstitial fluid pressure and measure the drainage of interstitial fluid into lymphatics and reveal a previously unappreciated ROCK2-mediated mechanism in regulating lymphatic drainage.

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