Lung Bone Marrow–derived Hematopoietic Progenitor Cells Enhance Pulmonary Fibrosis

Nakashima, Toshikatsu; Liu, Tianju; Yu, Hongfeng; Ding, Lin; Ullenbruch, Matthew; Hu, Biao; Wu, Zhe; Oguro, Hideyuki; Phan, Sem H.

doi:10.1164/rccm.201303-0479oc

Cited by 26 publications

(33 citation statements)

References 35 publications

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“…Given the BLM-induced recruitment of BM CD11c + cells into the lung as reported previously (18, 35), we evaluated the role of these cells in pulmonary fibrosis in vivo . The effect of depleting these cells on the BLM model was examined using CD11c-DTR BM chimera mice.…”

Section: Resultsmentioning

confidence: 92%

“…This is consistent with a previous report showing that human and mouse DCs, which express CD11c, are a source of AREG (17), while human lung tumor-associated DCs secrete high levels of AREG and promote cancer progression (16). Recently BM-derived cells recruited to BLM injured lung are found to be significantly increased in number, and they are mostly MHCII + CD11c + cells (28, 35). Notably, adoptive transfer of these cells exacerbates pulmonary fibrosis.…”

Section: Discussionmentioning

confidence: 99%

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Bone Marrow CD11c+ Cell–Derived Amphiregulin Promotes Pulmonary Fibrosis

Ding

Liu

et al. 2016

The Journal of Immunology

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Amphiregulin (AREG), an epidermal growth factor receptor ligand, is implicated in tissue repair and fibrosis but its cellular source and role in regeneration vs. fibrosis remain unclear. In this study we hypothesize that AREG induced in bone marrow derived CD11c+ cells is essential for pulmonary fibrosis. Thus the objectives were to evaluate the importance and role of AREG in pulmonary fibrosis, identify the cellular source of AREG induction and analyze its regulation of fibroblast function and activation. The results showed that lung AREG expression was significantly induced in bleomycin-induced pulmonary fibrosis. AREG deficiency in knockout (KO) mice significantly diminished pulmonary fibrosis. Analysis of AREG expression in major lung cell types revealed induction in fibrotic lungs predominantly occurred in CD11c+ cells. Moreover depletion of bone marrow derived CD11c+ cells suppressed both induction of lung AREG expression and pulmonary fibrosis. Conversely, adoptive transfer of bone marrow-derived CD11c+ cells from BLM-treated donor mice exacerbated pulmonary fibrosis but not if the donor cells were made AREG-deficient prior to transfer. CD11c+ cell conditioned media or co-culture stimulated fibroblast proliferation, activation and myofibroblast differentiation in an AREG dependent manner. Furthermore recombinant AREG induced telomerase reverse transcriptase (TERT) which appeared to be essential for the proliferative effect. Finally AREG significantly enhanced fibroblast motility, which was associated with increased expression of α6 integrin. These findings suggested that induced AREG specifically in recruited bone marrow-derived CD11c+ cells promoted bleomycin induced pulmonary fibrosis by activation of fibroblast TERT dependent proliferation, motility and indirectly, myofibroblast differentiation.

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Section: Resultsmentioning

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Bone Marrow CD11c+ Cell–Derived Amphiregulin Promotes Pulmonary Fibrosis

Ding

Liu

et al. 2016

The Journal of Immunology

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“…To date the origin of myofibroblasts in the lung are theorized to be epithelial cells (EC) via epithelial-tomesenchymal transition as well as bone marrow sources (69,77,78,84,87,98). Pericytes are defined by anatomical location adjacent to vascular endothelium and in capillary beds contact EC discontinuities in basement membranes (14,15).…”

Section: Abcg2mentioning

confidence: 99%

ABCG2^pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling

Marriott

Baskir

Gaskill

et al. 2014

American Journal of Physiology-Cell Physiology

115

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“…Consistent with the importance of bone marrow-derived leukocytes in PH pathogenesis, a recent study has shown that TGF-β activation in the lungs by hematopoietic cell-derived thrombospondin-1 triggers Schistosoma mansoni -induced PH [76]. Prior work has suggested that expansion of lung macrophages in PH is dependent on circulating progenitors originated in the bone marrow[2, 77, 78]. However, the contribution of hematopoietic stem cells (HSCs) in the origin of inflammatory perivascular lung macrophages in pulmonary hypertension is unknown.…”

Section: Importance Of Bone Marrow-derived Cells In Ph Pathogenesismentioning

confidence: 90%

Origin and production of inflammatory perivascular macrophages in pulmonary hypertension

Florentin

Dutta

2017

Cytokine

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Myeloid cells, including monocytes and macrophages participate in steady state immune homeostasis and help mount the adaptive immune response during infection. The function and production of these cells in sterile inflammation, such as pulmonary hypertension (PH), is understudied. Emerging data indicate that pulmonary inflammation mediated by lung perivascular macrophages is a key pathogenic driver of pulmonary remodeling leading to increased right ventricular systolic pressure (RVSP). However, the origin of these macrophages in pulmonary inflammation is unknown. Inflammatory monocytes, the precursors of pathogenic macrophages, are derived from hematopoietic stem and progenitor cells (HSPC) in the bone marrow and spleen during acute and chronic inflammation. Understanding the role of these organs in monocytopoiesis, and the mechanisms of HSPC proliferation and differentiation in PH are important to discover therapeutic targets curbing inflammation. This review will summarize the current limited knowledge of the origin of lung macrophage subsets and over-production of inflammatory monocytes in PH.

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Lung Bone Marrow–derived Hematopoietic Progenitor Cells Enhance Pulmonary Fibrosis

Cited by 26 publications

References 35 publications

Bone Marrow CD11c+ Cell–Derived Amphiregulin Promotes Pulmonary Fibrosis

Bone Marrow CD11c+ Cell–Derived Amphiregulin Promotes Pulmonary Fibrosis

ABCG2^pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling

Origin and production of inflammatory perivascular macrophages in pulmonary hypertension

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Lung Bone Marrow–derived Hematopoietic Progenitor Cells Enhance Pulmonary Fibrosis

Cited by 26 publications

References 35 publications

Bone Marrow CD11c+ Cell–Derived Amphiregulin Promotes Pulmonary Fibrosis

Bone Marrow CD11c+ Cell–Derived Amphiregulin Promotes Pulmonary Fibrosis

ABCG2pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling

Origin and production of inflammatory perivascular macrophages in pulmonary hypertension

Contact Info

Product

Resources

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ABCG2^pos lung mesenchymal stem cells are a novel pericyte subpopulation that contributes to fibrotic remodeling