Jain Rajan, Barkauskas Christina E, Takeda Norifumi, Bowie Emily J, Aghajanian Haig, Wang Qiaohong, Padmanabhan Arun, Manderfield Lauren J, Gupta Mudit, Li Deqiang, Li Li, Trivedi Chinmay M, Hogan Brigid L M, Epstein Jonathan A
Department of Cell and Developmental Biology, Penn Cardiovascular Institute, Institute of Regenerative Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Duke Medicine, Durham, North Carolina 27710, USA.
Nat Commun. 2015 Apr 13;6:6727. doi: 10.1038/ncomms7727.
The plasticity of differentiated cells in adult tissues undergoing repair is an area of intense research. Pulmonary alveolar type II cells produce surfactant and function as progenitors in the adult, demonstrating both self-renewal and differentiation into gas exchanging type I cells. In vivo, type I cells are thought to be terminally differentiated and their ability to give rise to alternate lineages has not been reported. Here we show that Hopx becomes restricted to type I cells during development. However, unexpectedly, lineage-labelled Hopx(+) cells both proliferate and generate type II cells during adult alveolar regrowth following partial pneumonectomy. In clonal 3D culture, single Hopx(+) type I cells generate organoids composed of type I and type II cells, a process modulated by TGFβ signalling. These findings demonstrate unanticipated plasticity of type I cells and a bidirectional lineage relationship between distinct differentiated alveolar epithelial cell types in vivo and in single-cell culture.
成年组织在进行修复时，分化细胞的可塑性是一个深入研究的领域。成年肺中的II型肺泡细胞可产生表面活性剂，并作为祖细胞发挥作用，表现出自我更新以及分化为进行气体交换的I型细胞的能力。在体内，I型细胞被认为是终末分化的，尚未有报道表明其具有产生其他谱系细胞的能力。在此我们表明，Hopx在发育过程中局限于I型细胞。然而，出乎意料的是，在部分肺切除术后的成年肺泡再生过程中，谱系标记的Hopx(+)细胞既能增殖又能产生II型细胞。在克隆三维培养中，单个Hopx(+) I型细胞可生成由I型和II型细胞组成的类器官，这一过程受TGFβ信号传导调节。这些发现证明了I型细胞具有意想不到的可塑性，以及在体内和单细胞培养中不同分化的肺泡上皮细胞类型之间存在双向谱系关系。
