Intersections between pulmonary development and disease

Abstract

Recent advances in cellular, molecular, and developmental biology have revolutionized our concepts regarding the process of organogenesis that have important implications for our understanding of both lung formation and pulmonary disease pathogenesis. Pulmonary investigators have long debated whether developmental processes are recapitulated during normal repair of the lung or in the setting of chronic pulmonary diseases. Although the cellular events involved in lung morphogenesis and those causing pulmonary disease are likely to include processes that are distinct, there is increasing evidence that the pathogenesis of many lung disorders involves the same genetic machinery that regulates cell growth,specification, and differentiation during normal lung development.

Figure 1.

A schematic of the regions of the mouse embryo from which distinct organs form along the rostral-caudal axis of the gut tube is shown. Lung progenitor cells are derived in the anterior foregut region of the embryo. Mouse lung buds form on embryonic day 10 from the ventral region (blue) marked by expression of thyroid transcription factor 1 (TTF-1), which serves as a critical regulator of lung morphogenesis and differentiation. Developmental stages of the mouse lung morphogenesis are shown at the left; by embryonic day E12.5, the branching structure of the lung is well established as indicated by staining for forkhead ortholog box (Fox)a2, a transcription factor that persists in airways and alveolar type II cells in the adult. Expression of Sry-related HMG box (Sox)2, octamer binding transcription factor 4, homeobox protein Nanog, and Krüpple-like factor can reprogram somatic cells (e.g., fibroblasts) to induce changes in chromatin and gene expression that activate stem cell activity. Embryonic stem cells (ESC) and induced pluripotent stem cells (iPSC) can be programmed or reprogrammed, respectively, and induced to differentiate in vitro or in vivo to multiple, distinct organ lineages, including the lung. Expression of Sox2, Oct4, Nanog, and Klf can reprogram somatic cells (e.g., fibroblasts) to induce changes in chromatin and gene expression that activate stem cell activity. Developmental stages required for the normal lung formation are shown in blue. The sequential expression of transcription factors mediates the process of lung differentiation, shown in red, that lead to the expression of distinct transcription factors (e.g., p63, Foxj1, Spdef) marking the differentiation of airway epithelial cell types.

Figure 2.

Transcription factors, regulating lung formation, play important roles in the pathogenesis of common lung diseases. Sry-related HMG box (SOX)2, thyroid transcription factor (TTF)-1, forkhead ortholog box (FOX)A2, and Sam pointed domain Ets-like factor (SPDEF) interact in a transcriptional network that regulates respiratory epithelial cell differentiation during development and in disease. SOX2 is selectively expressed in conducting airway epithelial cells, where it regulates basal, ciliated, and secretory cell differentiation. TTF-1 and FOXA2 are expressed in conducting and alveolar epithelial cells, where they are required for normal cell differentiation. FOXA2 is needed to suppress spontaneous Th2-mediated pulmonary inflammation after birth. Loss of FOXA2 induces SPDEF, a transcription factor regulating goblet cell differentiation and mucus production. SPDEF is expressed during aeroallergen and Th2-mediated lung inflammation and is induced in goblet cells associated with chronic obstructive pulmonary disease (COPD) and cystic fibrosis (CF). SPDEF is expressed in a mutually exclusive manner with TTF-1 and FOXA2. SOX2 is selectively expressed in squamous cell carcinomas, whereas TTF-1 marks the majority of non–small cell pulmonary adenocarcinomas. This transcriptional network both responds to and influences Th1- and Th2-mediated inflammation in the lung. Thus, the respiratory epithelium plays a critical role in instruction of innate immunity involved in the pathogenesis of common lung disease associated with metaplasia of the respiratory epithelium.