title: A paracrine network regulates the cross-talk between human lung stem cells and the stroma.
abstract: The signals that regulate stem cell self-renewal and differentiation in the lung remain elusive. Lung stem cells undergo self-renewal or lineage commitment to replenish tissue, depending on cross-talk with their environment. This environment, also known as the niche, includes mesenchymal and endothelial tissues. Here we define molecular mechanisms involved in the interaction between human lung Lgr6+ stem cells (LSCs) and fibroblasts in a functional microenvironment. We reveal a central role for p38α MAPK in establishing and maintaining such cross-talk, acting in both cell types. In LSCs, p38α induces the expression of SDF-1, which activates the stroma. p38α is essential for fibroblast activation and induction of cytokine expression, in particular TNFα. This paracrine network induces a hierarchical activation leading to the recruitment of endothelium, establishing a functional microenvironment. Disruption of this cross-talk abrogates proper LSC differentiation in vivo and may lead to lung dysfunction and disease.
authors.affiliation: SCI (Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge), Tennis Court Road, Cambridge, CB2 1QR, UK.
authors.forename: E Josue
authors.initials: EJ
authors.lastname: Ruiz
authors.affiliation: SCI (Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge), Tennis Court Road, Cambridge, CB2 1QR, UK.
authors.forename: Feride
authors.initials: F
authors.lastname: Oeztuerk-Winder
authors.affiliation: SCI (Wellcome Trust-Medical Research Council Stem Cell Institute, University of Cambridge), Tennis Court Road, Cambridge, CB2 1QR, UK.
authors.forename: Juan-Jose
authors.initials: JJ
authors.lastname: Ventura
mesh_terms: D002454:Cell Differentiation; D054377:Chemokine CXCL12 / Q000378:metabolism; D006801:Humans; D008168:Lung / Q000166:cytology*; D013234:Stem Cells / Q000166:cytology*; D017154:Stromal Cells / Q000166:cytology*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
chemical_list: C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha