Perivascular Gli1+ Progenitors Are Key Contributors to Injury-Induced Organ Fibrosis

Abstract

Summary Mesenchymal stem cells (MSCs) reside in the perivascular niche of many organs, including kidney, lung, liver, and heart, although their roles in these tissues are poorly understood. Here, we demonstrate that Gli1 marks perivascular MSC-like cells that substantially contribute to organ fibrosis. In vitro, Gli1+ cells express typical MSC markers, exhibit trilineage differentiation capacity, and possess colony-forming capacity, despite constituting a small fraction of the platelet-derived growth factor-β (PDGFRβ)+ cell population. Genetic lineage tracing analysis demonstrate that tissue-resident, but not circulating, Gli1+ cells proliferate following kidney, lung, liver, or heart injury to generate myofibroblasts. Genetic ablation of these cells substantially ameliorates kidney and heart fibrosis, and preserves ejection fraction in a model of induced heart failure. These findings implicate perivascular Gli1+ MSC-like cells as a major cellular origin of organ fibrosis and demonstrate these cells may be a relevant therapeutic target to prevent solid organ dysfunction following injury.

Lung Pericytes and Resident Fibroblasts

“…3,17,20,36,41 In support of this prospect, bleomycin lung injury reduces the number of ABCG2 þ MSCs, transferring exogenous MSCs ameliorates fibrosis, disabling the antioxidative functions of MSCs increases vulnerability to hypoxic stress, and fewer ABCG2 þ cells were detected in IPF than control samples from human donors. 17,36,41 However, MSCs also generate myofibroblasts and, although not tested in the lung, depletion of Gli1 þ MSCs reduces kidney and heart fibrosis.…”

“…3,5,17,20,36,41 ABCG2-expressing, or lineagemarked, NG2 À MSCs express mostly the same genes at similar levels as NG2 þ cells, but lower levels of Table 2). Dashed lines indicate additional hypotheses for the origins of a-smooth muscle actin (a-SMA) À pathogenic fibroblasts in injured lung.…”

“…37 In the mature lung, as well as kidney, liver, and heart, Gli1 expression is sustained within a small mesenchymal stem cell (MSC) subset of PDGFR-b þ perivascular and subepithelial cells that could differentiate into a-SMA þ myofibroblasts after lung injury. 20 Lineage tracing showed that these Gli1 þ MSCs do not express NG2 in healthy tissue nor do fibroblasts derived from them in the injured lung, yet >60% of pericytes in healthy lung express NG2. 10,20 Separate studies identified mesenchymal progenitors expressing the transcription factor FoxD1 transiently in posterior lung buds during early development.…”

“…20 Lineage tracing showed that these Gli1 þ MSCs do not express NG2 in healthy tissue nor do fibroblasts derived from them in the injured lung, yet >60% of pericytes in healthy lung express NG2. 10,20 Separate studies identified mesenchymal progenitors expressing the transcription factor FoxD1 transiently in posterior lung buds during early development. Lineage tracing of these FoxD1 progenitors, combined with a Col1 reporter system, identified four distinct mesenchymal populations in the healthy adult lung ( Figure 2 and Table 2): FoxD1 progenitor-derived Col1 À , FoxD1 progenitorderived Col1 þ , FoxD1-independent Col1 þ , and VSMC (referred to as FoxD1 þ /Col1 À , FoxD1 þ /Col1 þ , FoxD1 À / Col1 þ , and VSMC).…”

“…10 Perivascular Gli1 þ or ABCG2 þ MSCs also differentiate into myofibroblasts, although they might transition to become pericytes first. 17,20,41 Caveats apply to these data. Lineage tracing systems are limited by specificity, efficiency, and sensitivity.…”