Mesenchymal stromal cell aging impairs the self-organizing capacity of lung alveolar epithelial stem cells.
Mesenchymal stromal cell aging impairs the self-organizing capacity of lung alveolar epithelial stem cells.
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DOI：
10.7554/elife.68049
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发表时间：
2021-09-16
期刊：
影响因子：
7.7
通讯作者：
Thannickal VJ
中科院分区：
文献类型：
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作者：
Chanda D;Rehan M;Smith SR;Dsouza KG;Wang Y;Bernard K;Kurundkar D;Memula V;Kojima K;Mobley JA;Benavides GA;Darley-Usmar V;Kim YI;Zmijewski JW;Deshane JS;De Langhe S;Thannickal VJ
多细胞生物通过自发的自组织行为维持组织/器官的结构和功能。在本报告中，我们证明了肺间充质基质细胞 (L-MSC) 老化在确定与 2 型肺泡上皮细胞 (AEC2) 形成三维类器官或“肺泡球”的能力方面的关键作用。与来自老年小鼠的 L-MSC 相比，年轻的 L-MSC 与年轻或老年 AEC2 共培养时支持肺泡球的有效形成。老化的 L-MSC 表现出细胞衰老、生物能学改变和衰老相关分泌谱 (SASP) 的特征。活性氧生成酶 NADPH 氧化酶 4 (Nox4) 在衰老的 L-MSC 中高度激活，Nox4 下调足以（至少部分）逆转这种与年龄相关的能量不足，同时恢复肺泡球的自组织能力。总之，这些数据表明细胞生物能量学和氧化还原稳态在自组织类器官模型中的关键作用，并支持衰老生物学中热力学熵的概念。体内的许多组织都能够通过用新细胞替换有缺陷或磨损的细胞来再生。这个过程在很大程度上依赖于干细胞，干细胞是在体内缺乏固定作用的前体细胞，可以在适当的条件下发育成不同类型的细胞。组织通常有自己的干细胞库，用于补充受损细胞。但随着年龄的增长，这种再生过程变得不那么有效。我们的许多器官，例如肺，都衬有上皮细胞。这些细胞形成保护屏障，控制物质进出组织。肺泡是肺部的一部分，允许氧气和二氧化碳在肺部的血液和空气之间移动。肺泡依靠有效的上皮细胞衬里才能正常工作。为了补充这些上皮细胞，肺泡有袋，其中生活着一种称为 AEC2 的上皮细胞。这些细胞可以充当干细胞，在适当的条件下发育成不同类型的细胞。为了正常工作，AEC2 细胞需要与另一种称为 L-MSC 的细胞密切相互作用，L-MSC 支持其他细胞的维持，并且还具有分化成其他几种细胞类型的能力。在这些干细胞袋中可以发现两种细胞类型紧密结合在一起。到目前为止，尚不清楚衰老如何影响这些细胞如何共同补充肺泡上皮内层。为了调查，Chanda 等人。探测了年轻和年老小鼠肺泡中的 AEC2 和 L-MSC。研究人员从年轻（2-3 个月）和老年（22-24 个月）小鼠身上收集了两种细胞类型。这些细胞的各种组合被培养形成 3D 结构，模仿细胞在肺部的生长方式。年轻的 L-MSC 与年轻和老化的 AEC2 细胞形成正常的 3D 结构。但衰老的 L-MSC 与 AEC2 细胞（年轻细胞和老年细胞）一起形成异常、松散的结构。研究发现，与年轻的 L-MSC 相比，衰老的 L-MSC 具有更高水平的酶（称为 Nox4），该酶可产生氧化剂和其他“促衰老”因子。然而，降低衰老的 L-MSC 中的 Nox4 水平可以使这些细胞与年轻的 AEC2 细胞形成正常的 3D 结构，但不能与衰老的 AEC2 细胞形成正常的 3D 结构。这些发现强调了特定干细胞具有的不同影响，以及它们的行为如何受到促衰老因素的影响。此外，促衰老酶 Nox4 显示出作为治疗靶点的潜力——下调其活性可能会逆转细胞衰老的关键影响。
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. Many tissues in the body are capable of regenerating by replacing defective or worn-out cells with new ones. This process relies heavily on stem cells, which are precursor cells that lack a set role in the body and can develop into different types of cells under the right conditions. Tissues often have their own pool of stem cells that they use to replenish damaged cells. But as we age, this regeneration process becomes less effective. Many of our organs, such as the lungs, are lined with epithelial cells. These cells form a protective barrier, controlling what substances get in and out of the tissue. Alveoli are parts of the lungs that allow oxygen and carbon dioxide to move between the blood and the air in the lungs. And alveoli rely on an effective epithelial cell lining to work properly. To replenish these epithelial cells, alveoli have pockets, in which a type of epithelial cell, known as AEC2, lives. These cells can serve as stem cells, developing into a different type of cell under the right conditions. To work properly, AEC2 cells require close interactions with another type of cell called L-MSC, which supports the maintenance of other cells and also has the ability to differentiate into several other cell types. Both cell types can be found close together in these stem cell pockets. So far, it has been unclear how aging affects how these cells work together to replenish the epithelial lining of the alveoli. To investigate, Chanda et al. probed AEC2s and L-MSCs in the alveoli of young and old mice. The researchers collected both cell types from young (2-3 months) and aged (22-24 months) mice. Various combinations of these cells were grown to form 3D structures, mimicking how the cells grow in the lungs. Young L-MSCs formed normal 3D structures with both young and aged AEC2 cells. But aged L-MSCs developed abnormal, loose structures with AEC2 cells (both young and old cells). Aged L-MSCs were found to have higher levels of an enzyme (called Nox4) that produces oxidants and other ‘pro-aging’ factors, compared to young L-MSCs. However, reducing Nox4 levels in aged L-MSCs allowed these cells to form normal 3D structures with young AEC2 cells, but not aged AEC2 cells. These findings highlight the varying effects specific stem cells have, and how their behaviour is affected by pro-aging factors. Moreover, the pro-aging enzyme Nox4 shows potential as a therapeutic target – downregulating its activity may reverse critical effects of aging in cells.