Abstract
During acute kidney injury (AKI), tubular cell dedifferentiation initiates cell regeneration; hepatocyte growth factor (HGF) is involved in modulating cell dedifferentiation. Mesenchymal stem cell (MSC)-derived microvesicles (MVs) deliver RNA into injured tubular cells and alter their gene expression, thus regenerating these cells. We boldly speculated that MVs might induce HGF synthesis via RNA transfer, thereby facilitating tubular cell dedifferentiation and regeneration. In a rat model of unilateral AKI, the administration of MVs promoted kidney recovery. One of the mechanisms of action is the acceleration of tubular cell dedifferentiation and growth. Both in vivo and in vitro, rat HGF expression in damaged rat tubular cells was greatly enhanced by MV treatment. In addition, human HGF mRNA present in MVs was delivered into rat tubular cells and translated into the HGF protein as another mechanism of HGF induction. RNase treatment abrogated all MV effects. In the in vitro experimental setting, the conditioned medium of MV-treated injured tubular cells, which contains a higher concentration of HGF, strongly stimulated cell dedifferentiation and growth, as well as Erk1/2 signaling activation. Intriguingly, these effects were completely abrogated by either c-Met inhibitor or MEK inhibitor, suggesting that HGF induction is a crucial contributor to the acceleration of cell dedifferentiation and growth. All these findings indicate that MV-induced HGF synthesis in damaged tubular cells via RNA transfer facilitates cell dedifferentiation and growth, which are important regenerative mechanisms.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Acute Kidney Injury / genetics
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Acute Kidney Injury / pathology
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Animals
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Apoptosis / drug effects
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Cell Dedifferentiation* / drug effects
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Cell Proliferation / drug effects
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Cell-Derived Microparticles / drug effects
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Cell-Derived Microparticles / metabolism*
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Culture Media, Conditioned / pharmacology
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Epithelial Cells / cytology*
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Epithelial Cells / drug effects
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Epithelial Cells / metabolism
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Hepatocyte Growth Factor / genetics
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Hepatocyte Growth Factor / metabolism*
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Humans
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Hypoxia / pathology
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Ischemia / pathology
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Kidney Tubules / cytology*
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Male
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Mesenchymal Stem Cells / cytology*
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Mesenchymal Stem Cells / drug effects
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Mesenchymal Stem Cells / metabolism
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Mitogen-Activated Protein Kinase Kinases / antagonists & inhibitors
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Mitogen-Activated Protein Kinase Kinases / metabolism
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Oxygen / metabolism
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Protein Biosynthesis / drug effects
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Protein Kinase Inhibitors / pharmacology
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Proto-Oncogene Proteins c-met / antagonists & inhibitors
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Proto-Oncogene Proteins c-met / metabolism
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RNA, Messenger / genetics
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RNA, Messenger / metabolism
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Rats, Sprague-Dawley
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Umbilical Cord / cytology*
Substances
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Culture Media, Conditioned
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Protein Kinase Inhibitors
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RNA, Messenger
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Hepatocyte Growth Factor
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Proto-Oncogene Proteins c-met
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Mitogen-Activated Protein Kinase Kinases
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Oxygen
Grants and funding
This study is supported by grants from the National Natural Science Foundation of China (81170642, 81270689), and the Research Program of Science and Technology Commission of Shanghai Municipality (12ZR1419200). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.