GATA6 regulates aging of human mesenchymal stem/stromal cells,STEM CELLS

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GATA6 regulates aging of human mesenchymal stem/stromal cells
STEM CELLS ( IF 4.0 ) Pub Date : 2020-11-30 , DOI: 10.1002/stem.3297
Hongli Jiao ₁ , Brian E Walczak ₁ , Ming-Song Lee _{1,

2} , Madeleine E Lemieux ₃ , Wan-Ju Li _{1,

2}

Affiliation

Cellular reprogramming forcing the expression of pluripotency markers can reverse aging of cells, but how molecular mechanisms through which reprogrammed cells alter aging‐related cellular activities still remains largely unclear. In this study, we reprogrammed human synovial fluid‐derived mesenchymal stem cells (MSCs) into induced pluripotent stem cells (iPSCs) using six reprogramming factors and reverted the iPSCs back to MSCs, as an approach to cell rejuvenation. Using the parental and reprogrammed MSCs as control nonrejuvenated and rejuvenated cells, respectively, for comparative analysis, we found that aging‐related activities were greatly reduced in reprogrammed MSCs compared with those in their parental lines, indicating reversal of cell aging. Global transcriptome analysis revealed differences in activities of regulatory networks associated with inflammation and proliferation. Mechanistically, we demonstrated that, compared with control cells, the expression of GATA binding protein 6 (GATA6) in reprogrammed cells was attenuated, resulting in an increase in the activity of sonic hedgehog signaling and the expression level of downstream forkhead box P1 (FOXP1), in turn ameliorating cellular hallmarks of aging. Lower levels of GATA6 expression were also found in cells harvested from younger mice or lower passage cultures. Our findings suggest that GATA6 is a critical regulator increased in aged MSCs that controls the downstream sonic hedgehog signaling and FOXP1 pathway to modulate cellular senescence and aging‐related activities.

中文翻译：

GATA6 调节人类间充质干/基质细胞的衰老

迫使多能性标志物表达的细胞重编程可以逆转细胞的衰老，但重编程细胞如何改变与衰老相关的细胞活动的分子机制仍不清楚。在这项研究中，我们使用六种重编程因子将人类滑液来源的间充质干细胞 (MSC) 重编程为诱导多能干细胞 (iPSC)，并将 iPSC 恢复为 MSC，作为细胞再生的一种方法。分别使用亲代和重编程的 MSC 作为对照未再生和再生细胞进行比较分析，我们发现重编程的 MSC 与其亲代细胞相比，衰老相关活性大大降低，表明细胞衰老发生逆转。全球转录组分析揭示了与炎症和增殖相关的调节网络活动的差异。在机制上，我们证明，与对照细胞相比，重编程细胞中 GATA 结合蛋白 6 (GATA6) 的表达减弱，导致声波刺猬信号的活性和下游叉头盒 P1 (FOXP1) 的表达水平增加，进而改善衰老的细胞特征。在从年轻小鼠或较低传代培养物中收获的细胞中也发现了较低水平的 GATA6 表达。我们的研究结果表明，GATA6 是衰老 MSC 中增加的关键调节因子，它控制下游声波刺猬信号和 FOXP1 通路，以调节细胞衰老和衰老相关活动。我们证明，与对照细胞相比，重编程细胞中 GATA 结合蛋白 6 (GATA6) 的表达减弱，导致声波刺猬信号的活性和下游叉头盒 P1 (FOXP1) 的表达水平增加，在转变改善衰老的细胞特征。在从年轻小鼠或较低传代培养物中收获的细胞中也发现了较低水平的 GATA6 表达。我们的研究结果表明，GATA6 是衰老 MSC 中增加的关键调节因子，它控制下游声波刺猬信号和 FOXP1 通路，以调节细胞衰老和衰老相关活动。我们证明，与对照细胞相比，重编程细胞中 GATA 结合蛋白 6 (GATA6) 的表达减弱，导致声波刺猬信号的活性和下游叉头盒 P1 (FOXP1) 的表达水平增加，在转变改善衰老的细胞特征。在从年轻小鼠或较低传代培养物中收获的细胞中也发现了较低水平的 GATA6 表达。我们的研究结果表明，GATA6 是衰老 MSC 中增加的关键调节因子，它控制下游声波刺猬信号和 FOXP1 通路，以调节细胞衰老和衰老相关活动。导致声波刺猬信号的活性和下游叉头盒 P1 (FOXP1) 的表达水平增加，进而改善细胞衰老特征。在从年轻小鼠或较低传代培养物中收获的细胞中也发现了较低水平的 GATA6 表达。我们的研究结果表明，GATA6 是衰老 MSC 中增加的关键调节因子，它控制下游声波刺猬信号和 FOXP1 通路，以调节细胞衰老和衰老相关活动。导致声波刺猬信号的活性和下游叉头盒 P1 (FOXP1) 的表达水平增加，进而改善细胞衰老特征。在从年轻小鼠或较低传代培养物中收获的细胞中也发现了较低水平的 GATA6 表达。我们的研究结果表明，GATA6 是衰老 MSC 中增加的关键调节因子，它控制下游声波刺猬信号和 FOXP1 通路，以调节细胞衰老和衰老相关活动。

更新日期：2020-12-29

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