Cross-Talk Between Inflammation and Fibroblast Growth Factor 10 During Organogenesis and Pathogenesis: Lessons Learnt From the Lung and Other Organs

The adult human lung is constantly exposed to irritants like particulate matter, toxic chemical compounds, and biological agents (bacteria and viruses) present in the external environment. During breathing, these irritants travel through the bronchi and bronchioles to reach the deeper lung containing the alveoli, which constitute the minimal functional respiratory units. The local biological responses in the alveoli that follow introduction of irritants need to be tightly controlled in order to prevent a massive inflammatory response leading to loss of respiratory function. Cells, cytokines, chemokines and growth factors intervene collectively to re-establish tissue homeostasis, fight the aggression and replace the apoptotic/necrotic cells with healthy cells through proliferation and/or differentiation. Among the important growth factors at play during inflammation, members of the fibroblast growth factor (Fgf) family regulate the repair process. Fgf10 is known to be a key factor for organ morphogenesis and disease. Inflammation is influenced by Fgf10 but can also impact Fgf10 expression per se. Unfortunately, the connection between Fgf10 and inflammation in organogenesis and disease remains unclear. The aim of this review is to highlight the reported players between Fgf10 and inflammation with a focus on the lung and to propose new avenues of research.

Nicotinic Receptor Subunits Atlas in the Adult Human Lung

Nicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels responsible for rapid neural and neuromuscular signal transmission. Although it is well documented that 16 subunits are encoded by the human genome, their presence in airway epithelial cells (AECs) remains poorly understood, and contribution to pathology is mainly discussed in the context of cancer. We analysed nAChR subunit expression in the human lungs of smokers and non-smokers using transcriptomic data for whole-lung tissues, isolated large AECs, and isolated small AECs. We identified differential expressions of nAChRs in terms of detection and repartition in the three modalities. Smoking-associated alterations were also unveiled. Then, we identified an nAChR transcriptomic print at the single-cell level. Finally, we reported the localizations of detectable nAChRs in bronchi and large bronchioles. Thus, we compiled the first complete atlas of pulmonary nAChR subunits to open new avenues to further unravel the involvement of these receptors in lung homeostasis and respiratory diseases.

Nicotinic receptors atlas in the adult human lung

ABSTRACTNicotinic acetylcholine receptors (nAChRs) are pentameric ligand-gated ion channels responsible for the rapid neural and neuromuscular signal transmission. Although it is well documented that 16 subunits are encoded by the human genome, their presence in airway epithelial cells (AEC) remains poorly understood, and contribution to pathology is mainly discussed in the context of cancer. We analysed nAChR subunit expression in the human lung of smokers and non-smokers using transcriptomic data for whole lung tissues, isolated large AEC, and isolated small AEC. We identified differential expressions of nAChRs in terms of detection and repartition in the three modalities. Smoking-associated alterations were also unveiled. Then, we identified a nAChR transcriptomic print at a single cell level. Finally, we reported the localizations of detectable nAChRs in bronchi and large bronchioles. Thus, we compiled the first complete atlas of pulmonary nAChRs to open new avenues to further unravel the involvement of these receptors in lung homeostasis and respiratory diseases.

Human alveolar Type 2 epithelium transdifferentiates into metaplastic KRT5+ basal cells during alveolar repair

SUMMARYUnderstanding differential lineage potential of orthologous stem cells across species can shed light on human disease. Here, utilizing 3D organoids, single cell RNAseq, and xenotransplants, we demonstrate that human alveolar type 2 cells (hAEC2s), unlike murine AEC2s, are multipotent and able to transdifferentiate into KRT5+ basal cells when co-cultured with primary fibroblasts in 3D organoids. Trajectory analyses and immunophenotyping of epithelial progenitors in idiopathic pulmonary fibrosis (IPF) indicate that hAEC2s transdifferentiate into metaplastic basal cells through alveolar-basal intermediate (ABI) cells that we also identify in hAEC2-derived organoids. Modulating hAEC2-intrinsic and niche factors dysregulated in IPF can attenuate metaplastic basal cell transdifferentiation and preserve hAEC2 identity. Finally, hAEC2s transplanted into fibrotic immune-deficient murine lungs engraft as either hAEC2s or differentiated KRT5+ basal cells. Our study indicates that hAEC2s-loss and expansion of alveolar metaplastic basal cells in IPF are causally connected, which would not have been revealed utilizing murine AEC2s as a model.HighlightsHuman AEC2s transdifferentiate into KRT5+ basal cells when accompanied by primary adult human lung mesenchyme in 3D organoid culture.Alterations of hAEC2-intrinsic and niche factors dysregulated in IPF can modify metaplastic hAEC2 transdifferentiation.hAEC2s engraft into fibrotic lungs of immune-deficient mice and transdifferentiate into metaplastic basal cells.Transcriptional trajectory analysis suggests that hAEC2s in IPF gives rise to metaplastic basal cells via alveolar-basal intermediate cells.

Gravity outweighs the contribution of structure to passive ventilation-perfusion matching in the supine adult human lung

Gravity and matched airway/vascular tree geometries are both hypothesized to be key contributors to ventilation-perfusion (V̇/Q̇) matching in the lung, but their relative contributions are challenging to quantify experimentally. We used a structure-based model to conduct an analysis of the relative contributions of tissue deformation (the “Slinky” effect), other gravitational mechanisms (weight of blood and gravitational gradient in tissue elastic recoil), and matched airway and arterial tree geometry to V̇/Q̇ matching and therefore to total lung oxygen exchange. Our results showed that the heterogeneity in V̇ and Q̇ were lowest and the correlation between V̇ and Q̇ was highest when the only mechanism for V̇/Q̇ matching was either tissue deformation or matched geometry. Heterogeneity in V̇ and Q̇ was highest and their correlation was poorest when all mechanisms were active (that is, at baseline). Eliminating the contribution of matched geometry did not change the correlation between V̇ and Q̇ at baseline. Despite the much larger heterogeneities in V̇ and Q̇ at baseline, the contribution of in-common (to V̇ and Q̇) gravitational mechanisms provided sufficient compensatory V̇/Q̇ matching to minimize the impact on oxygen transfer. In summary, this model predicts that during supine normal breathing under gravitational loading, passive V̇/Q̇ matching is predominantly determined by shared gravitationally induced tissue deformation, compliance distribution, and the effect of the hydrostatic pressure gradient on vessel and capillary size and blood pressures. Contribution from the matching airway and arterial tree geometries in this model is minor under normal gravity in the supine adult human lung. NEW & NOTEWORTHY We use a computational model to systematically analyze contributors to ventilation-perfusion matching in the lung. The model predicts that the multiple effects of gravity are the predominant mechanism in providing passive ventilation-perfusion matching in the supine adult human lung under normal gravitational loads, while geometric matching of airway and arterial trees plays a minor role.

A bioengineered niche promotes in vivo engraftment and maturation of pluripotent stem cell derived human lung organoids

Human pluripotent stem cell (hPSC) derived tissues often remain developmentally immature in vitro, and become more adult-like in their structure, cellular diversity and function following transplantation into immunocompromised mice. Previously we have demonstrated that hPSC-derived human lung organoids (HLOs) resembled human fetal lung tissue in vitro (<xref ref-type="bibr" rid="bib10">Dye et al., 2015</xref>). Here we show that HLOs required a bioartificial microporous poly(lactide-co-glycolide) (PLG) scaffold niche for successful engraftment, long-term survival, and maturation of lung epithelium in vivo. Analysis of scaffold-grown transplanted tissue showed airway-like tissue with enhanced epithelial structure and organization compared to HLOs grown in vitro. By further comparing in vitro and in vivo grown HLOs with fetal and adult human lung tissue, we found that in vivo transplanted HLOs had improved cellular differentiation of secretory lineages that is reflective of differences between fetal and adult tissue, resulting in airway-like structures that were remarkably similar to the native adult human lung.

PDE4 inhibitors roflumilast and rolipram augment PGE2 inhibition of TGF-β1-stimulated fibroblasts

Fibrotic diseases are characterized by the accumulation of extracellular matrix together with distortion and disruption of tissue architecture. Phosphodiesterase (PDE)4 inhibitors, by preventing the breakdown of cAMP, can inhibit fibroblast functions and may be able to mitigate tissue remodeling. Transforming growth factor (TGF)-β1, a mediator of fibrosis, can potentially modulate cAMP by altering PGE2 metabolism. The present study assessed whether PDE4 inhibitors functionally antagonize the profibrotic activity of fibroblasts stimulated by TGF-β1. The PDE4 inhibitors roflumilast and rolipram both inhibited fibroblast-mediated contraction of three-dimensional collagen gels and fibroblast chemotaxis toward fibronectin in the widely studied human fetal lung fibroblast strain HFL-1 and several strains of fibroblasts from adult human lung. Roflumilast was ∼10-fold more potent than rolipram. There was a trend for PDE4 inhibitors to inhibit more in the presence of TGF-β1 (0.05 < P < 0.08). The effect of the PDE4 inhibitors was mediated through cAMP-stimulated protein kinase A (PKA), although a PKA-independent effect on gel contraction was also observed. The effect of PDE4 inhibitors depended on fibroblast production of PGE2 and TGF-β1-induced PGE2 production. PDE4 inhibitors together with TGF-β1 resulted in augmented PGE2 production together with increased expression of COX mRNA and protein. The present study supports the concept that PDE4 inhibitors may attenuate fibroblast activities that can lead to fibrosis and that PDE4 inhibitors may be particularly effective in the presence of TGF-β1-induced fibroblast stimulation.