ArticleFASEB journal : official publication of the Federation of American Societies for Experimental Biology2021
Matrix stiffness primes lymphatic tube formation directed by vascular endothelial growth factor-C.
Article in FASEB journal : official publication of the Federation of American Societies for Experimental Biology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed, 58 citations in OpenAlex.
- Article
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- Interventions and platforms that direct lymphangiogenesis to restore physiological homeostasis and enhance immunoregulation.NPJ Regenerative medicine · 2026Review
- [Research on tissue regeneration and engineered scaffold materials in prevention and treatment of lymphedema].Zhongguo xiu fu chong jian wai ke za zhi = Zhongguo xiufu chongjian waike zazhi = Chinese journal of reparative and reconstructive surgery · 2026Review
- Lymphatics-on-a-chip microphysiological system: engineering lymphatic structure and functionLab on a chip · 2026Review
- Matrix Metalloproteinase 14 in Corneal Neovascularization.International journal of molecular sciences · 2026Review
- Blocking glutamine transport normalizes lymphatic vessels in hypoxic environments by attenuating glycolysis.bioRxiv : the preprint server for biology · 2026Article
- Exosomes derived from ADSCs suppress the fibrosis process of derma in secondary lymphedema.Scientific reports · 2026Article
- Metabolic Syndrome-Driven Changes in Cardiac Lymphatic Endothelium: mRNA Expression and Emerging Questions.Pathophysiology : the official journal of the International Society for Pathophysiology · 2026Article
- Lymphedema: current treatment strategies and future directions in tissue engineering.Frontiers in medicine · 2026Review
- Three-dimensional modelling of lymphangiogenesis in-vitro using bioorthogonal click-crosslinked gelatin hydrogels.Materials today. Bio · 2025Article
- Intracellular pH dynamics respond to extracellular matrix stiffening and mediate vasculogenic mimicry through β-catenin.Cell death & disease · 2025Article
- Utility of anLab on a chip · 2025Article
- Tuning the Morphological Properties of Granular Hydrogels to Control Lymphatic Capillary Formation.Advanced materials interfaces · 2025Article
- Intracellular pH dynamics respond to extracellular matrix stiffening and mediate vasculogenic mimicry through β-catenin.bioRxiv : the preprint server for biology · 2025Article
- Extracellular matrix in vascular homeostasis and disease.Nature reviews. Cardiology · 2025Review
- Understanding the Lymphatic System: Tissue-on-Chip Modeling.Annual review of biomedical engineering · 2025Review
- Tissue-Engineered Therapeutics for Lymphatic Regeneration: Solutions for Myocardial Infarction and Secondary Lymphedema.Advanced healthcare materials · 2025Review
- Tissue engineering approaches for lymphedema: biomaterial innovations and clinical potential.Frontiers in cell and developmental biology · 2025Review
- Extracellular matrix stiffness regulates the proliferation and migration capacities of lymphatic endothelial cells via FAT1.Frontiers in cell and developmental biology · 2025Article
Corrections and comments
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Authors and funding
5 authors at 1 institution in 1 country.
Funding
Abstract
Dysfunction of the lymphatic system is associated with a wide range of disease phenotypes. The restoration of dysfunctional lymphatic vessels has been hypothesized as an innovative method to rescue healthy phenotypes in diseased states including neurological conditions, metabolic syndromes, and cardiovascular disease. Compared to the vascular system, little is known about the molecular regulation that controls lymphatic tube morphogenesis. Using synthetic hyaluronic acid (HA) hydrogels as a chemically and mechanically tunable system to preserve lymphatic endothelial cell (LECs) phenotypes, we demonstrate that low matrix elasticity primes lymphatic cord-like structure (CLS) formation directed by a high concentration of vascular endothelial growth factor-C (VEGF-C). Decreasing the substrate stiffness results in the upregulation of key lymphatic markers, including PROX-1, lymphatic vessel endothelial hyaluronan receptor 1 (LYVE-1), and VEGFR-3. Consequently, higher levels of VEGFR-3 enable stimulation of LECs with VEGF-C which is required to both activate matrix metalloproteinases (MMPs) and facilitate LEC migration. Both of these steps are critical in establishing CLS formation in vitro. With decreases in substrate elasticity, we observe increased MMP expression and increased cellular elongation, as well as formation of intracellular vacuoles, which can further merge into coalescent vacuoles. RNAi studies demonstrate that MMP-14 is required to enable CLS formation and that LECs sense matrix stiffness through YAP/TAZ mechanosensors leading to the activation of their downstream target genes. Collectively, we show that by tuning both the matrix stiffness and VEGF-C concentration, the signaling pathways of CLS formation can be regulated in a synthetic matrix, resulting in lymphatic networks which will be useful for the study of lymphatic biology and future approaches in tissue regeneration.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.