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

We isolated adipose-derived mesenchymal stem cells (ASCs) from the lymphedema adipose tissue from liposuction specimens of 10 patients with malignancy-related extremity lymphedema, and we used adipose tissue from the normal upper abdomen of the same patients as control tissue. We compared the proliferation and adipogenic differentiation capacity between the two kinds of ASCs, and we explored the transcriptomic differences between them. We found that lymphedema-associated ASCs had more rapid proliferation and a higher adipogenic differentiation capacity. CDK1 inhibitors could return the abnormal biological characteristics of these cells to normal phenotype, suggesting that CDK1 is a key driver of proliferation and adipogenic differentiation in these cells, which might expound the accumulation of adipose tissue extensively observed in secondary lymphedema, indicating the CDK1 may be a potential target for lymphedema therapy. On the other hand, our finding showed that ASCs from lymphedema adipose tissues have higher immunosuppressive effect, and the inhibition of up-regulated cytokine CHI3L1 may be clinically beneficial. In summary, explore the underlying mechanisms of fat deposition in lymphedema may provide powerful strategies for the treatment of lymphedema. Overall design: mRNA sequencing of ASCs from the affected thighs of 10 patients with lymphedema, and as control, ASCs from the normal upper abdomen of the same patients were also sequenced.

本研究从10例恶性肿瘤相关性肢体淋巴水肿患者的吸脂标本的淋巴水肿脂肪组织中分离得到脂肪间充质干细胞（adipose-derived mesenchymal stem cells, ASCs），并以同一患者的正常上腹部脂肪组织作为对照组织。本研究比较了两组脂肪间充质干细胞的增殖能力与成脂分化能力，并探究了二者的转录组差异。研究发现，淋巴水肿相关的脂肪间充质干细胞增殖速度更快，成脂分化能力更强。细胞周期蛋白依赖性激酶1（CDK1）抑制剂可将此类细胞的异常生物学特性恢复至正常表型，表明CDK1是调控该类细胞增殖与成脂分化的关键驱动因子，这或可解释继发性淋巴水肿中广泛观察到的脂肪组织堆积现象，提示CDK1或可成为淋巴水肿治疗的潜在靶点。另一方面，本研究发现源自淋巴水肿脂肪组织的脂肪间充质干细胞具有更强的免疫抑制效果，抑制上调的细胞因子CHI3L1或具有临床获益。综上，探索淋巴水肿中脂肪沉积的潜在机制，可为淋巴水肿的治疗提供有效策略。整体实验设计：对10例淋巴水肿患者患肢大腿来源的脂肪间充质干细胞进行mRNA测序，并以同一患者正常上腹部来源的脂肪间充质干细胞作为对照进行测序。