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Forefront: MiR-34a-Knockout Mice with Wild Type Hematopoietic Cells, Retain Persistent Fibrosis Following Lung Injury

1
Lung Cellular and Molecular Biology Laboratory, Institute of Pulmonary Medicine, Hadassah—Hebrew University Medical Center, POB 12000, Jerusalem 9112102, Israel
2
The Lautenberg Center for Immunology and Cancer Research, Institute of Medical Research Israel-Canada, Hadassah Hebrew University Medical Center, Jerusalem 9112102, Israel
3
Department of Pathology and Laboratory Medicine, 670 Albany St, 4th Floor, Boston University School of Medicine, Boston, MA 02118, USA
*
Author to whom correspondence should be addressed.
Int. J. Mol. Sci. 2020, 21(6), 2228; https://doi.org/10.3390/ijms21062228
Received: 23 February 2020 / Revised: 15 March 2020 / Accepted: 19 March 2020 / Published: 23 March 2020
MicroRNAs (miRs) are known to limit gene expression at the post-transcriptional level and have important roles in the pathogenesis of various conditions, including acute lung injury (ALI) and fibrotic diseases such as idiopathic pulmonary fibrosis (IPF). In this study, we found increased levels of miR-34 at times of fibrosis resolution following injury, in myofibroblasts from Bleomycin-treated mouse lungs, which correlates with susceptibility to cell death induced by immune cells. On the contrary, a substantial downregulation of miR-34 was detected at stages of evolution, when fibroblasts resist cell death. Concomitantly, we found an inverse correlation between miR-34 levels with that of the survival molecule FLICE-like inhibitory protein (FLIP) in lung myofibroblasts from humans with IPF and the experimental model. Forced upregulation of miR-34 with miR-34 mimic in human IPF fibrotic-lung myofibroblasts led to decreased cell survival through downregulation of FLIP. Using chimeric miR-34 knock-out (KO)-C57BL/6 mice with miR34KO myofibroblasts but wild-type (WT) hematopoietic cells, we found, in contrast to WT mice, increased and persistent FLIP levels with a more severe fibrosis and with no signs of resolution as detected in pathology and collagen accumulation. Moreover, a mimic of miR-34a decreased FLIP expression and susceptibility to cell death was regained in miR-34KO fibroblasts. Through this study, we show for the first time an inverse correlation between miR-34a and FLIP expression in myofibroblasts, which affects survival, and accumulation in lung fibrosis. Reprogramming fibrotic-lung myofibroblasts to regain susceptibility to cell-death by specifically increasing their miR34a and downregulating FLIP, may be a useful strategy, enabling tissue regeneration following lung injury. View Full-Text
Keywords: miR34; FLIP; acute lung injury; cell-death; fibroblasts/myofibroblasts; fibrosis resolution; idiopathic pulmonary fibrosis miR34; FLIP; acute lung injury; cell-death; fibroblasts/myofibroblasts; fibrosis resolution; idiopathic pulmonary fibrosis
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Bulvik, R.; Biton, M.; Berkman, N.; Breuer, R.; Wallach-Dayan, S.B. Forefront: MiR-34a-Knockout Mice with Wild Type Hematopoietic Cells, Retain Persistent Fibrosis Following Lung Injury. Int. J. Mol. Sci. 2020, 21, 2228.

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