Laboratory of Biomedical Embryology, Department of Veterinary Medicine and Animal Sciences, Center for Stem Cell Research, Università degli Studi di Milano, 20134, Milan, Italy.
Laboratory of Biomedical Embryology, Department of Agricultural and Environmental Sciences - Production, Landscape, Agroenergy, Università degli Studi di Milano, Milan, 20133, Italy.
Stem Cell Rev Rep. 2023 Feb;19(2):417-429. doi: 10.1007/s12015-022-10438-5. Epub 2022 Aug 27.
Aging is defined as a complex, multifaceted degenerative process that causes a gradual decline of physiological functions and a rising mortality risk with time. Stopping senescence or even rejuvenating the body represent one of the long-standing human dreams. Somatic cell nuclear transfer as well as cell reprogramming have suggested the possibility to slow or even reverse signs of aging. We exploited miR-200 family ability to induce a transient high plasticity state in human skin fibroblasts isolated from old individuals and we investigated whether this ameliorates cellular and physiological hallmarks of senescence. In addition, based on the assumption that extracellular matrix (ECM) provides biomechanical stimuli directly influencing cell behavior, we examine whether ECM-based bio-scaffolds, obtained from decellularized ovaries of young swine, stably maintain the rejuvenated phenotype acquired by cells after miR-200 exposure. The results show the existence of multiple factors that cooperate to control a unique program, driving the cell clock. In particular, miR-200 family directly regulates the molecular mechanisms erasing cell senescence. However, this effect is transient, reversible, and quickly lost. On the other hand, the use of an adequate young microenvironment stabilizes the miR-200-mediated rejuvenating effects, suggesting that synergistic interactions occur among molecular effectors and ECM-derived biomechanical stimuli. The model here described is a useful tool to better characterize these complex regulations and to finely dissect the multiple and concurring biochemical and biomechanical cues driving the cell biological clock.
衰老是一个复杂的、多方面的退行过程，随着时间的推移，它会导致生理功能逐渐下降和死亡风险增加。阻止衰老甚至使身体恢复活力是人类长期以来的梦想之一。体细胞核转移和细胞重编程表明，有可能减缓甚至逆转衰老的迹象。我们利用 miR-200 家族在体外诱导人类老年皮肤成纤维细胞短暂高可塑性的能力，研究了这是否能改善衰老细胞和生理特征。此外，基于细胞外基质 (ECM) 提供直接影响细胞行为的生物力学刺激的假设，我们检查了从年轻猪去细胞化卵巢获得的基于 ECM 的生物支架是否能稳定维持细胞在 miR-200 暴露后获得的年轻化表型。结果表明，存在多种因素共同控制一个独特的程序，驱动细胞时钟。特别是，miR-200 家族直接调控消除细胞衰老的分子机制。然而，这种效应是短暂的、可逆的，并且很快就会消失。另一方面，使用适当的年轻微环境可以稳定 miR-200 介导的年轻化效应，这表明分子效应器和 ECM 衍生的生物力学刺激之间存在协同相互作用。这里描述的模型是一个有用的工具，可以更好地描述这些复杂的调节，并精细地剖析驱动细胞生物钟的多种并发生化和生物力学线索。
