Functional Regulatory Mechanisms Underlying Bone Marrow Mesenchymal Stem Cell Senescence During Cell Passages
Functional Regulatory Mechanisms Underlying Bone Marrow Mesenchymal Stem Cell Senescence During Cell Passages
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DOI：
10.1007/s12013-021-00969-y
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发表时间：
2021-02-09
影响因子：
2.6
通讯作者：
Kurihara, H.
中科院分区：
文献类型：
--
作者：
Iwata, T.;Mizuno, N.;Kurihara, H.
间充质干细胞移植是一种有效的牙周再生治疗方法。MSCs具有多能性、自我更新能力，可分化为牙周细胞。然而，msc的衰老是不可避免的。在体外，有或没有细胞传代的长期培养均可诱导细胞衰老。然而，MSC衰老的调控机制尚不清楚。未分化的MSC特异性转录因子可调节MSC功能。在此，我们确定了参与MSC衰老的调控转录因子，并阐明了它们的作用机制。通过重复细胞传代培养人间充质干细胞（hMSCs），诱导细胞衰老，并检测细胞衰老相关基因mRNA和蛋白的表达。此外，我们沉默了细胞衰老诱导的转录因子GATA结合蛋白6 （GATA6）和SRY-box 11 (SOX11)，并研究了衰老相关的信号通路。随着传代次数的增加，衰老细胞数量增加，细胞增殖能力下降；GATA6 mRNA表达上调，SOX11 mRNA表达下调。重复的细胞传代降低了Wnt和骨形态发生蛋白（BMP）信号通路相关基因的表达。沉默GATA6和SOX11可调控Wnt和BMP信号通路相关基因，影响细胞衰老相关基因；此外，SOX11沉默可调节GATA6的表达。因此，我们确定它们是通过Wnt和BMP信号通路调控hMSCs细胞衰老的一对转录因子。
Mesenchymal stem cell (MSC) transplantation is an effective periodontal regenerative therapy. MSCs are multipotent, have self-renewal ability, and can differentiate into periodontal cells. However, senescence is inevitable for MSCs. In vitro, cell senescence can be induced by long-term culture with/without cell passage. However, the regulatory mechanism of MSC senescence remains unclear. Undifferentiated MSC-specific transcription factors can regulate MSC function. Herein, we identified the regulatory transcription factors involved in MSC senescence and elucidated their mechanisms of action. We cultured human MSCs (hMSCs) with repetitive cell passages to induce cell senescence and evaluated the mRNA and protein expression of cell senescence-related genes. Additionally, we silenced the cell senescence-induced transcription factors, GATA binding protein 6 (GATA6) and SRY-box 11 (SOX11), and investigated senescence-related signaling pathways. With repeated passages, the number of senescent cells increased, while the cell proliferation capacity decreased; GATA6 mRNA expression was upregulated and that of SOX11 was downregulated. Repetitive cell passages decreased Wnt and bone morphogenetic protein (BMP) signaling pathway-related gene expression. Silencing of GATA6 and SOX11 regulated Wnt and BMP signaling pathway-related genes and affected cell senescence-related genes; moreover, SOX11 silencing regulated GATA6 expression. Hence, we identified them as pair of regulatory transcription factors for cell senescence in hMSCs via the Wnt and BMP signaling pathways.