Beyond PROX1: transcriptional, epigenetic, and noncoding RNA regulation of lymphatic identity and function

The lymphatic vascular system acts as the major transportation highway of tissue fluids, and its activation or impairment is associated with a wide range diseases. There has been increasing interest in understanding mechanisms that control vessel formation (lymphangiogenesis) function development disease. Here, we discuss recent insights into new players whose identification contributed to deciphering regulatory code. We reveal how endothelial cells, building blocks vessels, utilize their transcriptional, post-transcriptional, epigenetic portfolio commit maintain lineage identity function, particular focus on development. physiological functioning organism ensured through interplay between two systems present our body: blood vasculature. While former broadly studied since discovery, gained research only last 20 years. Since then, significant advances have made elucidating responsible for well role progression several diseases such cancer, chronic inflammation, lymphedema (Oliver et al., 2020Oliver G. Kipnis J. Randolph G.J. Harvey N.L. vasculature 21st century: novel functional roles homeostasis disease.Cell. 2020; 182: 270-296https://doi.org/10.1016/j.cell.2020.06.039Abstract Full Text PDF PubMed Scopus (23) Google Scholar). unidirectional, blind-ended composed lymph nodes vessels (capillaries, pre-collecting, collecting vessels) (Figure 1A). In peripheral tissues, dense network non-contracting capillaries, single layer cells (LECs), draining fluid, macromolecules pressure-dependent manner from interstitial space. high drainage capacity capillaries by specialized “button-like” junctions (a.k.a. primary valves), discontinuous basement membrane, absence pericyte coverage, anchoring surrounding extracellular matrix. Lymph fluid then transported pre-collectors, containing valves sporadic smooth muscle (SMCs), vessels. Lymphatic collectors possess complete tight “zipper-like” junctions, are surrounded SMCs. Both pre-collecting contain bicuspid structures, namely valves, prevent backflow ensure unidirectionality flow. content actively multiple due intrinsic contractions mediated perivascular It worth mentioning transport can also be achieved additional extrinsic mechanisms, especially lacking SMC pulmonary lymphatics. contraction those relies forces generated (Zawieja, 2009Zawieja D.C. Contractile physiology lymphatics.Lymphat. Res. Biol. 2009; 7: 87-96https://doi.org/10.1089/lrb.2009.0007Crossref (191) Once passed, finally returned trunks, thoracic duct, (Escobedo Oliver, 2016Escobedo N. Oliver Lymphangiogenesis: origin, specification, cell fate determination.Annu. Rev. Cell Dev. 2016; 32: 677-691https://doi.org/10.1146/annurev-cellbio-111315-124944Crossref (42) Scholar) 1B). Thanks this highly structured network, suited maintenance homeostasis, uptake dietary lipids gastrointestinal tract, and, importantly, trafficking route antigens immune drive initiation responses. Giving these important functions, it not surprising most organs, networks barrier structures against foreign molecules pathogens, skin, intestine, mucosal surfaces (Breslin 2018Breslin J.W. Yang Y. Scallan J.P. Sweat R.S. Adderley S.P. Murfee W.L. structure physiology.Compr. Physiol. 2018; 9: 207-299https://doi.org/10.1002/cphy.c180015Crossref (49) context, LECs must follow specific robust programs, leading expression markers, which cellular but proper maturation organization tree. review, will distinct transcription factor networks, regulators, post-transcriptional actors regulating indispensable LEC differentiation, function. For long time, debated proponents venous (or “centrifugal”) non-venous “centripetal”) origin (Huntington McClure, 1910Huntington G.S. 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Embryonic malleable gene signature.BMC 2010; 72https://doi.org/10.1186/1471-213X-10-72Crossref (33) Collectively, indicate potential reversibility process, demonstrating, one hand, possible without undergoing state case PAX5. highlight continuous requirement even lower levels, seen postnatal compared sufficient (Kazenwadel 2010Kazenwadel Michael M.Z. negatively regulated miR-181 cells.Blood. 2395-2401https://doi.org/10.1182/blood-2009-12-256297Crossref (115) Scholar).Figure 4Key maturationShow full caption(A–C) Transcriptional (A), (B), (C) maturation. Arrows bar-headed lines represent positive negative interactions, respectively. Dashed interactions. Condensed dashed production transcription/translation.View Large Image Figure ViewerDownload Hi-res image Download (PPT) (A–C) transcription/translation. Two play stages development: SRY-Box 18 (SOX18) chick ovalbumin upstream promoter-transcription (COUP-TFII; a.k.a. NR2F2) 3A). 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