Acquisition of cellular properties during alveolar formation requires differential activity and distribution of mitochondria.
Acquisition of cellular properties during alveolar formation requires differential activity and distribution of mitochondria.
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DOI：
10.7554/elife.68598
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发表时间：
2022-04-06
期刊：
影响因子：
7.7
通讯作者：
Koenigshoff, Melanie
中科院分区：
文献类型：
--
作者：
Zhang, Kuan;Yao, Erica;Chen, Biao;Chuang, Ethan;Wong, Julia;Seed, Robert, I;Nishimura, Stephen L.;Wolters, Paul J.;Chuang, Pao-Tien;Koenigshoff, Melanie
肺泡形成需要肺泡上皮细胞、间充质肌成纤维细胞和内皮细胞/周细胞之间的协调运动和相互作用以产生次级隔膜。这些过程依赖于获得不同的细胞特性，以使配体分泌用于细胞-细胞信号传导，并通过细胞收缩、细胞迁移和细胞形状变化启动形态发生。在这项研究中，我们发现，线粒体的活性和分布在赋予细胞功能的肺泡上皮细胞和间充质肌成纤维细胞产生次级隔膜，形成肺泡在小鼠中发挥关键作用。这些结果表明，线粒体功能受到严格调控，以空间特异性方式赋予细胞机制。事实上，通过线粒体的这种调节是从肺泡上皮细胞分泌配体（如血小板衍生生长因子）以影响肌成纤维细胞增殖和收缩/迁移所必需的。此外，线粒体功能使得肌成纤维细胞在肺泡形成期间收缩/迁移。总之，这些发现产生了线粒体如何调节肺泡发生的关键步骤的新机制见解。它们强调了细胞中能量的选择性利用以及发育过程中不同细胞过程中的不同能量需求。我们的工作为研究线粒体如何控制组织模式提供了范例。肺部呈现出复杂的树状结构，能够进行生命所需的复杂气体交换。每个微小的“分支”的末端都有精致的气囊或肺泡，它们被称为隔膜的内壁进一步分开。在哺乳动物中，这种最终结构是在肺发育的最后阶段获得的。然后，许多不同类型的细胞在未成熟的肺泡繁殖，并到达正确的位置，开始构建额外的隔膜。虽然强调肺泡成熟的结构变化得到了很好的研究，但该过程的能量需求仍然知之甚少。特别是，线粒体的确切作用，为大多数生命过程提供动力的细胞隔室，仍然不清楚。因此，Zhang等人着手详细绘制线粒体在肺泡发育中的作用。显微镜成像揭示了线粒体在新生小鼠肺细胞中的不均匀分布。线粒体聚集在控制气囊上皮细胞中蛋白质分泌的机器周围，以及底层细胞（“肌成纤维细胞”）中的收缩装置周围。通过遗传改变小鼠以降低线粒体活性或扰乱线粒体在这两种细胞类型中的位置，产生了具有较少隔膜的缺陷性肺泡，但它对肺泡形成之前的肺发育没有影响。这表明肺泡的形成比肺发育的其他步骤需要更多的能量。线粒体活性或位置的破坏也会损害上皮细胞产生肌成纤维细胞收缩或迁移所需的化学信号的方式。总之，这些结果突出了在肺模式化期间严格调节线粒体活性和位置的重要性。在未来，这一见解可以为确定各种组织中的能量需求如何塑造健康和疾病中的其他生物过程奠定基础。
Alveolar formation requires coordinated movement and interaction between alveolar epithelial cells, mesenchymal myofibroblasts, and endothelial cells/pericytes to produce secondary septa. These processes rely on the acquisition of distinct cellular properties to enable ligand secretion for cell-cell signaling and initiate morphogenesis through cellular contraction, cell migration, and cell shape change. In this study, we showed that mitochondrial activity and distribution play a key role in bestowing cellular functions on both alveolar epithelial cells and mesenchymal myofibroblasts for generating secondary septa to form alveoli in mice. These results suggest that mitochondrial function is tightly regulated to empower cellular machineries in a spatially specific manner. Indeed, such regulation via mitochondria is required for secretion of ligands, such as platelet-derived growth factor, from alveolar epithelial cells to influence myofibroblast proliferation and contraction/migration. Moreover, mitochondrial function enables myofibroblast contraction/migration during alveolar formation. Together, these findings yield novel mechanistic insights into how mitochondria regulate pivotal steps of alveologenesis. They highlight selective utilization of energy in cells and diverse energy demands in different cellular processes during development. Our work serves as a paradigm for studying how mitochondria control tissue patterning. The lungs display an intricate, tree-shaped structure which enables the complex gas exchanges required for life. The end of each tiny ‘branch’ hosts delicate air sacs, or alveoli, which are further divided by internal walls called septa. In mammals, this final structure is acquired during the last stage of lung development. Then, many different types of cells in the immature alveoli multiply and reach the right location to start constructing additional septa. While the structural changes underlining alveoli maturation are well-studied, the energy requirements for that process remain poorly understood. In particular, the exact role of the mitochondria, the cellular compartments that power most life processes, is still unclear. Zhang et al. therefore set out to map, in detail, the role of mitochondria in alveolar development. Microscope imaging revealed how mitochondria were unevenly distributed within the lung cells of newborn mice. Mitochondria accumulated around the machinery that controls protein secretion in the epithelial cells that line the air sacs, and around the contractile apparatus in the underlying cells (the ‘myofibroblasts’). Genetically altering the mice to reduce mitochondrial activity or perturb mitochondrial location in these two cell types produced defective alveoli with fewer septa, but it had no effect on lung development before alveoli formation. This suggests that the formation of alveoli requires more energy than other steps of lung development. Disrupting mitochondrial activity or location also compromised how epithelial cells produced chemical signals necessary for the contraction or migration of the myofibroblasts. Together, these results highlight the importance of tightly regulating mitochondrial activity and location during lung patterning. In the future, this insight could lay the groundwork to determine how energy requirements in various tissues shape other biological processes in health and disease.