Mast-Cell Tryptase Release Contributes to Disease Progression in Lymphangioleiomyomatosis

Babaei‐Jadidi, Roya; Dongre, Arundhati; Miller, Suzanne; Uribe, Marcos Castellanos; Stewart, Iain; Thompson, Zoe M; Nateri, Abdolrahman S.; Bradding, Peter; May, Sean; Clements, Debbie; Johnson, Simon R.

doi:10.1164/rccm.202007-2854oc

Cited by 17 publications

(21 citation statements)

References 49 publications

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“…Our previous analysis of primary LAM-associated fibroblasts exposed in vitro to 621-101 TSC2 À/À cells revealed numerous transcriptional changes (25). Here we identify elevated expression of the epithelial chemokine and mitogen FGF7 in LAFs exposed to 621-101 TSC2 À/À cells and observe expression of FGF7 in LAM lesions.…”

Section: Discussionsupporting

confidence: 49%

“…Previously, we showed that the composition of LAM nodules is heterogeneous, and evolves as lung disease worsens, with tuberin-deficient LAM cells becoming progressively outnumbered by LAM-associated fibroblasts (22). Furthermore, we determined that LAFs cocultured with TSC2 À/À LAM-derived cells underwent significant transcriptional changes, including upregulation of inflammatory cytokines and other growth factors (25). Both Guo et al in LAM-associated AT2 cells relative to cells derived from normal lung using single-cell sequencing.…”

Section: Discussionmentioning

confidence: 90%

“…We sought to identify soluble factors which could mediate the observed effects of LAFs on epithelial cells. Previously, we examined how TSC2 null LAM-derived cells affect the transcriptional profile of lung fibroblasts (25). In primary LAFs derived from human LAM lungs cultured with LAMderived TSC2 null 621-101 cells, we observed that transcription of FGF7, a known chemotactic and mitogenic factor for epithelial cells, was elevated in LAFs cocultured with 621-101 cells when compared with LAFs cultured alone (fold change = 1.9, P = 0.0268).…”

Section: Tsc2-null Cells Upregulate Fgf7 Expression In Lafsmentioning

confidence: 97%

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Cross talk between LAM cells and fibroblasts may influence alveolar epithelial cell behavior in lymphangioleiomyomatosis

Clements

Miller

Babaei‐Jadidi

et al. 2022

American Journal of Physiology-Lung Cellular and Molecular Phys

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Lymphangioleiomyomatosis (LAM) is a female specific cystic lung disease in which TSC2 deficient LAM cells, LAM-Associated Fibroblasts (LAFs) and other cell types infiltrate the lungs. LAM lesions can be associated with type II alveolar epithelial cells (AT2 cells). We hypothesised that the behaviour of AT2 cells in LAM is influenced locally by LAFs. We tested this hypothesis in patient samples and in vitro. In human LAM lung, nodular AT2 cells show enhanced proliferation when compared to parenchymal AT2 cells, demonstrated by increased Ki67 expression. Further, nodular AT2 cells express proteins associated with epithelial activation in other disease states including Matrix Metalloproteinase 7, and Fibroblast Growth Factor 7 (FGF7). In vitro, LAF conditioned medium is mitogenic and positively chemotactic for epithelial cells, increases the rate of epithelial repair and protects against apoptosis. In vitro, LAM patient-derived TSC2 null cells cocultured with LAFs upregulate LAF expression of the epithelial chemokine and mitogen FGF7, which is a potential mediator of fibroblast-epithelial crosstalk, in an mTOR dependent manner. In a novel in vitro model of LAM, ex vivo cultured LAM lung-derived microtissues promote both epithelial migration and adhesion. Our findings suggest that AT2 cells in LAM display a proliferative, activated phenotype and that fibroblast accumulation following LAM cell infiltration into the parenchyma contributes to this change in AT2 cell behaviour. Fibroblast-derived FGF7 may contribute to the cross-talk between LAFs and hyperplastic epithelium in vivo, but does not appear to be the main driver of the effects of LAFs on epithelial cells in vitro.

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Section: Discussionsupporting

confidence: 49%

Section: Discussionmentioning

confidence: 90%

Section: Tsc2-null Cells Upregulate Fgf7 Expression In Lafsmentioning

confidence: 97%

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Cross talk between LAM cells and fibroblasts may influence alveolar epithelial cell behavior in lymphangioleiomyomatosis

Clements

Miller

Babaei‐Jadidi

et al. 2022

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…LAM cells have biallelic loss-of-function mutations in tuberous sclerosis complex (TSC) 1 or 2, which act to inhibit the mechanistic target of rapamycin complex 1 (mTORC1). LAM cells aberrantly express proteases (predominantly matrix metalloproteinase (MMP) 2 and 9 [ 3 – 5 ] and cathepsin K (CTSK)), which have collagenolytic activity [ 6 ] and may contribute directly to lung degradation and cyst formation [ 7 – 9 ]. Consistent with the role of mTORC1 in this disease process, rapamycin is the standard of care for patients with LAM [ 10 , 11 ].…”

Section: Introductionmentioning

confidence: 99%

Protease activity sensors enable real-time treatment response monitoring in lymphangioleiomyomatosis

et al. 2021

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Biomarkers of disease progression and treatment response are urgently needed for patients with lymphangioleiomyomatosis (LAM). Activity-based nanosensors, an emerging biosensor class, detect dysregulated proteases in vivo and release a reporter to provide a urinary readout of disease. Because proteases are dysregulated in LAM and may directly contribute to lung function decline, activity-based nanosensors may enable quantitative, real-time monitoring of LAM progression and treatment response. We aimed to assess the diagnostic utility of activity-based nanosensors in a preclinical model of pulmonary LAM.Tsc2-null cells were injected intravenously into female nude mice to establish a mouse model of pulmonary LAM. A library of 14 activity-based nanosensors, designed to detect proteases across multiple catalytic classes, was administered into the lungs of LAM mice and healthy controls, urine was collected, and mass spectrometry was performed to measure nanosensor cleavage products. Mice were then treated with rapamycin and monitored with activity-based nanosensors. Machine learning was performed to distinguish diseased from healthy and treated from untreated mice.Multiple activity-based nanosensors [PP03 (cleaved by metallo, aspartic, and cysteine proteases), padj<0.0001; PP10 (cleaved by serine, aspartic, and cysteine proteases), padj=0.017)] were differentially cleaved in diseased and healthy lungs, enabling strong classification with a machine learning model (AUC=0.95 from healthy). Within two days after rapamycin initiation, we observed normalisation of PP03 and PP10 cleavage, and machine learning enabled accurate classification of treatment response (AUC=0.94 from untreated).Activity-based nanosensors enable noninvasive, real-time monitoring of disease burden and treatment response in a preclinical model of LAM.

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“…In this issue of the Journal, Babaei-Jadidi and colleagues (pp. 431–444 ) have focused on the tumor microenvironment and identified a critical role for the mast cell in LAM nodule proliferation, adding an important and already targetable mTOR-independent pathway to the LAM armamentarium ( 17 ). The authors beautifully lay out a translational investigation by first identifying increased tryptase positive mast cell presence in LAM nodules, correlating with disease progression.…”

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confidence: 99%

Raising the Flag for Mast Cells as a Novel Target in Lymphangioleiomyomatosis

Goldklang

2021

Am J Respir Crit Care Med

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Mast-Cell Tryptase Release Contributes to Disease Progression in Lymphangioleiomyomatosis

Abstract: Author contributions: RB-J, AD, SM, ASN, ZMT, PB and DC performed the experimental work.AD, MCU, DC and STM performed the Affymetrix analysis. IDS performed statistical analysis, SRJ conceived the study, obtained the funding, saw the patients and is guarantor for the study.

Cited by 17 publications

References 49 publications

Cross talk between LAM cells and fibroblasts may influence alveolar epithelial cell behavior in lymphangioleiomyomatosis

Cross talk between LAM cells and fibroblasts may influence alveolar epithelial cell behavior in lymphangioleiomyomatosis

Protease activity sensors enable real-time treatment response monitoring in lymphangioleiomyomatosis

Raising the Flag for Mast Cells as a Novel Target in Lymphangioleiomyomatosis

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