Role of Lung Pericytes and Resident Fibroblasts in the Pathogenesis of Pulmonary Fibrosis

Rationale: The origin of cells that make pathologic fibrillar collagen matrix in lung disease has been controversial. Recent studies suggest mesenchymal cells may contribute directly to fibrosis. Objectives: To characterize discrete populations of mesenchymal cells in the normal mouse lung and to map their fate after bleomycin-induced lung injury. Methods: We mapped the fate of Foxd1-expressing embryonic progenitors and their progeny during lung development, adult homeostasis, and after fibrosing injury in Foxd1-Cre; Rs26-tdTomato-R mice. We studied collagen-I(alpha) 1-producing cells in normal and diseased lungs using Coll-GFP(Tg) mice. Measurements and Main Results: Foxd1-expressing embryonic progenitors enter lung buds before 13.5 days post-conception, expand, and form an extensive lineage of mesenchymal cells that have characteristics of pericytes. A collagen-I(alpha) 1-expressing mesenchymal population of distinct lineage is also found in adult lung, with features of a resident fibroblast. In contrast to resident fibroblasts, Foxd1 progenitor-derived pericytes are enriched in transcripts for innate immunity, vascular development, WNT signaling pathway, and cell migration. Foxd1 progenitor-derived pericytes expand after bleomycin lung injury, and activate expression of collagen-I(a) 1 and the myofibroblast marker alpha SMA in fibrotic foci. In addition, our studies suggest a distinct lineage of collagen-I(a) 1-expressing resident fibroblasts that also expands after lung injury is a second major source of myofibroblasts. Conclusions: We conclude that the lung contains an extensive population of Foxd1 progenitor-derived pericytes that are an important lung myofibroblast precursor population.