Gli1+ mesenchymal stromal cells form a pathological niche to promote airway progenitor metaplasia in the fibrotic lung

Abstract

Aberrant epithelial reprogramming can induce metaplastic differentiation at sites of tissue injury, culminating in transformed barriers composed of scar and metaplastic epithelium. While the plasticity of epithelial stem cells is well-characterized, the identity and role of the niche has not been delineated in metaplasia. Here we show that Gli1 + mesenchymal stromal cells (MSCs), previously shown to contribute to myofibroblasts during scarring, promote metaplastic differentiation of airway progenitors into KRT5+ basal cells. During fibrotic repair, Gli1 + MSCs integrate hedgehog activation to upregulate BMP antagonism in the progenitor niche that promotes metaplasia. Restoring the balance towards BMP activation attenuated metaplastic KRT5+ differentiation while promoting adaptive alveolar differentiation into SFTPC+ epithelium. Finally, fibrotic human lungs demonstrate altered BMP activation in the metaplastic epithelium. These findings show that Gli1 + MSCs integrate hedgehog signaling as a rheostat to control BMP activation in the progenitor niche to determine regenerative outcome in fibrosis.

Organoid: a powerful tool to study lung regeneration and disease

“…The absence of non-epithelial cells fails to recapitulate the architecture of real organ. Incorporation of mesenchymal cells in organoids has already been shown to promote self-renewal and direct the stem cell differentiation (Barkauskas et al, 2013 ; Kathiriya et al, 2020b ; Cassandras et al, 2020 ). Macrophages are also reported to support AEC2s in 3D cultures (Lechner et al, 2017 ).…”

“…In mouse distal airways, club cells and BASCs generate three distinct colony types when co-cultured with mesenchymal cells or mouse lung endothelial cells (LuMECs) (Lee et al, 2014 ; Lee et al, 2017 ). p63 pos LNEPs form bronchiolar organoids, while p63 neg LNEPs mainly form alveolar organoids (Xi et al, 2017 ; Kathiriya et al, 2020a ; Cassandras et al, 2020 ). It remains to be determined whether there is stem/progenitor cell population in the distal human airways, as in mice …”

“…Signals from mesenchyme function as specialized niche directing the response of adjacent airway epithelium. After fibrotic injury, activated Gli1 pos mesenchymal stromal cells form a pathological niche to promote the metaplastic Krt5 differentiation of Sox2 pos airway progenitors by upregulating BMP antagonists (Cassandras et al, 2020 ). Restoring BMP4 attenuated the metaplastic airway progenitor differentiation concurrent with an increase of alveolar cell fate and lung function recovery, consistent with earlier study showing that BMP4 promotes alveolar repair (Lee et al, 2014 ).…”

“…Organoids derived from Sox2 pos or Integrin β4 pos distal airway cells display alveolar or bronchiolar differentiation with or without the supporting cells (Xi et al, 2017 ; Cassandras et al, 2020 ; Kathiriya & Brumwell, 2020 ) (Fig. 1 ).…”

EZH2-dependent transcriptional complex promotes aberrant epithelial remodelling after injury

“…As MCs have been shown to shape epithelial homeostasis (Zepp et al, 2017;Cassandras et al, 2020), we next assessed whether activated MCs in turn influence AECs. To test this, we injured AECs for 3 h in co-culture with MCs, followed by substitution with either (i) ▸ Figure 1.…”