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Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury.

Bruno S, Grange C, Collino F, Deregibus MC, Cantaluppi V, Biancone L, Tetta C, Camussi G - PLoS ONE (2012)

Bottom Line: The single administration of MVs ameliorated renal function and morphology, and improved survival but did not prevent chronic tubular injury and persistent increase in BUN and creatinine.The mechanism of protection was mainly ascribed to an anti-apoptotic effect of MVs.In conclusion, MVs released from MSCs were found to exert a pro-survival effect on renal cells in vitro and in vivo, suggesting that MVs may contribute to renal protection conferred by MSCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine and Molecular Biotechnology Center, University of Torino, Torino, Italy.

ABSTRACT
Several studies demonstrated that treatment with mesenchymal stem cells (MSCs) reduces cisplatin mortality in mice. Microvesicles (MVs) released from MSCs were previously shown to favor renal repair in non lethal toxic and ischemic acute renal injury (AKI). In the present study we investigated the effects of MSC-derived MVs in SCID mice survival in lethal cisplatin-induced AKI. Moreover, we evaluated in vitro the effect of MVs on cisplatin-induced apoptosis of human renal tubular epithelial cells and the molecular mechanisms involved. Two different regimens of MV injection were used. The single administration of MVs ameliorated renal function and morphology, and improved survival but did not prevent chronic tubular injury and persistent increase in BUN and creatinine. Multiple injections of MVs further decreased mortality and at day 21 surviving mice showed normal histology and renal function. The mechanism of protection was mainly ascribed to an anti-apoptotic effect of MVs. In vitro studies demonstrated that MVs up-regulated in cisplatin-treated human tubular epithelial cells anti-apoptotic genes, such as Bcl-xL, Bcl2 and BIRC8 and down-regulated genes that have a central role in the execution-phase of cell apoptosis such as Casp1, Casp8 and LTA. In conclusion, MVs released from MSCs were found to exert a pro-survival effect on renal cells in vitro and in vivo, suggesting that MVs may contribute to renal protection conferred by MSCs.

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Schematic representation of the protocol of cisplatin induced AKI and MV administration regimens and survival curves.A) Graph showing time-points of cisplatin administration, siMVs or miMVs and the time-points of sacrifice. B) Survival curves of SCID mice with cisplatin induced AKI treated with different regiments of MVs administration. All mice receiving vehicle alone died within 5 days. Mice that received siMVs or miMVs injections survived significantly longer than control mice treated with vehicle alone or with a si(RNase-inactivated)MVs. Data was analysed via a log-rank test: * p<0.05 siMV vs CIS; ** p<0.05 miMV vs siMV. Abbreviations: vehicle = cisplatin treated mice injected with vehicle alone; siMV = cisplatin treated mice with single injection of MVs; miMV = cisplatin treated mice with multiple injection of MVs; RNase MV = cisplatin treated mice injected with a single dose of MVs pre-treated with RNase.
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pone-0033115-g001: Schematic representation of the protocol of cisplatin induced AKI and MV administration regimens and survival curves.A) Graph showing time-points of cisplatin administration, siMVs or miMVs and the time-points of sacrifice. B) Survival curves of SCID mice with cisplatin induced AKI treated with different regiments of MVs administration. All mice receiving vehicle alone died within 5 days. Mice that received siMVs or miMVs injections survived significantly longer than control mice treated with vehicle alone or with a si(RNase-inactivated)MVs. Data was analysed via a log-rank test: * p<0.05 siMV vs CIS; ** p<0.05 miMV vs siMV. Abbreviations: vehicle = cisplatin treated mice injected with vehicle alone; siMV = cisplatin treated mice with single injection of MVs; miMV = cisplatin treated mice with multiple injection of MVs; RNase MV = cisplatin treated mice injected with a single dose of MVs pre-treated with RNase.

Mentions: SCID mice are known to be very sensitive to cisplatin treatment [3]. In our experimental setting, SCID mice invariably died within 5 days. Survival curves of SCID mice with AKI given vehicle alone or MVs are shown in figure 1 and table 1. Two regimens of MV administration were used. The single injection (siMVs) of 100 µg MVs 8 hours after cisplatin administration significantly increased survival to 60% at day 14 and 40% at day 21, in respect to mice treated with vehicle alone or with a single dose of RNase-inactivated MVs. Multiple injections of MVs (miMVs) (Figure 1) further increased survival to 80% at day 21.


Microvesicles derived from mesenchymal stem cells enhance survival in a lethal model of acute kidney injury.

Bruno S, Grange C, Collino F, Deregibus MC, Cantaluppi V, Biancone L, Tetta C, Camussi G - PLoS ONE (2012)

Schematic representation of the protocol of cisplatin induced AKI and MV administration regimens and survival curves.A) Graph showing time-points of cisplatin administration, siMVs or miMVs and the time-points of sacrifice. B) Survival curves of SCID mice with cisplatin induced AKI treated with different regiments of MVs administration. All mice receiving vehicle alone died within 5 days. Mice that received siMVs or miMVs injections survived significantly longer than control mice treated with vehicle alone or with a si(RNase-inactivated)MVs. Data was analysed via a log-rank test: * p<0.05 siMV vs CIS; ** p<0.05 miMV vs siMV. Abbreviations: vehicle = cisplatin treated mice injected with vehicle alone; siMV = cisplatin treated mice with single injection of MVs; miMV = cisplatin treated mice with multiple injection of MVs; RNase MV = cisplatin treated mice injected with a single dose of MVs pre-treated with RNase.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3303802&req=5

pone-0033115-g001: Schematic representation of the protocol of cisplatin induced AKI and MV administration regimens and survival curves.A) Graph showing time-points of cisplatin administration, siMVs or miMVs and the time-points of sacrifice. B) Survival curves of SCID mice with cisplatin induced AKI treated with different regiments of MVs administration. All mice receiving vehicle alone died within 5 days. Mice that received siMVs or miMVs injections survived significantly longer than control mice treated with vehicle alone or with a si(RNase-inactivated)MVs. Data was analysed via a log-rank test: * p<0.05 siMV vs CIS; ** p<0.05 miMV vs siMV. Abbreviations: vehicle = cisplatin treated mice injected with vehicle alone; siMV = cisplatin treated mice with single injection of MVs; miMV = cisplatin treated mice with multiple injection of MVs; RNase MV = cisplatin treated mice injected with a single dose of MVs pre-treated with RNase.
Mentions: SCID mice are known to be very sensitive to cisplatin treatment [3]. In our experimental setting, SCID mice invariably died within 5 days. Survival curves of SCID mice with AKI given vehicle alone or MVs are shown in figure 1 and table 1. Two regimens of MV administration were used. The single injection (siMVs) of 100 µg MVs 8 hours after cisplatin administration significantly increased survival to 60% at day 14 and 40% at day 21, in respect to mice treated with vehicle alone or with a single dose of RNase-inactivated MVs. Multiple injections of MVs (miMVs) (Figure 1) further increased survival to 80% at day 21.

Bottom Line: The single administration of MVs ameliorated renal function and morphology, and improved survival but did not prevent chronic tubular injury and persistent increase in BUN and creatinine.The mechanism of protection was mainly ascribed to an anti-apoptotic effect of MVs.In conclusion, MVs released from MSCs were found to exert a pro-survival effect on renal cells in vitro and in vivo, suggesting that MVs may contribute to renal protection conferred by MSCs.

View Article: PubMed Central - PubMed

Affiliation: Department of Internal Medicine and Molecular Biotechnology Center, University of Torino, Torino, Italy.

ABSTRACT
Several studies demonstrated that treatment with mesenchymal stem cells (MSCs) reduces cisplatin mortality in mice. Microvesicles (MVs) released from MSCs were previously shown to favor renal repair in non lethal toxic and ischemic acute renal injury (AKI). In the present study we investigated the effects of MSC-derived MVs in SCID mice survival in lethal cisplatin-induced AKI. Moreover, we evaluated in vitro the effect of MVs on cisplatin-induced apoptosis of human renal tubular epithelial cells and the molecular mechanisms involved. Two different regimens of MV injection were used. The single administration of MVs ameliorated renal function and morphology, and improved survival but did not prevent chronic tubular injury and persistent increase in BUN and creatinine. Multiple injections of MVs further decreased mortality and at day 21 surviving mice showed normal histology and renal function. The mechanism of protection was mainly ascribed to an anti-apoptotic effect of MVs. In vitro studies demonstrated that MVs up-regulated in cisplatin-treated human tubular epithelial cells anti-apoptotic genes, such as Bcl-xL, Bcl2 and BIRC8 and down-regulated genes that have a central role in the execution-phase of cell apoptosis such as Casp1, Casp8 and LTA. In conclusion, MVs released from MSCs were found to exert a pro-survival effect on renal cells in vitro and in vivo, suggesting that MVs may contribute to renal protection conferred by MSCs.

Show MeSH
Related in: MedlinePlus