Editors' ChoiceLUNG FIBROSIS

Matrix in the Driver’s Seat

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Science Translational Medicine  16 Apr 2014:
Vol. 6, Issue 232, pp. 232ec68
DOI: 10.1126/scitranslmed.3009249

Idiopathic pulmonary fibrosis, or IPF, is a chronic and fatal lung disease characterized by progressive lung scarring and lung function decline. IPF is a result of abnormal and excessive proliferation of activated fibroblasts. It also involves abnormal remodeling of the extracellular matrix (ECM) with excessive collagen deposition in the lung. Even though it is known that fibroblasts and ECM are abnormal and play important roles in this devastating disease, their relative contribution to the pathogenic fibrotic process is unclear. Surprisingly, little is known about how a diseased ECM affects fibroblast gene expression. Does fibrosis result from defective fibroblast cells, a diseased ECM, or both? Insights into this important question will help focus the search for therapeutic targets in IPF.

Parker et al. set out to address this question using genome-wide profiling of both steady-state transcripts (transcriptome) and polysome-associated RNAs that are enriched for translated mRNAs (translatome). They isolated primary fibroblasts from IPF and control patients and cultured on either decellularized lung ECM from either IPF or control patients in vitro. They showed that the predominant driver of the pathological fibrotic gene expression response was the diseased ECM and not the diseased fibroblast cells. ECM from diseased fibrotic lungs was able to drive control healthy fibroblasts to pathological gene expression. Interestingly, the ECM-driven gene expression was primarily modulated at the translational control level and not at the transcription level. Furthermore, the genes activated by the IPF ECM were enriched for ECM proteins, such as collagen and laminin, commonly found in IPF lung, suggesting that IPF ECM can help drive the expression of fibrotic genes.

To determine what regulates the pathological ECM translational process, the investigators focused on microRNAs that can negatively regulate mRNA translation. Translation profiling of genes, whose proteins were present in IPF lung ECM, identified multiple targets for miR-29 which was downregulated in fibroblasts grown in IPF-derived ECMs. In fact, these miR-29–targeted IPF proteins (many of which have been implicated in pulmonary fibrosis) were more likely to be translationally regulated by IPF ECM. Downregulation of miR-29 is not only important in IPF but also in other fibrotic diseases. Overexpression of miR-29c in IPF fibroblasts by lentivirus infection restored potentially pathological fibrotic gene expression to baseline levels, opening up the possibility of this microRNA or this ECM-directed pathway as potential viable therapeutic target for IPF. Their overall model highlights the importance of how the ECM by itself can alter fibroblasts and affect the fibrogenic process that leads to disease. How the altered matrix affects miR-29 expression remains to be determined and is an exciting area of research to explore. This work also highlights the value of decellularization technologies on human diseased tissues to better understand the ECM-cellular interaction, potentially moving the matrix to the driver’s seat in the pathogenesis of many disease processes.

M. W. Parker et al., Fibrotic extracellular matrix activates a profibrotic positive feedback loop. J. Clin. Invest. 124, 1622–1635 (2014). [Full Text]

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