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.
Highlights
The signals that regulate stem cell self-renewal and differentiation in the lung remain elusive
To functionally test the ability of Lgr6 þ stem cells (LSCs) to recruit stromal cells, we used lung slices treated with bleomycin, to remove all kind of cellular constituents, including bronchiolar, alveolar, mesenchymal and endothelial cell types (Supplementary Fig. 1 and 8)
As a DNA-damaging and ROS-induced apoptotic agent[17], it kills most cell types, without any inflammatory response, producing a physiological scaffold that allows studying the process followed by LSCs to promote the recruitment of stromal cells
Summary
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, known as the niche, includes mesenchymal and endothelial tissues. P38a is essential for fibroblast activation and induction of cytokine expression, in particular TNFa 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. Activation of stromal cells, and specially fibroblasts, to induce their migration and production of other paracrine signals plays an essential role in niche formation in cancer and homeostasis[9,10]. Stromal regulation is pivotal for proper lung homeostasis and the existence of a niche is necessary to create a functional adult tissue with a turnover potential[12]
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