The Pathology of Bleomycin-Induced Fibrosis Is Associated with Loss of Resident Lung Mesenchymal Stem Cells That Regulate Effector T-cell Proliferation

Abstract

Tissue resident mesenchymal stem cells (MSC) are important regulators of tissue repair or regeneration, fibrosis, inflammation, angiogenesis and tumor formation. Here we define a population of resident lung mesenchymal stem cells (luMSC) that function to regulate the severity of bleomycin injury via modulation of the T-cell response. Bleomycin induced loss of these endogenous luMSC and elicited fibrosis (PF), inflammation and pulmonary arterial hypertension (PAH). Replacement of resident stem cells by administration of isolated luMSC attenuated the bleomycin-associated pathology and mitigated the development of PAH. In addition, luMSC modulated a decrease in numbers of lymphocytes and granulocytes in bronchoalveolar fluid and demonstrated an inhibition of effector T cell proliferation in vitro. Global gene expression analysis indicated that the luMSC are a unique stromal population differing from lung fibroblasts in terms of proinflammatory mediators and pro-fibrotic pathways. Our results demonstrate that luMSCs function to protect lung integrity following injury however when endogenous MSC are lost this function is compromised illustrating the importance of this novel population during lung injury. The definition of this population in vivo in both murine and human pulmonary tissue facilitates the development of a therapeutic strategy directed at the rescue of endogenous cells to facilitate lung repair during 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. 20 Therefore, delivering or expanding MSCs may not be beneficial, or even detrimental, unless the signals stimulating their differentiation into myofibroblasts are first inhibited.…”

“…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.…”

“…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.…”

Mesenchymal Stem Cell Therapy Protects Lungs from Radiation-Induced Endothelial Cell Loss by Restoring Superoxide Dismutase 1 Expression

“…The reduced infiltration of myeloid cells with an assumed profibrotic phenotype here after MSC therapy highlighted the importance of the proper function of the vascular system to avoid fibrosis development. Interestingly, a normal function of resident MSCs in adult lungs is crucial for pulmonary tissue homeostasis as they contribute to the maintenance of tissue integrity by various mechanisms (39,53,55). As an example, endogenous lung MSCs normally exert anti-inflammatory properties; these are, however, negatively affected by bleomycin treatment, thereby contributing to fibrosis development in a murine model of bleomycin-induced fibrosis (39).…”

Shared Gene Expression Patterns in Mesenchymal Progenitors Derived from Lung and Epidermis in Pulmonary Arterial Hypertension: Identifying Key Pathways in Pulmonary Vascular Disease

“…[13][14][15] We have identified ABCG2 MPCs as a noncontractile pericyte precursor population. These MPCs support microvessels during homeostasis and contribute to remodeled microvasculature and parenchyma after injury.…”