Gli1+ mesenchymal stromal cells modulate epithelial metaplasia in lung fibrosis

Abstract

Highlights• Gli1+ MSCs are required for metaplastic airway progenitor differentiation into KRT5+ basal cells.• Hedgehog activation of MSCs promotes KRT5 differentiation of airway progenitors by suppressing BMP activation.• Restoring BMP activation attenuates metaplastic KRT5 differentiation• Metaplastic KRT5+ basal cells in human fibrotic lungs demonstrate altered BMP activation.

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

“…Unlike MRC5 cells, AHLM cells placed in 3D organoids upregulate a group of secretory products that antagonize BMP signaling and downregulate HHIP, an inhibitor of sonic hedgehog (SHH) signaling. BMP signaling is known to promote murine AEC2 differentiation whereas SHH signaling favors differentiation of murine epithelial progenitors to KRT5+ basal cells by promoting BMP antagonism (Cassandras et al, 2019;Wang et al, 2018). The addition of HHIP or BMP4 to the 3D organoid co-cultures attenuates airway differentiation and maintains hAEC2 lineage, consistent with a causal impact of altered BMP and SHH signaling on hAEC2 fate.…”

“…2A). We and others have previously shown that secreted BMP antagonists are upregulated in the mesenchyme of IPF lungs (Adams et al, 2019;Cassandras et al, 2019;Koli et al, 2006;Myllarniemi et al, 2008) (Fig. S3A), where ectopic basal cells appear in the alveoli accompanied by the loss of hAEC2s.…”

A census of the lung: CellCards from LungMAP

“…In mouse following severe H1N1 influenza infection, rare Trp63+ basal progenitor cells, or lineage negative epithelial progenitors (LNEPs), can give rise to alveolar Krt5+ pods which act as an emergency response to re-establish barrier in the lung (Xi et al, 2017;Yang et al, 2018). In mouse following bleomycin injury, Trp63+ basal cells contributed less efficiently to alveolar Krt5+ pods than Scgb1a1 creERT2 lineaged cells (Cassandras et al, 2020).…”

“…Regenerative potential: Secretory cells can self-renew and differentiate into ciliated cells during mouse airway development, homeostasis, and airway epithelium injury repair (Rock et al, 2009). Following severe lung injury such as bleomycin-induced damage, both Sox2 creERT2 -lineaged cells and Scgb1a1 creERT2 -lineaged cells can give rise to a small percentage of AT1 and AT2 cells, as well as Krt5+ pods in the alveolar region (Yuan et al, 2019;Cassandras et al, 2020). As the common cell type that is lineage traced by both of these cre lines is secretory cells, these results suggest that secretory cells can give rise to a minority of alveolar epithelial cells following bleomycin-induced injury.…”

“…As the common cell type that is lineage traced by both of these cre lines is secretory cells, these results suggest that secretory cells can give rise to a minority of alveolar epithelial cells following bleomycin-induced injury. The absolute number and precentage of alveolar epithelial cell generated from secretory cells after injury varies, depending on the severity and injury type including influenza and bleomycin based injuries (Ray et al, 2016;Yuan et al, 2019;Cassandras et al, 2020;Kathiriya et al, 2020). Use of the Scgb1a1 creERT2 mouse line to lineage trace the contribution of secretory cells to the alveolar epithelium is confounded by the finding that this cre line marks a subset of AT2 cells at homeostasis in the uninjured lung (Rawlins et al, 2009b;Ray et al, 2016).…”