Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Birmingham, United States.
John W. Deming Department of Medicine, Tulane University School of Medicine, New Orleans, United States.
Elife. 2021 Sep 16;10:e68049. doi: 10.7554/eLife.68049.
Multicellular organisms maintain structure and function of tissues/organs through emergent, self-organizing behavior. In this report, we demonstrate a critical role for lung mesenchymal stromal cell (L-MSC) aging in determining the capacity to form three-dimensional organoids or 'alveolospheres' with type 2 alveolar epithelial cells (AEC2s). In contrast to L-MSCs from aged mice, young L-MSCs support the efficient formation of alveolospheres when co-cultured with young or aged AEC2s. Aged L-MSCs demonstrated features of cellular senescence, altered bioenergetics, and a senescence-associated secretory profile (SASP). The reactive oxygen species generating enzyme, NADPH oxidase 4 (Nox4), was highly activated in aged L-MSCs and Nox4 downregulation was sufficient to, at least partially, reverse this age-related energy deficit, while restoring the self-organizing capacity of alveolospheres. Together, these data indicate a critical role for cellular bioenergetics and redox homeostasis in an organoid model of self-organization and support the concept of thermodynamic entropy in aging biology.
多细胞生物通过涌现的自组织行为来维持组织/器官的结构和功能。在本报告中，我们证明了肺间质基质细胞（L-MSC）衰老在决定与 2 型肺泡上皮细胞（AEC2）形成三维类器官或“肺泡球体”的能力方面起着关键作用。与老年小鼠的 L-MSC 相比，年轻的 L-MSC 在与年轻或老年 AEC2 共培养时，能够有效地形成肺泡球体。衰老的 L-MSC 表现出细胞衰老的特征、改变的生物能量和衰老相关分泌表型（SASP）。活性氧生成酶 NADPH 氧化酶 4（Nox4）在衰老的 L-MSC 中高度激活，Nox4 的下调足以至少部分逆转这种与年龄相关的能量不足，同时恢复肺泡球体的自组织能力。这些数据共同表明，细胞生物能量和氧化还原稳态在自组织类器官模型中起着关键作用，并支持衰老生物学中热力学熵的概念。
