Department of Anatomy and Cell Biology, University Medical School Göttingen, 37075 Göttingen, Germany.
NGS-Integrative Genomics Core Unit (NIG), Institute of Human Genetics, University Medical Center Göttingen, 37075 Göttingen, Germany.
Cells. 2021 Apr 24;10(5):1008. doi: 10.3390/cells10051008.
Lymphedema (LE) affects millions of people worldwide. It is a chronic progressive disease with massive development of fibrosclerosis when untreated. There is no pharmacological treatment of lymphedema. The disease is associated with swelling of the interstitium of the affected organ, mostly arm or leg, impressive development of adipose tissue, fibrosis and sclerosis with accumulation of huge amounts of collagen, and . Malnutrition and reduced oxygenation of the affected tissues is a hallmark of lymphedema. Here, we investigated if the hypoxia of lymphatic endothelial cells (LECs) might contribute to fibrosis. We applied RNASeq and qPCR to study the concordant changes of the exome of three human foreskin-derived LEC isolates after 4 days of hypoxia (1% O) vs. normoxia (21% O). Of the approximately 16,000 genes expressed in LECs, 162 (1%) were up- or down-regulated by hypoxia. Of these, 21 genes have important functions in the production or modification of the extracellular matrix (ECM). In addition to the down-regulation of elastin, we found up-regulation of druggable enzymes and regulators such as the long non-coding RNA H19, inter-alpha-trypsin inhibitor heavy chain family member 5 (ITIH5), lysyl-oxidase (LOX), prolyl 4-hydroxylase subunit alpha 1 (P4HA1), procollagen-lysine 2-oxoglutarate 5-dioxygenase 2 (PLOD2), and others that are discussed in the paper. Initial lymphatics do not produce a continuous basement membrane; however, our study shows that hypoxic LECs have an unexpectedly high ability to alter the ECM.
淋巴水肿（LE）影响着全球数百万人。如果不进行治疗，它是一种慢性进行性疾病，会大量发展纤维化。目前尚无治疗淋巴水肿的药物。该疾病与受影响器官间质的肿胀有关，主要是手臂或腿部，大量脂肪组织、纤维化和硬化的显著发展，伴有大量胶原蛋白的积累，以及。受影响组织的营养不良和缺氧是淋巴水肿的一个标志。在这里，我们研究了淋巴内皮细胞（LEC）的缺氧是否可能导致纤维化。我们应用 RNA-seq 和 qPCR 研究了三个源自人包皮的 LEC 分离物在缺氧（1% O）与常氧（21% O）条件下培养 4 天后外显子组的一致变化。在 LEC 中表达的大约 16000 个基因中，有 162 个（1%）被缺氧上调或下调。其中，21 个基因在细胞外基质（ECM）的产生或修饰中具有重要功能。除了弹性蛋白的下调外，我们还发现了一些可药物治疗的酶和调节剂的上调，如长链非编码 RNA H19、α-胰蛋白酶抑制剂重链家族成员 5（ITIH5）、赖氨酰氧化酶（LOX）、脯氨酰 4-羟化酶亚基α1（P4HA1）、原胶原赖氨酸 2-酮戊二酸 5-双加氧酶 2（PLOD2）等，本文对此进行了讨论。初始淋巴管不产生连续的基底膜；然而，我们的研究表明，缺氧 LEC 具有出人意料的改变 ECM 的能力。
