Lin Eric Chang-Yi, Davis Madison P, Lee Ming-Song, Ma Gui, Xu Wei, Chang Yuan-I, Li Wan-Ju
Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, Wisconsin, USA; Institute of Physiology, College of Medicine, National Yang Ming Chiao Tung University, Taipei City, Taiwan.
Department of Orthopedics and Rehabilitation, University of Wisconsin-Madison, Madison, Wisconsin, USA; Department of Biomedical Engineering, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Cytotherapy. 2025 Jan;27(1):85-97. doi: 10.1016/j.jcyt.2024.08.001. Epub 2024 Aug 8.
The immunomodulatory capacity of mesenchymal stem/stromal cells (MSCs) is a key feature that makes them particularly valuable for regenerative medicine. However, this potential is affected by the chronological aging of the donors and the cell expansion procedures in culture. We have demonstrated that GATA binding protein 6 (GATA6) plays a pivotal role in the aging of MSCs and inhibiting GATA6 rejuvenates the characteristics of MSCs.
In this study, we compared the immunomodulatory capabilities of young and old MSC models, using induced pluripotent stem cells-derived rejuvenated MSCs (rMSCs) and their parental MSCs (pMSCs), respectively, to identify a key mechanism involved in the differential regulation of these capabilities. Additionally, we explored the role of GATA6 in mediating the mechanism.
Our results demonstrated that rMSCs exhibited downregulated aging-associated regulators, including p53, p21 and GATA6, and showed enhanced suppression of T cell proliferation compared to pMSCs. Through analyzing our previous RNA-seq data and employing target gene knockdown, we determined both suppressors of cytokine signaling 3 (SOCS3) and interleukin 6 were involved in GATA6-induced regulation, collectively affecting the expression of programmed death ligand 1 (PDL1) in both pMSCs and rMSCs.
Our findings underline the significance of the GATA6/SOCS3/PDL1 pathway in regulating aging-associated changes in MSC immunomodulatory activity, providing valuable insights into the potential use of rMSCs in the treatment of immune diseases and regenerative medicine.
间充质干/基质细胞（MSC）的免疫调节能力是使其在再生医学中具有特殊价值的关键特性。然而，这种潜能会受到供体的自然衰老以及培养过程中细胞扩增程序的影响。我们已经证明，GATA结合蛋白6（GATA6）在MSC衰老过程中起关键作用，抑制GATA6可使MSC的特性恢复活力。
在本研究中，我们分别使用诱导多能干细胞来源的恢复活力的MSC（rMSC）及其亲代MSC（pMSC）比较了年轻和老年MSC模型的免疫调节能力，以确定参与这些能力差异调节的关键机制。此外，我们探讨了GATA6在介导该机制中的作用。
我们的结果表明，与pMSC相比，rMSC表现出衰老相关调节因子（包括p53、p21和GATA6）的下调，并且对T细胞增殖的抑制作用增强。通过分析我们之前的RNA测序数据并采用靶基因敲低技术，我们确定细胞因子信号传导抑制因子3（SOCS3）和白细胞介素6均参与GATA6诱导的调节，共同影响pMSC和rMSC中程序性死亡配体1（PDL1）的表达。
我们的研究结果强调了GATA6/SOCS3/PDL1途径在调节MSC免疫调节活性中与衰老相关变化的重要性，为rMSC在免疫疾病治疗和再生医学中的潜在应用提供了有价值的见解。
