Transcription factor FOXF1 identifies compartmentally distinct mesenchymal cells with a role in lung allograft fibrogenesis

Abstract

In this study, we demonstrate that Forkhead Box F1 (FOXF1), a mesenchymal transcriptional factor essential for lung development, is retained in a topographically distinct mesenchymal stromal cell population along the bronchovascular space in an adult lung and identify this distinct subset of collagen-expressing cells as a key player in lung allograft remodeling and fibrosis. Utilizing Foxf1_tdTomato BAC (Foxf1_tdTomato) and Foxf1_tdTomato;Col1a1_GFP mice, we show that Lin − Foxf1 + cells encompass the Sca1 + CD34 + subset of collagen I-expressing mesenchymal cells (MCs) with capacity to generate colony forming units and lung epithelial organoids. Histologically, Foxf1-expressing MCs formed a three-dimensional network along the conducting airways; FOXF1 was noted to be conspicuously absent in MCs in the alveolar compartment. Bulk and single-cell RNA sequencing confirmed distinct transcriptional signatures of Foxf1 pos/neg MCs, with Foxf1-expressing cells delineated by their high Gli1 and low Integrin α8 expression, from other collagen-expressing MCs. Foxf1 + Gli1 + MCs demonstrated proximity to Sonic hedgehog (Shh) expressing bronchial epithelium, and mesenchymal Foxf1/Gli1 expression was found to be dependent on the paracrine Shh signaling in epithelial organoids. Utilizing a murine lung transplant model, we show dysregulation of the epithelial mesenchymal Shh/Gli1/Foxf1 crosstalk and expansion of this specific peri-bronchial MC population in chronically rejecting fibrotic lung allografts.

Gene expression profiles in mesenchymal stromal cells from bone marrow, adipose tissue and lung tissue of COPD patients and controls

“…Of interest, forkhead box F1 (FOXF1) is a lung embryonic mesenchyme-specific transcription factor with persistent expression into adulthood in mesenchymal stromal cells [23]. In murine studies, Foxf1 + cells were shown to encompass a stem cell subset of collagen 1-expressing mesenchymal cells with clonogenic potential and capacity to generate lung epithelial organoids [24]. Interactions between FOXF1 and sonic hedgehog (SHH), T-box transcription factor (TBX4), TBX2 and FGF10 pathways have been described, proposing an essential transcriptional network during early lung organogenesis [25].…”

Reprogramming alveolar macrophage responses to TGF-β reveals CCR2+ monocyte activity that promotes bronchiolitis obliterans syndrome

“…Most of the investigative focus into TGF-β–mediated fibrogenesis has led to the elucidation of mechanisms that control extracellular matrix remodeling, epithelial-to-mesenchymal transition, and fibrogenesis. Although these pathways are involved in BOS pathogenesis ( 71 ), the additional requirement for leukocyte-dependent recognition of alloantigens mechanistically distinguishes BOS from other pulmonary fibrotic diseases. We were initially surprised by reports of ECP’s effectiveness in BOS patients, given that previous studies have demonstrated that ECP stimulates TGF-β protein expression along with the expansion of Foxp3 + CD4 + T cells ( 15 ).…”

Gene expression profiles in mesenchymal stromal cells from bone marrow, adipose tissue and lung tissue of COPD patients and controls

“…Of interest, forkhead box F1 (FOXF1) is a lung embryonic mesenchyme-speci c transcription factor with persistent expression into adulthood in mesenchymal stromal cells [23]. In murine studies, Foxf1 + cells were shown to encompass a stem cell subset of collagen 1-expressing mesenchymal cells with clonogenic potential and capacity to generate lung epithelial organoids [24]. Interactions between FOXF1 and sonic hedgehog (SHH), T-box transcription factor (TBX4), TBX2 and FGF10 pathways have been described, proposing an essential transcriptional network during early lung organogenesis [25].…”