Mapping spatially resolved transcriptomes in human and mouse pulmonary fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease with poor prognosis and limited treatment options. Efforts to identify effective treatments are thwarted by limited understanding of IPF pathogenesis and poor translatability of available preclinical models. Here we generated spatially resolved transcriptome maps of human IPF (n = 4) and bleomycin-induced mouse pulmonary fibrosis (n = 6) to address these limitations.

FGF10-FGFR2B Signaling Generates Basal Cells and Drives Alveolar Epithelial Regeneration by Bronchial Epithelial Stem Cells after Lung Injury.

Idiopathic pulmonary fibrosis is a common form of interstitial lung disease resulting in alveolar remodeling and progressive loss of pulmonary function because of chronic alveolar injury and failure to regenerate the respiratory epithelium. Histologically, fibrotic lesions and honeycomb structures expressing atypical proximal airway epithelial markers replace alveolar structures, the latter normally lined by alveolar type 1 (AT1) and AT2 cells. Bronchial epithelial stem cells (BESCs) can give rise to AT2 and AT1 cells or honeycomb cysts following bleomycin-mediated lung injury.

Hippo signaling promotes lung epithelial lineage commitment by curbing Fgf10 and β-catenin signaling.

Organ growth and tissue homeostasis rely on the proliferation and differentiation of progenitor cell populations. In the developing lung, localized expression maintains distal -expressing epithelial progenitors and promotes basal cell differentiation in the cartilaginous airways. Mesenchymal expression is induced by Wnt signaling but inhibited by Shh signaling, and epithelial Fgf10 signaling activates β-catenin signaling.

Fgf10 Signaling in Lung Development, Homeostasis, Disease, and Repair After Injury.

The lung is morphologically structured into a complex tree-like network with branched airways ending distally in a large number of alveoli for efficient oxygen exchange. At the cellular level, the adult lung consists of at least 40-60 different cell types which can be broadly classified into epithelial, endothelial, mesenchymal, and immune cells. Fibroblast growth factor 10 (Fgf10) located in the lung mesenchyme is essential to regulate epithelial proliferation and lineage commitment during embryonic development and post-natal life, and to drive epithelial regeneration after injury.

Developmental pathways in the pathogenesis of lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is a progressive and terminal lung disease with no known cure. IPF is a disease of aging, with median age of diagnosis over 65 years. Median survival is between 3 and 5 years after diagnosis.

Fgf10-Hippo Epithelial-Mesenchymal Crosstalk Maintains and Recruits Lung Basal Stem Cells.

The lung harbors its basal stem/progenitor cells (BSCs) in the protected environment of the cartilaginous airways. After major lung injuries, BSCs are activated and recruited to sites of injury. Here, we show that during homeostasis, BSCs in cartilaginous airways maintain their stem cell state by downregulating the Hippo pathway (resulting in increased nuclear Yap), which generates a localized Fgf10-expressing stromal niche; in contrast, differentiated epithelial cells in non-cartilaginous airways maintain quiescence by activating the Hippo pathway and inhibiting Fgf10 expression in airway smooth muscle cells (ASMCs).

Wnt and FGF mediated epithelial-mesenchymal crosstalk during lung development.

Background: The adaptation to terrestrial life required the development of an organ capable of efficient air-blood gas exchange. To meet the metabolic load of cellular respiration, the mammalian respiratory system has evolved from a relatively simple structure, similar to the two-tube amphibian lung, to a highly complex tree-like system of branched epithelial airways connected to a vast network of gas exchanging units called alveoli. The development of such an elaborate organ in a relatively short time window is therefore an extraordinary feat and involves an intimate crosstalk between mesodermal and endodermal cell lineages.

Lung epithelial stem cells and their niches: Fgf10 takes center stage.

Throughout life adult animals crucially depend on stem cell populations to maintain and repair their tissues to ensure life-long organ function. Stem cells are characterized by their capacity to extensively self-renew and give rise to one or more differentiated cell types. These powerful stem cell properties are key to meet the changing demand for tissue replacement during normal lung homeostasis and regeneration after lung injury.

c-Myc regulates proliferation and Fgf10 expression in airway smooth muscle after airway epithelial injury in mouse.

During lung development, Fibroblast growth factor 10 (Fgf10), which is expressed in the distal mesenchyme and regulated by Wnt signaling, acts on the distal epithelial progenitors to maintain them and prevent them from differentiating into proximal (airway) epithelial cells. Fgf10-expressing cells in the distal mesenchyme are progenitors for parabronchial smooth muscle cells (PSMCs). After naphthalene, ozone or bleomycin-induced airway epithelial injury, surviving epithelial cells secrete Wnt7b which then activates the PSMC niche to induce Fgf10 expression.

Localized Fgf10 expression is not required for lung branching morphogenesis but prevents differentiation of epithelial progenitors.

Localized Fgf10 expression in the distal mesenchyme adjacent to sites of lung bud formation has long been thought to drive stereotypic branching morphogenesis even though isolated lung epithelium branches in the presence of non-directional exogenous Fgf10 in Matrigel. Here, we show that lung agenesis in Fgf10 knockout mice can be rescued by ubiquitous overexpression of Fgf10, indicating that precisely localized Fgf10 expression is not required for lung branching morphogenesis in vivo. Fgf10 expression in the mesenchyme itself is regulated by Wnt signaling.

Parabronchial smooth muscle constitutes an airway epithelial stem cell niche in the mouse lung after injury.

During lung development, parabronchial SMC (PSMC) progenitors in the distal mesenchyme secrete fibroblast growth factor 10 (Fgf10), which acts on distal epithelial progenitors to promote their proliferation. β-catenin signaling within PSMC progenitors is essential for their maintenance, proliferation, and expression of Fgf10. Here, we report that this Wnt/Fgf10 embryonic signaling cascade is reactivated in mature PSMCs after naphthalene-induced injury to airway epithelium.

Oligodendrocyte-specific FADD deletion protects mice from autoimmune-mediated demyelination.

Apoptosis of oligodendrocytes (ODCs), the myelin-producing glial cells in the CNS, plays a central role in demyelinating diseases such as multiple sclerosis and experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis. To investigate the mechanism behind ODC apoptosis in EAE, we made use of conditional knockout mice lacking the adaptor protein FADD specifically in ODCs (FADD(ODC-KO)). FADD mediates apoptosis by coupling death receptors with downstream caspase activation.