Transcriptome analysis and functional identification of adipose-derived mesenchymal stem cells in secondary lymphedema
Transcriptome analysis and functional identification of adipose-derived mesenchymal stem cells in secondary lymphedema
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继发性淋巴水肿中脂肪间充质干细胞的转录组分析及功能鉴定
DOI：
10.21037/gs.2020.02.09
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发表时间：
2020
期刊：
影响因子：
1.8
通讯作者：
Zhou Zhou
中科院分区：
文献类型：
--
作者：
Qinqin Xiang;Fen Xu;Yunzhu Li;Xuanyu Liu;Qianlong Chen;Jiuzuo Huang;Xiaojun Wang;Ziyi Zeng;Meng Yuan;Qixu Zhang;Xiao Long;Zhou Zhou
继发性水肿是影响恶性肿瘤患者的常见病症。保守治疗不能提供持久的缓解，因为它们不能解决潜在的病理性过度脂肪积累。为阐明水肿脂肪组织成脂分化异常的分子机制，我们比较了10例四肢水肿患者脂肪组织中脂肪源性间充质干细胞（adipose-derived mesenchymal stem cells，ASCs）的增殖和成脂潜能，并与同一患者正常上腹部脂肪组织中的ASCs进行比较。通过转录组分析比较两种ASCs的差异。本研究采用细胞周期蛋白依赖性激酶1（CDK 1）抑制剂对水肿脂肪组织中异常ASCs进行治疗，结果表明两种ASCs在功能和转录水平上存在显著差异。上调的基因主要与细胞增殖和分裂有关，下调的基因主要与免疫反应、炎症反应、成骨分化和成肌分化有关。此外，我们发现，过度增殖和脂肪形成的ASCs从水肿脂肪组织恢复正常表型的CDK 1抑制剂。水肿脂肪组织来源的ASCs具有更强的免疫抑制作用，与免疫抑制相关的细胞因子表达显著上调，说明水肿脂肪组织来源的ASCs具有更快的增殖和更强的成脂分化能力。CDK 1可能是这些细胞增殖和成脂分化的关键驱动因素，这可能解释了在继发性水肿中广泛观察到的脂肪组织积累。水肿脂肪组织来源的ASCs存在免疫调节功能障碍，免疫调节可能在水肿的发病中起重要作用。
Secondary lymphedema is a common condition that affects patients with malignant tumors. Conservative treatments fail to provide lasting relief because they do not address the underlying pathological accumulation of excessive fat. Our aim is to clarify the molecular mechanisms of abnormal adipogenic differentiation in lymphedema adipose tissue.We compared the proliferation and adipogenesis potential of adipose-derived mesenchymal stem cells (ASCs) from the lymphedema adipose tissue from liposuction specimens of 10 patients with extremity lymphedema with that of ASCs from adipose tissue from the normal upper abdomen of the same patients. Transcriptome analysis were performed to identify the differences between the two kinds of ASCs. Cyclin-dependent kinase 1 (CDK1) inhibitors were used to treat the abnormal ASCs in lymphedema adipose tissue.Our results demonstrate that significant functional and transcriptomic differences exist between the two kinds of ASCs. Up-regulated genes were mainly involved in cell proliferation and division while down-regulated genes were mainly associated with immune responses and inflammatory as well as osteogenic and myogenic differentiation. Furthermore, we find that the excessive proliferation and adipogenesis of ASCs from lymphedema adipose tissue returned to the normal phenotype by CDK1 inhibitors. ASCs from lymphedema adipose tissues have higher immunosuppressive effect and the cytokines related to immunosuppressive was significantly up-regulated.In conclusion, lymphedema-associated ASCs had more rapid proliferation and a higher adipogenic differentiation capacity. CDK1 may be a key driver of proliferation and adipogenic differentiation in these cells, which might expound the accumulation of adipose tissue extensively observed in secondary lymphedema. ASCs from lymphedema adipose tissues showed immunomodulation dysfunction and immunomodulation may play an important role in the pathogenesis of lymphedema.