Resident Interstitial Lung Fibroblasts and their Role in Alveolar Stem Cell Niche Development, Homeostasis, Injury, and Regeneration

Abstract

Developing, regenerating, and repairing a lung all require interstitial resident fibroblasts (iReFs) to direct the behavior of the epithelial stem cell niche. During lung development, distal lung fibroblasts, in the form of matrix-, myo-, and lipofibroblasts, form the extra cellular matrix (ECM), create tensile strength, and support distal epithelial differentiation, respectively. During de novo septation in a murine pneumonectomy lung regeneration model, developmental processes are reactivated within the iReFs, indicating progenitor function well into adulthood. In contrast to the regenerative activation of fibroblasts upon acute injury, chronic injury results in fibrotic activation. In murine lung fibrosis models, fibroblasts can pathologically differentiate into lineages beyond their normal commitment during homeostasis. In lung injury, recently defined alveolar niche cells support the expansion of alveolar epithelial progenitors to regenerate the epithelium. In human fibrotic lung diseases like bronchopulmonary dysplasia (BPD), idiopathic pulmonary fibrosis (IPF), and chronic obstructive pulmonary disease (COPD), dynamic changes in matrix-, myo-, lipofibroblasts, and alveolar niche cells suggest differential requirements for injury pathogenesis and repair. In this review, we summarize the role of alveolar fibroblasts and their activation stage in alveolar septation and regeneration and incorporate them into the context of human lung disease, discussing fibroblast activation stages and how they contribute to BPD, IPF, and COPD.

Alveologenesis: What Governs Secondary Septa Formation

“…For example, understanding the nature and development of lipogenic versus myogenic fibroblast phenotypes might help to develop new therapeutic strategies for pulmonary diseases. Despite a large amount of data, there is still no established view on the grouping of iReFs, and researchers do this in different ways [26,46,93]. Moreover, many markers of these populations may overlap.…”

“…Myofibroblast TBX4 [12] ACTA2 [27] PDGFRA [27,[47][48][49] FGF18 [37] ELN [50,51] Matrix fibroblast COL13A1, COL14A1 [52] CD34 [46] PDGFRA [46] Lipofibroblast THY [53] FGF10 [18] TCF21 [54] PLIN2 (ADRP) [55] Leptin [56] PPARγ [57] PDGFRA [46,58] Alveolar niche cell AXIN2 [9] LGR5 [59] WNT2 [5] WNT5A [60] PDGFRA [61,62] In simple terms, one can say that as septa mature, SCMFs produce elastin, contract and ensure the elongation of the septal tips, SCMFs and matrix fibroblasts secrete metalloproteinases and ECM-forming and remodeling proteins to thin the septal tips and ensure structural support, while lipofibroblasts support AT2 cell surfactant production. At the end of alveolarization, adult alveolar niche stem cells become defined, consisting of the lipofibroblast-like MANCs, which support alveolar growth and regeneration [9,19,26,38,59,[63][64][65]. Recent lineage tracing and RNA sequencing (RNAseq) data identified Lgr5 + and Wnt-responsive/PDGFRα + mesenchymal cell subsets within alveolar niches that influence the differentiation of alveolar epithelial cells during repair of the mature lung [59,65].…”

Maladaptive functional changes in alveolar fibroblasts due to perinatal hyperoxia impair epithelial differentiation

“…Myofibroblasts contract the ECM and are absolutely required for alveolarization but are known to aberrantly populate the lung in BPD patients and BDP animal models (27)(28)(29)(30). Lipofibroblasts provide neutral lipids and paracrine ligands to alveolar type II epithelial cells (AT2 cells) and express Pdgfra, Tcf21, Plin2, and Fgf10 (17,(31)(32)(33)(34).…”

Single-cell RNA sequencing-based characterization of resident lung mesenchymal stromal cells in bronchopulmonary dysplasia

“…However, very little is currently known about the role of L-MSCs in postnatal lung development and in BPD. Lung stromal cells, including lipofibroblasts, myofibroblasts and matrix fibroblasts are a potent source of inter-cellular signaling and are known to play an important role in BPD pathogenesis [12]. However, how L-MSCs communicate with other cell populations and contribute to the development of BPD remains unknown.…”