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The lipofibroblast: more than a lipid-storage depot.

Lipid-laden cells (initially named lipid-interstitial cells, LIC, and later termed lipofibrobasts, LiF) were first observed in the pulmonary alveolar interstitium of rats and mice during the saccular and alveolar stages of development (7, 10). Their location and neutral rather than phospholipid storage granules distinguished them from alveolar type 2 (AT2) epithelial cells and macrophages, and their proliferation kinetics distinguished them from interstitial cells that lacked lipid granules (3). The LiF population peaked during the first two postnatal weeks, when plasma chylomicrons and very-low-density lipoproteins were elevated (3, 15). When cultured, the lipid granules dissipated and the cells contained ACTA2 and produced elastin, but lipid storage could be enhanced by exposure to neonatal rat serum or peroxisome proliferator-activated receptor agonists (14, 17). When fibroblasts, which had been isolated in the saccular stage and loaded with [H]triolein, were cocultured with AT2 cells, the triolein was observed in surfactant lipoproteins, leading to the hypothesis that LiF provide surfactant lipids when alveoli rapidly increase in number (26). Comparable to hepatic stellate cells, LiF store retinyl esters, an endogenous precursor for retinoic acid, which supports elastin synthesis and alveolar formation (16). However, an understanding of the function of LiFs was limited by the transient presence of lipid granules and because the cells lost the granules when cultured. With the development of more sensitive tools to analyze gene expression and proteins in small populations or individual cells, the unique phenotype of LiFs has been defined at a molecular level during alveolarization and during compensatory lung growth after pneumonectomy (1, 6). Signaling by PDGF-A through platelet-derived growth factor receptor(PDGFR ) is required for alveolarization, and LiF express PDGFR , but their lineage is not directly defined by PDGF-A signaling (25). Lineage-tracing established that sonic hedgehog signaling differentiates fibroblast progenitors to a myofibroblast (MF), -smooth muscle actin ( SMA)-containing phenotype before postnatal day 2 (P2) when Lif progenitors begin to express the differentiated adipocyte protein perilipin 2 (adipose differentiation-related protein, ADRP), the protein that encapsulates neutral lipid droplets (11, 12, 21). Myofibroblast differentiation depends on inactivation of a Wnt inhibitory pathway and on sustained sonic hedgehog signaling. Lipofibroblasts are most abundant from P4 to P8 and exhibit other markers of white adipocyte-like differentiation [transcription factor-21 (Tcf21)] and G0/G1 switch protein-2 (GOS2) (18). Using transgelin (tagln)-Cre to delete PDGFR , increased adipocyte progenitor markers Tcf21, peroxisome proliferator activated receptor(PPAR ), and delta-like ligand-1 (Dlk1-C) and reduced the proportion of fibroblasts that contained -smooth muscle actin, ACTA2 ( SMA) (18). Thus, whereas PDGFR gene expression does not drive the lineage distinction between LiF and MF, it influences the characteristics of an incompletely committed progenitor population (Fig. 1). Park and associates (22) studied lung cell populations that lineage-labeled for Tcf21, which is a specific marker of white adipose tissue and defines progenitor populations in the heart and kidney (2, 8). Lineage labeling at embryonic day (E)11.5, shortly after outpouching of the laryngeo-tracheal groove, which heralds airway branching, identified both peribronchial and vascular smooth muscle cells. Labeling during the canalicular stage (E14.5 or E15.5) identified cells that at E18.5 (the early saccular stage) were also observed more diffusely in the distal parenchyma. Using 10 m sections for immunochemistry they observed that 20–30% of Tcf21 lineage-labeled cells also stained for PDGFR , and that colocalization occurred in a majority of cells when adults were lineage labeled. Although, their approach was less precise than others using three-dimensional reconstruction and stereology, they showed that PDGFR cells that were Tcf21 also contained neutral lipid droplets. An important and unique observation by Park and associates is that the Tcf21 is expressed in the adult lung, in PDGFR -expressing cells that contain perilipin 2. Prior studies using electron microscopy, histochemical staining for lipids, or fluorescent markers with a lower quantum yield did not identify lipid droplets in adults. These earlier studies raised doubts about the existence of potential relevance of LiF to lung disease in adults. Using adult mouse lungs, Park and associates also observed that lineage-labeled perilipin-2 positive cells colocalized with Col1a1 (collagen I), expressed fibroblast growth factor-10 (FGF10) and the membrane-tethered Col13a1 (collagen XIII). Using adenovirus to exogenously express Tcf21 in primary lung fibroblasts, which were isolated at P7 from wild-type or Tcf21 lineage-labeled mice, they observed more intense lipid-droplet staining in individual cells, although viral transduction of Tcf21 did not increase the number of lipid-droplet containing cells. Because only some of the lung fibroblasts would endogenously express Tcf21, and the cells were not cultured under conditions which enhance droplet accumulation, this indicates that Tcf21 enables fibroblasts to assume a lipid storage phenotype. This suggests that manipulating Tcf21 expression alters lipid acquisition by lung fibroblasts that may not have expressed Tcf21 in the embryonic lung. Address for reprint requests and other correspondence: S. E. McGowan, Division of Pulmonary, Critical Care, and Occupational Medicine, C33B GH, Department of Internal Medicine, University of Iowa Hospitals and Clinics, 200 Hawkins Dr., Iowa City, IA 52242 (e-mail: stephen-mcgowan@uiowa.edu). Am J Physiol Lung Cell Mol Physiol 316: L869–L871, 2019; First published March 6, 2019; doi:10.1152/ajplung.00109.2019.