Liebler Janice M, Marconett Crystal N, Juul Nicholas, Wang Hongjun, Liu Yixin, Flodby Per, Laird-Offringa Ite A, Minoo Parviz, Zhou Beiyun
Division of Pulmonary, Critical Care and Sleep Medicine, Department of Medicine, Will Rogers Institute Pulmonary Research Center, Keck School of Medicine, University of Southern California, Los Angeles, California;
Department of Surgery, Keck School of Medicine, University of Southern California, Los Angeles, California; Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California; Department of Biochemistry and Molecular Biology, Keck School of Medicine, University of Southern California, Los Angeles, California; and.
Am J Physiol Lung Cell Mol Physiol. 2016 Jan 15;310(2):L114-20. doi: 10.1152/ajplung.00337.2015. Epub 2015 Nov 6.
Distal lung epithelium is maintained by proliferation of alveolar type II (AT2) cells and, for some daughter AT2 cells, transdifferentiation into alveolar type I (AT1) cells. We investigated if subpopulations of alveolar epithelial cells (AEC) exist that represent various stages in transdifferentiation from AT2 to AT1 cell phenotypes in normal adult lung and if they can be identified using combinations of cell-specific markers. Immunofluorescence microscopy showed that, in distal rat and mouse lungs, ∼ 20-30% of NKX2.1(+) (or thyroid transcription factor 1(+)) cells did not colocalize with pro-surfactant protein C (pro-SP-C), a highly specific AT2 cell marker. In distal rat lung, NKX2.1(+) cells coexpressed either pro-SP-C or the AT1 cell marker homeodomain only protein x (HOPX). Not all HOPX(+) cells colocalize with the AT1 cell marker aquaporin 5 (AQP5), and some AQP5(+) cells were NKX2.1(+). HOPX was expressed earlier than AQP5 during transdifferentiation in rat AEC primary culture, with robust expression of both by day 7. We speculate that NKX2.1 and pro-SP-C colocalize in AT2 cells, NKX2.1 and HOPX or AQP5 colocalize in intermediate or transitional cells, and HOPX and AQP5 are expressed without NKX2.1 in AT1 cells. These findings suggest marked heterogeneity among cells previously identified as exclusively AT1 or AT2 cells, implying the presence of subpopulations of intermediate or transitional AEC in normal adult lung.
远端肺上皮由肺泡II型（AT2）细胞增殖维持，并且对于一些子代AT2细胞而言，通过转分化形成肺泡I型（AT1）细胞。我们研究了在正常成年肺中是否存在代表从AT2到AT1细胞表型转分化不同阶段的肺泡上皮细胞（AEC）亚群，以及是否可以使用细胞特异性标志物组合来识别它们。免疫荧光显微镜显示，在大鼠和小鼠的远端肺中，约20 - 30%的NKX2.1（+）（或甲状腺转录因子1（+））细胞不与前表面活性蛋白C（pro-SP-C）共定位，pro-SP-C是一种高度特异性的AT2细胞标志物。在大鼠远端肺中，NKX2.1（+）细胞共表达pro-SP-C或AT1细胞标志物仅含同源结构域蛋白x（HOPX）。并非所有HOPX（+）细胞都与AT1细胞标志物水通道蛋白5（AQP5）共定位，并且一些AQP5（+）细胞是NKX2.1（+）。在大鼠AEC原代培养的转分化过程中，HOPX的表达早于AQP5，到第7天时两者均有强烈表达。我们推测NKX2.1和pro-SP-C在AT2细胞中共定位，NKX2.1和HOPX或AQP5在中间或过渡细胞中共定位，而在AT1细胞中HOPX和AQP5的表达不依赖于NKX2.1。这些发现表明，先前被确定为仅为AT1或AT2细胞的细胞之间存在明显的异质性，这意味着在正常成年肺中存在中间或过渡性AEC亚群。
