College of Literature, Science and the Arts, University of Michigan, Ann Arbor, MI 48109, USA.
Division of Pulmonary and Critical Care Medicine, Department of Internal Medicine, University of Michigan, 109 Zina Pitcher Place, Ann Arbor, MI 48109-2200, USA.
Int J Mol Sci. 2020 Apr 30;21(9):3188. doi: 10.3390/ijms21093188.
The alveolar epithelium consists of (ATI) and type II (ATII) cells. ATI cells cover the majority of the alveolar surface due to their thin, elongated shape and are largely responsible for barrier function and gas exchange. During lung injury, ATI cells are susceptible to injury, including cell death. Under some circumstances, ATII cells also die. To regenerate lost epithelial cells, ATII cells serve as progenitor cells. They proliferate to create new ATII cells and then differentiate into ATI cells [,,]. Regeneration of ATI cells is critical to restore normal barrier and gas exchange function. Although the signaling pathways by which ATII cells proliferate have been explored [,,,,,,,,], the mechanisms of ATII-to-ATI cell differentiation have not been well studied until recently. New studies have uncovered signaling pathways that mediate ATII-to-ATI differentiation. Bone morphogenetic protein (BMP) signaling inhibits ATII proliferation and promotes differentiation. Wnt/β-catenin and ETS variant transcription factor 5 (Etv5) signaling promote proliferation and inhibit differentiation. Delta-like 1 homolog (Dlk1) leads to a precisely timed inhibition of Notch signaling in later stages of alveolar repair, activating differentiation. Yes-associated protein/Transcriptional coactivator with PDZ-binding motif (YAP/TAZ) signaling appears to promote both proliferation and differentiation. We recently identified a novel transitional cell state through which ATII cells pass as they differentiate into ATI cells, and this has been validated by others in various models of lung injury. This intermediate cell state is characterized by the activation of Transforming growth factor beta (TGFβ) and other pathways, and some evidence suggests that TGFβ signaling induces and maintains this state. While the abovementioned signaling pathways have all been shown to be involved in ATII-to-ATI cell differentiation during lung regeneration, there is much that remains to be understood. The up- and down-stream signaling events by which these pathways are activated and by which they induce ATI cell differentiation are unknown. In addition, it is still unknown how the various mechanistic steps from each pathway interact with one another to control differentiation. Based on these recent studies that identified major signaling pathways driving ATII-to-ATI differentiation during alveolar regeneration, additional studies can be devised to understand the interaction between these pathways as they work in a coordinated manner to regulate differentiation. Moreover, the knowledge from these studies may eventually be used to develop new clinical treatments that accelerate epithelial cell regeneration in individuals with excessive lung damage, such as patients with the Acute Respiratory Distress Syndrome (ARDS), pulmonary fibrosis, and emphysema.
肺泡上皮由Ⅰ型肺泡细胞（ATI）和Ⅱ型肺泡细胞（ATII）组成。由于 ATI 细胞呈薄而细长的形状，因此覆盖了大部分肺泡表面，主要负责屏障功能和气体交换。在肺损伤时，ATI 细胞容易受到损伤，包括细胞死亡。在某些情况下，ATII 细胞也会死亡。为了再生丢失的上皮细胞，ATII 细胞作为祖细胞。它们增殖以产生新的 ATII 细胞，然后分化为 ATI 细胞[,,]。ATI 细胞的再生对于恢复正常的屏障和气体交换功能至关重要。尽管已经探索了 ATII 细胞增殖的信号通路[,,,,,,,,]，但直到最近才对 ATII 到 ATI 细胞分化的机制进行了很好的研究。新的研究揭示了介导 ATII 到 ATI 分化的信号通路。骨形态发生蛋白（BMP）信号抑制 ATII 增殖并促进分化。Wnt/β-catenin 和 ETS 变体转录因子 5（Etv5）信号促进增殖并抑制分化。Delta-like 1 同源物（Dlk1）导致 Notch 信号在肺泡修复的后期阶段被精确地抑制，从而激活分化。Yes 相关蛋白/含 PDZ 结合基序的转录共激活因子（YAP/TAZ）信号似乎促进增殖和分化。我们最近通过 ATII 细胞在分化为 ATI 细胞的过程中通过的一种新型过渡细胞状态，这已被其他人在各种肺损伤模型中验证。这种中间细胞状态的特征是转化生长因子β（TGFβ）和其他途径的激活，并且有证据表明 TGFβ 信号诱导并维持这种状态。虽然已经证明上述信号通路都参与了肺再生过程中 ATII 到 ATI 细胞的分化，但仍有许多方面需要了解。这些途径被激活以及它们诱导 ATI 细胞分化的上、下游信号事件尚不清楚。此外，尚不清楚每个途径的各种机制步骤如何相互作用以控制分化。基于这些最近的研究，确定了在肺泡再生过程中驱动 ATII 到 ATI 分化的主要信号通路，可以设计更多的研究来了解这些通路在协调工作以调节分化时的相互作用。此外，这些研究的知识最终可能用于开发新的临床治疗方法，以加速个体中上皮细胞的再生，这些个体的肺损伤过多，例如患有急性呼吸窘迫综合征（ARDS）、肺纤维化和肺气肿的患者。
