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Mesenchymal stem cell-derived microvesicles protect against acute tubular injury
Stefania Bruno1, Cristina Grange, Maria Chiara Deregibus
1Department of Internal Medicine, Research Center for Experimental Medicine, University of Torino, Torino, Italy.
Abstract:
Administration of mesenchymal stem cells (MSCs) improves the recovery from acute kidney injury (AKI). The mechanism may involve paracrine factors promoting proliferation of surviving intrinsic epithelial cells, but these factors remain unknown. In the current study, we found that microvesicles derived from human bone marrow MSCs stimulated proliferation in vitro and conferred resistance of tubular epithelial cells to apoptosis. The biologic action of microvesicles required their CD44- and beta1-integrin-dependent incorporation into tubular cells. In vivo, microvesicles accelerated the morphologic and functional recovery of glycerol-induced AKI in SCID mice by inducing proliferation of tubular cells. The effect of microvesicles on the recovery of AKI was similar to the effect of human MSCs. RNase abolished the aforementioned effects of microvesicles in vitro and in vivo, suggesting RNA-dependent biologic effects. Microarray analysis and quantitative real time PCR of microvesicle-RNA extracts indicate that microvesicles shuttle a specific subset of cellular mRNA, such as mRNAs associated with the mesenchymal phenotype and with control of transcription, proliferation, and immunoregulation. These results suggest that microvesicles derived from MSCs may activate a proliferative program in surviving tubular cells after injury via a horizontal transfer of mRNA.
Insights
Mesenchymal stem cell (MSC)-derived microvesicles promote kidney repair after acute kidney injury (AKI) by transferring mRNA to tubular cells, enhancing their proliferation and survival. These microvesicles offer a cell-free therapeutic approach for AKI recovery.
Area of Science:
- Regenerative Medicine
- Cell Biology
- Nephrology
Background:
- Mesenchymal stem cells (MSCs) aid recovery from acute kidney injury (AKI).
- The exact mechanisms, potentially involving paracrine factors, are not fully understood.
- Identifying these factors is crucial for developing targeted therapies.
Purpose of the Study:
- To investigate the role of microvesicles derived from human bone marrow MSCs in AKI recovery.
- To elucidate the mechanisms by which MSC-derived microvesicles exert their therapeutic effects.
- To determine if these microvesicles can serve as a cell-free therapeutic agent for AKI.
Main Methods:
- Isolation and characterization of microvesicles from human bone marrow MSCs.
- In vitro studies assessing microvesicle effects on tubular epithelial cell proliferation and apoptosis.
- In vivo experiments using a glycerol-induced AKI mouse model to evaluate microvesicle efficacy.
- RNA analysis (microarray, qRT-PCR) of microvesicles to identify transferred RNA species.
Main Results:
- MSC-derived microvesicles stimulated tubular cell proliferation and conferred resistance to apoptosis in vitro.
- Microvesicle uptake by tubular cells was dependent on CD44 and beta1-integrin.
- In vivo, microvesicles accelerated functional and morphological recovery from AKI, mimicking MSC effects.
- RNase treatment abolished microvesicle effects, indicating RNA-dependent mechanisms.
- Microvesicles were found to shuttle specific mRNAs related to mesenchymal phenotype, transcription, proliferation, and immunoregulation.
Conclusions:
- MSC-derived microvesicles promote AKI recovery by enhancing tubular cell proliferation and survival.
- The therapeutic action of microvesicles is mediated by horizontal mRNA transfer to recipient tubular cells.
- MSC-derived microvesicles represent a promising cell-free therapeutic strategy for acute kidney injury.
