Here we provide the first definitive evidence that

Here we provide the first definitive evidence that an alternative airway progenitor cell, marked by expression of SOX2, is the predominant cell of origin for nascent KRT5+ trpv1 antagonist after influenza infection. This was true for nascent KRT5+ cells that emerge in the airways and those that appear later in the alveolar parenchyma, suggesting a common SOX2 lineage ancestry (Figure 4). Thus, given that SOX2 is exclusively expressed in the airway epithelium in the adult lung, these studies suggest that the wound-healing response initiates with SOX2+ SCGB1A1− KRT5− HOPX− SFTPC− (SOX2+ Lin−) cells giving rise to nascent KRT5+ cells in the airways, which then populate the damaged alveolar parenchyma. A limitation of this study is the broad expression of SOX2 in all airway epithelial cells, which prevents us from establishing the precise molecular identity of these progenitor cells. Thus, while we can rule out club cells, bronchioalveolar stem cells, and basal airway cells because of their SCGB1A1 or KRT5 lineages, it is unclear how the SOX2+ Lin− cells relate to previously identified α6+β4+ multipotent epithelial stem cells (Chapman et al., 2011; McQualter et al., 2010) and β4+ CD200+ CD14+ progenitor cells (Vaughan et al., 2015). In summary, these studies suggest that the widespread destruction of airway and alveolar epithelial cells following severe influenza infection triggers a wound-healing response that initiates in the airways with the proliferation of rare airway-resident SOX2+ Lin− progenitor cells. These cells then give rise to nascent KRT5+ cells in remodeled airways and populate the damaged alveolar parenchyma. Overall, this study provides important insights into the selective use of different progenitor cell pools and their role in repair after severe tissue damage such as that induced by H1N1 influenza virus infection.
Experimental Procedures
Author Contributions
Acknowledgments We are grateful to T. Mizuno and G. Carraro for insightful discussions, support, and critical input during the study and manuscript preparation, and M. Kostelny for help with maintaining the animal colonies. This study was funded by CIRMLA1-06915 and LRRC-UO1HL111018.
Introduction To keep up with daily demands, the intestine is highly proliferative and has a high rate of cellular turnover. Self-renewing intestinal stem cells (ISCs) located in the crypt at the base of the intestinal epithelium constantly give rise to new progeny. Maintenance of the adult stem cell population requires β-CATENIN-dependent WNT signaling (“canonical” WNT signaling, herein referred to as WNT/β-CATENIN signaling). Inhibition or loss of WNT/β-CATENIN signaling in the epithelium results in loss of stem cells in the crypt (Chiacchiera et al., 2016; Das et al., 2015; Farin et al., 2012; Pinto et al., 2003; Valenta et al., 2016), while activating mutations leading to constitutive WNT activation are causative in colorectal cancer (Barker et al., 2009; Fearon and Spence, 2012; Fearon and Wicha, 2014; Korinek et al., 1997; Morin et al., 1997). Unlike the plethora of information about regulation of the adult ISC, it is much less clear whether and when WNT/β-CATENIN signaling plays a role in the embryonic intestine, and in particular we understand very little about intestine development prior to the formation of villi. For example, studies in mice null for the β-catenin transcriptional binding partner Tcf7l2 (Tcf4) or mice in which the FRIZZLED co-receptors Lrp5 and Lrp6 have been conditionally deleted both demonstrate a loss of intestinal proliferation and collapse of the intervillus progenitor domain late in fetal development (embryonic day 17.5 [E17.5]) (Korinek et al., 1998; Zhong et al., 2012). However, WNT/β-CATENIN signaling has not been directly interrogated prior to villus morphogenesis, a time when the epithelium is a relatively flat, simple pseudostratified epithelium that proliferates uniformly, and lacks stereotypical intestinal villi and differentiated cell types seen following villus morphogenesis (Grosse et al., 2011; Shyer et al., 2013, 2015; Walton et al., 2012, 2016).