Department of Pediatric Respiratory Medicine, National Key Clinical Specialty of Pediatric Respiratory Medicine, Institute of Pediatrics, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, 325027, Zhejiang, China.
Department of Cell Biology, Duke University School of Medicine, Durham, NC27710, USA.
Cell Mol Life Sci. 2023 May 11;80(6):145. doi: 10.1007/s00018-023-04789-6.
Alveolar epithelial type II cells (AT2s) together with AT1s constitute the epithelial lining of lung alveoli. In contrast to the large flat AT1s, AT2s are cuboidal and smaller. In addition to surfactant production, AT2s also serve as prime alveolar progenitors in homeostasis and play an important role during regeneration/repair. Based on different lineage tracing strategies in mice and single-cell transcriptomic analysis, recent reports highlight the heterogeneous nature of AT2s. These studies present compelling evidence for the presence of stable or transitory AT2 subpopulations with distinct marker expression, signaling pathway activation and functional properties. Despite demonstrated progenitor potentials of AT2s in maintaining homeostasis, through self-renewal and differentiation to AT1s, the exact identity, full progenitor potential and regulation of these progenitor cells, especially in the context of human diseases remain unclear. We recently identified a novel subset of AT2 progenitors named "Injury-Activated Alveolar Progenitors" (IAAPs), which express low levels of Sftpc, Sftpb, Sftpa1, Fgfr2b and Etv5, but are highly enriched for the expression of the surface receptor programmed cell death-ligand 1 (Pd-l1). IAAPs are quiescent during lung homeostasis but activated upon injury with the potential to proliferate and differentiate into AT2s. Significantly, a similar population of PD-L1 positive cells expressing intermediate levels of SFTPC are found to be expanded in human IPF lungs. We summarize here the current understanding of this newly discovered AT2 progenitor subpopulation and also try to reconcile the relationship between different AT2 stem cell subpopulations regarding their progenitor potential, regulation, and relevance to disease pathogenesis and therapeutic interventions.
肺泡上皮 II 型细胞 (AT2) 与 AT1 共同构成了肺肺泡的上皮衬里。与大型扁平 AT1 不同，AT2 呈立方体形且较小。除了产生表面活性剂外，AT2 还是维持肺内稳态的主要肺泡祖细胞，并在再生/修复过程中发挥重要作用。基于小鼠的不同谱系追踪策略和单细胞转录组分析，最近的报告强调了 AT2 的异质性。这些研究为稳定或瞬时 AT2 亚群的存在提供了令人信服的证据，这些亚群具有不同的标记表达、信号通路激活和功能特性。尽管 AT2 在维持内稳态方面具有祖细胞的潜力，可通过自我更新和分化为 AT1 来实现，但这些祖细胞的确切身份、完整的祖细胞潜力及其调控，尤其是在人类疾病的背景下，仍不清楚。我们最近鉴定了一种新型 AT2 祖细胞亚群，称为“损伤激活的肺泡祖细胞”（IAAP），其表达低水平的 Sftpc、Sftpb、Sftpa1、Fgfr2b 和 Etv5，但高水平表达表面受体程序性细胞死亡配体 1（Pd-l1）。IAAP 在肺内稳态期间处于静止状态，但在损伤时被激活，具有增殖和分化为 AT2 的潜力。重要的是，在人类 IPF 肺中发现了类似的 PD-L1 阳性细胞群，其表达中等水平的 SFTPC。我们在这里总结了对这个新发现的 AT2 祖细胞亚群的认识，并试图协调不同的 AT2 干细胞亚群之间的关系，包括它们的祖细胞潜力、调控以及与疾病发病机制和治疗干预的相关性。
