Lymphedema has become a global health issue following the growing number of cancer surgeries. Curative or supportive therapeutics have long been awaited for this refractory condition. Transcription factor GATA2 is crucial in lymphatic development and maintenance, as GATA2 haploinsufficient disease often manifests as lymphedema. We recently demonstrated that Gata2 heterozygous deficient mice displayed delayed lymphatic recanalization upon lymph node resection. However, whether GATA2 contributes to lymphatic regeneration by functioning in the damaged lymph vessels' microenvironment remains explored. In this study, our integrated analysis demonstrated that dermal collagen fibers were more densely accumulated in the Gata2 heterozygous deficient mice. The collagen metabolism-related transcriptome was perturbed, and collagen matrix contractile activity was aberrantly increased in Gata2 heterozygous embryonic fibroblasts. Notably, soluble collagen placement ameliorated delayed lymphatic recanalization, presumably by modulating the stiffness of the extracellular matrix around the resection site of Gata2 heterozygous deficient mice. Our results provide valuable insights into mechanisms underlying GATA2-haploinsufficiency-mediated lymphedema and shed light on potential therapeutic avenues for this intractable disease.

中文翻译：

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Gata2杂合子缺陷小鼠中胶原蛋白代谢紊乱是淋巴管再通失败的原因

随着癌症手术数量的增加，淋巴水肿已成为全球健康问题。对于这种难治性疾病，人们长期以来一直期待着治愈性或支持性疗法。转录因子 GATA2 在淋巴管发育和维持中至关重要，因为 GATA2 单倍体不足性疾病通常表现为淋巴水肿。我们最近证明，Gata2 杂合缺陷小鼠在淋巴结切除后表现出延迟的淋巴再通。然而，GATA2 是否通过在受损淋巴管的微环境中发挥作用来促进淋巴再生仍有待探索。在这项研究中，我们的综合分析表明，Gata2 杂合缺陷小鼠的真皮胶原纤维积累得更密集。Gata2 杂合胚胎成纤维细胞中胶原代谢相关转录组受到干扰，胶原基质收缩活性异常增加。值得注意的是，可溶性胶原蛋白的放置改善了延迟的淋巴再通，可能是通过调节 Gata2 杂合缺陷小鼠切除部位周围细胞外基质的硬度。我们的结果为 GATA2 单倍体不足介导的淋巴水肿的机制提供了宝贵的见解，并揭示了这种难治性疾病的潜在治疗途径。