Perhaps the most convincing evidence of robust epithelial regeneration in the adult human lung comes from a recent observation of extensive regenerative lung growth in a 33-year-old woman 15 years after a right-sided pneumonectomy for treatment of lung cancer [32]. Comparable studies in mice suggest that pneumonectomy stimulates pulmonary capillary endothelial cells to produce paracrine growth factors that induce proliferation of epithelial progenitor cells [33]. The authors provide evidence that activated endothelial cells support alveologenesis through MMP14-mediated release of EGF-like ligands. These studies clearly demonstrate that endothelial cells are also an important component of the epithelial stem cell niche in vivo.

Cell culture studies also suggest that endothelial cells communicate directly with lung epithelial stem/progenitor cells and support their proliferation and differentiation in vitro. Co-culture of the human bronchial epithelial cell line VA10, which is a p63⁺ K5⁺ K14⁺ basal cell line, with human umbilical vein endothelial cells (HUVECS) results in epithelial branching in 3D culture [34]. Similarly, another study demonstrated that the proliferation of primary human airway basal cells was significantly increased when co-cultured with HUVECs. Mechanistically, they showed that basal cell secretion of VEGFA activated endothelial cells to produce trophic factors, which in turn support basal cell proliferation [35]. Lastly, CD31⁺ endothelial cells have been shown to be capable of supporting the proliferation and differentiation of multipotent epithelial stem/progenitor cells in vitro and after subcutaneous injection. In this study, the authors showed that BMP4-induced NFATc1-dependent expression of thrombospondin-1 (Tsp1) in lung endothelial cells was involved in driving alveolar lineage specification [36]. Thus, a change in the stromal niche (including endothelial cells) is one mechanism by which the fate and specificity of lung epithelial stem cells might be regulated in response to lung injury in vivo.

In recent years, it has become increasingly clear that tumours comprise a heterogeneous population of cells that are hierarchically organized with cancer-initiating stem cells at the apex with the greatest tumorigenic potential. In parallel with this idea, it is becoming evident that, similar to normal epithelial stem cells, the tumorigenic and metastatic potential of cancer-initiating stem cells may be regulated by the tumour niche [37, 38]. Based on our growing understanding of the lung epithelial stem cell niche, it is likely that alterations in the composition of MSC in the lung may create a tumorigenic niche that allows for the growth of epithelial tumours. In lung squamous cell carcinoma, the profusion of podoplanin-expressing mesenchymal cells, referred to as cancer-associated fibroblasts (CAFs), in the tumour microenvironment is a negative prognostic indicator for patient survival [39]. CAFs are a population of stromal cells that regulate the fate of epithelial tumours through the secretion of various cytokines, including members of the FGF family, EGF and VEGF, which participate in tumour cell growth, metastasis, and neovascularization as reviewed in [37, 40]. Notably, primary isolated CAFs from non-small cell lung cancer (NSCLC) patients have the capacity to enhance the proliferation of lung tumour cell lines and enrich for cancer-initiating stem cell populations through the insulin-like growth factor-II (IGF-II)/IGF1 receptor (IGF1R) pathway. Moreover, activation of the IGF-II/IGF1R pathway correlates with poor-prognosis for overall survival and relapse-free survival in stage I NSCLC patients [41]. Hence, the preexisting squamous phenotype observed in COPD and the chronic injurious state of this lung microenvironment favour the acquisition of a sufficient number of mutations to facilitate a classical pattern of tumour development progressing from metaplasia, dysplasia, carcinoma in situ, and subsequent malignant transformation.

Although our understanding of the epithelial stem cell niche is incomplete, evidence is accumulating to suggest that resident lung mesenchymal progenitor cells function as the architects of lung regeneration by creating a dynamic and hierarchically organized niche so as to exactly regulate the growth of epithelial stem cells and maintain homeostasis of the lung. I propose a simplified model in which the recruitment and/or activation of mesenchymal progenitor cells creates a permissive niche by providing molecular signals, such as FGF-10, to drive the proliferation of epithelial stem and progenitor cells , while myofibroblast differentiation acts to resolve the regenerative process by creating restrictive niche. With this in mind, I would suggest that regulating the niche is arguably more important than the intrinsic potential of stem cells themselves when it comes to maintaining homeostasis in the lung. Therefore, future studies should include characterization of the stem cell–niche interactions in models of lung disease.