Deficient repair response of IPF fibroblasts in a co-culture model of epithelial injury and repair

Prasad, Sony; Hogaboam, Cory M.; Járai, Gábor

doi:10.1186/1755-1536-7-7

Cited by 49 publications

(39 citation statements)

References 44 publications

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“…The fibroblasts with elevated PIM1 level demonstrated enlarged number of cells with a myofibroblast/CAFs-like phenotype when co-cultivated with epithelial cells, suggesting that PIM1 activity had a priming effect on the ability of these fibroblasts to differentiate into myofibroblasts in response to the stimuli produced by epithelial cells. This type of interaction between fibroblasts and epithelial cells, has been previously documented in fibroblast-keratinocytes or fibroblast-lung epithelial co-cultures (35, 36) where myofibroblast differentiation was induced. Also, a co-implantation assay demonstrated that human mammary fibroblasts progressively convert to myofibroblasts when fibroblast-epithelial cell mixtures were inoculated into animals (37).…”

Section: Discussionsupporting

confidence: 63%

Regulation of prostate stromal fibroblasts by the PIM1 protein kinase

Zemskova

Song

Cen

et al. 2015

Cellular Signalling

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The PIM1 oncogene is over-expressed in human prostate cancer epithelial cells. Importantly, we observe that in human hyperplastic and cancerous prostate glands PIM1 is also markedly elevated in prostate fibroblasts, suggesting an important role for this kinase in epithelial/stromal crosstalk. The ability of PIM1 to regulate the biologic activity of stromal cells is demonstrated by the observation that expression of PIM1 kinase in human prostate fibroblasts increases the level and secretion of the extracellular matrix molecule, collagen 1A1 (COL1A1), the pro-inflammatory chemokine CCL5, and the platelet-derived growth factor receptors (PDGFR). PIM1 is found to regulate the transcription of CCL5. In co-cultivation assays where PIM1 overexpressing fibroblasts are grown with BPH1 prostate epithelial cells, PIM1 activity markedly enhances the ability of these fibroblasts to differentiate into myofibroblasts and express known markers of cancer-associated fibroblasts (CAFs). This differentiation can be reversed by the addition of small molecule PIM kinase inhibitors. Western blots demonstrate that PIM1 expression in prostate fibroblasts stimulates the phosphorylation of molecules that regulate 5’Cap driven protein translation, including 4EBP1 and eIF4B. Consistent with the hypothesis that the kinase controls translation of specific mRNAs in prostate fibroblasts, we demonstrate that PIM1 expression markedly increases the level of COL1A1 and PDGFRβ mRNA bound to polysomes. Together these results point on PIM1 as a novel factor in regulation of the phenotype and differentiation of fibroblasts in prostate cancer by controlling both the transcription and translation of specific mRNAs.

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Section: Discussionsupporting

confidence: 63%

Regulation of prostate stromal fibroblasts by the PIM1 protein kinase

Zemskova

Song

Cen

et al. 2015

Cellular Signalling

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“…However, the same study and others reported decreased [87–89] or unchanged [90] rates of proliferation in fibroblasts isolated specifically from IPF lung tissue. These studies also reported that IPF fibroblasts have decreased responsiveness to mitogens including serum and PDGF [87–90]. Moreover, evidence demonstrating robust cell proliferation within fibroblastic foci of IPF lung biopsies is lacking [29, 32, 91].…”

Section: Fibrotic Lung Mesenchymal Cells and The Hallmarks Of Cancermentioning

confidence: 70%

“…In one study, fibroblasts isolated from patients with active alveolitis (including both IPF and sarcoidosis) had increased proliferative rates [87]. However, the same study and others reported decreased [87–89] or unchanged [90] rates of proliferation in fibroblasts isolated specifically from IPF lung tissue. These studies also reported that IPF fibroblasts have decreased responsiveness to mitogens including serum and PDGF [87–90].…”

Section: Fibrotic Lung Mesenchymal Cells and The Hallmarks Of Cancermentioning

confidence: 99%

“Scar-cinoma”: viewing the fibrotic lung mesenchymal cell in the context of cancer biology

et al. 2016

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Lung cancer and pulmonary fibrosis are common, yet distinct, pathological processes that represent urgent unmet medical needs. Striking clinical and mechanistic parallels exist between these distinct disease entities. The goal of this article is to examine lung fibrosis from the perspective of cancer-associated phenotypic hallmarks, to discuss areas of mechanistic overlap and distinction, and to highlight profibrotic mechanisms that contribute to carcinogenesis. Ultimately, we speculate that such comparisons might identify opportunities to leverage our current understanding of the pathobiology of each disease process in order to advance novel therapeutic approaches for both. We anticipate that such “outside the box” concepts could be translated to a more precise and individualised approach to fibrotic diseases of the lung.

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“…28,37,60 To coat the microsphere templates with cells, A549 cells and fibronectin-loaded microspheres were combined in an ultra-low adhesion 24-well plate and incubated on an orbital shaker. The wells were monitored by bright field microscopy, and cells were shown to completely cover the microspheres within 24 hours (Fig.…”

Section: Resultsmentioning

confidence: 99%

In vitro model alveoli from photodegradable microsphere templates

et al. 2015

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Recreating the 3D cyst-like architecture of the alveolar epithelium in vitro has been challenging to achieve in a controlled fashion with primary lung epithelial cells. Here, we demonstrate model alveoli formed within a tunable synthetic biomaterial platform using photodegradable microspheres as templates to create physiologically relevant, cyst structures. Poly(ethylene glycol) (PEG)-based hydrogels were polymerized in suspension to form microspheres on the order of 120 μm in diameter. The gel chemistry was designed to allow erosion of the microspheres with cytocompatible light doses (≤15 min exposure to 10 mW cm−2 of 365 nm light) via cleavage of a photolabile nitrobenzyl ether crosslinker. Epithelial cells were incubated with intact microspheres, modified with adhesive peptide sequences to facilitate cellular attachment to and proliferation on the surface. A tumor-derived alveolar epithelial cell line, A549, completely covered the microspheres after only 24 hours, whereas primary mouse alveolar epithelial type II (ATII) cells took ~3 days. The cell-laden microsphere structures were embedded within a second hydrogel formulation at user defined densities; the microsphere templates were subsequently removed with light to render hollow epithelial cysts that were cultured for an additional 6 days. The resulting primary cysts stained positive for cell–cell junction proteins (β-catenin and ZO-1), indicating the formation of a functional epithelial layer. Typically, primary ATII cells differentiated in culture to the alveolar epithelial type I (ATI) phenotype; however, each cyst contained ~1–5 cells that stained positive for an ATII marker (surfactant protein C), which is consistent with ATII cell numbers in native mouse alveoli. This biomaterial-templated alveoli culture system should be useful for future experiments to study lung development and disease progression, and is ideally suited for co-culture experiments where pulmonary fibroblasts or endothelial cells could be presented in the hydrogel surrounding the epithelial cysts.

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Deficient repair response of IPF fibroblasts in a co-culture model of epithelial injury and repair

Cited by 49 publications

References 44 publications

Regulation of prostate stromal fibroblasts by the PIM1 protein kinase

Regulation of prostate stromal fibroblasts by the PIM1 protein kinase

“Scar-cinoma”: viewing the fibrotic lung mesenchymal cell in the context of cancer biology

In vitro model alveoli from photodegradable microsphere templates

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