Development and physiological functions of the lymphatic system: insights from human genetic studies of primary lymphedema

Abstract

Primary lymphedema is a long-term (chronic) condition characterized by tissue lymph retention and swelling that can affect any part of the body, although it usually develops in the arms or legs. Due to the relevant contribution of the lymphatic system to human physiology, while this review mainly focusses on the clinical and physiological aspects related to the regulation of fluid homeostasis and edema, clinicians need to know that the impact of lymphatic dysfunction with a genetic origin can be wide ranging. Lymphatic gene dysfunction can affect immune function so leading to infection; it can influence cancer development and spread; and it can determine fat transport so impacting on nutrition and obesity. Genetic studies and the development of imaging techniques for the assessment of lymphatic function have enabled the recognition of primary lymphedema as a heterogenic condition in terms of genetic causes and disease mechanisms. In this review, the known biological function of several genes crucial to the development and function of the lymphatic system are used as a basis for understanding normal lymphatic biology. The disease conditions originating from mutations in these genes are discussed together with a detailed clinical description of the phenotype and the up-to-date knowledge in terms of disease mechanisms acquired from in vitro and in vivo research models.

FOXC2 controls adult lymphatic endothelial specialization, function, and gut lymphatic barrier preventing multiorgan failure

“…To evaluate the clinical relevance of our scRNA-seq atlas, we examined the expression of genes, mutated in different subtypes of human primary lymphedemas ( Fig. 7F ) ( 16 ). High expression of Flt4 in capLECs is consistent with lymphatic capillary hypoplasia in Vegfr3 -haploinsufficient mice and in Milroy disease patients ( 16 ).…”

“…7F ) ( 16 ). High expression of Flt4 in capLECs is consistent with lymphatic capillary hypoplasia in Vegfr3 -haploinsufficient mice and in Milroy disease patients ( 16 ). Selective expression of Met in collLECs and vLECs predicts defects of collLVs in patients with mutations in MET and its ligand hepatocyte growth factor (HGF) ( 40 ).…”

“…Fifteen genes are already known to be causative for various forms of primary lymphedema; however, many new causative mutations remain to be identified ( 16 ). Our survey of LEC subsets and associated stromal subpopulations ( Fig.…”

“…Lymph flow–induced forkhead transcription factor FOXC2 controls formation of lymphatic valves and specialization of collLVs during embryonic and postnatal development ( 5 , 8 , 15 ). Inactivating mutations in FOXC2 underlie the lymphedema-distichiasis syndrome (LDS) ( 16 ), a human hereditary disease of LVs. LDS is characterized by late-onset swelling of legs as a result of defective collLVs and valve function and lymph reflux ( 17 ).…”

“…LDS is characterized by late-onset swelling of legs as a result of defective collLVs and valve function and lymph reflux ( 17 ). While lymph stasis and swelling of extremities are features of all hereditary lymphedemas ( 16 ), LDS patients uniquely develop ectopic peritoneal lymphoid nodules ( 17 ), indicating that loss of FOXC2 leads to organ-specific immunological defects.…”