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Microvesicles derived from human umbilical cord mesenchymal stem cells facilitate tubular epithelial cell dedifferentiation and growth via hepatocyte growth factor induction.

Ju GQ, Cheng J, Zhong L, Wu S, Zou XY, Zhang GY, Gu D, Miao S, Zhu YJ, Sun J, Du T - PLoS ONE (2015)

Bottom Line: In a rat model of unilateral AKI, the administration of MVs promoted kidney recovery.RNase treatment abrogated all MV effects.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

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.

No MeSH data available.


Related in: MedlinePlus

MV administration promotes tubular cell dedifferentiation and proliferation at 48 h post-injury, whereas cell apoptosis is inhibited.Representative micrographs showing vimentin, PCNA and TUNEL staining of tubular cells. Immuno-staining for vimentin and PCNA proteins, which are indictors for tubular cell dedifferentiation and cell proliferation, respectively, was employed. TUNEL staining was used to detect cell apoptosis. In contrast to the rats treated with vehicle or with RNase-MVs, the rats receiving MV treatment displayed more PCNA- and vimentin-positive stained tubular cells and fewer TUNEL-positive cells on kidney tissue sections. Magnification, ×40.
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pone.0121534.g002: MV administration promotes tubular cell dedifferentiation and proliferation at 48 h post-injury, whereas cell apoptosis is inhibited.Representative micrographs showing vimentin, PCNA and TUNEL staining of tubular cells. Immuno-staining for vimentin and PCNA proteins, which are indictors for tubular cell dedifferentiation and cell proliferation, respectively, was employed. TUNEL staining was used to detect cell apoptosis. In contrast to the rats treated with vehicle or with RNase-MVs, the rats receiving MV treatment displayed more PCNA- and vimentin-positive stained tubular cells and fewer TUNEL-positive cells on kidney tissue sections. Magnification, ×40.

Mentions: PCNA staining and vimentin staining in tubule cells were adopted as indicators for cell proliferation and dedifferentiation, respectively. At 48 h, MV administration greatly accelerated tubular cell dedifferentiation, in parallel with an increased number of proliferating tubular cells (P<0.05, Fig. 2). Additionally, tubular cell apoptosis was remarkably inhibited (P<0.05, Fig. 2). As expected, RNase pretreatment abolished these MV effects (P<0.05, Fig. 2). Tubular cell dedifferentiation is known to initiate cell growth and to protect cells against apoptosis [8], and our finding is consistent with this notion.


Microvesicles derived from human umbilical cord mesenchymal stem cells facilitate tubular epithelial cell dedifferentiation and growth via hepatocyte growth factor induction.

Ju GQ, Cheng J, Zhong L, Wu S, Zou XY, Zhang GY, Gu D, Miao S, Zhu YJ, Sun J, Du T - PLoS ONE (2015)

MV administration promotes tubular cell dedifferentiation and proliferation at 48 h post-injury, whereas cell apoptosis is inhibited.Representative micrographs showing vimentin, PCNA and TUNEL staining of tubular cells. Immuno-staining for vimentin and PCNA proteins, which are indictors for tubular cell dedifferentiation and cell proliferation, respectively, was employed. TUNEL staining was used to detect cell apoptosis. In contrast to the rats treated with vehicle or with RNase-MVs, the rats receiving MV treatment displayed more PCNA- and vimentin-positive stained tubular cells and fewer TUNEL-positive cells on kidney tissue sections. Magnification, ×40.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4368636&req=5

pone.0121534.g002: MV administration promotes tubular cell dedifferentiation and proliferation at 48 h post-injury, whereas cell apoptosis is inhibited.Representative micrographs showing vimentin, PCNA and TUNEL staining of tubular cells. Immuno-staining for vimentin and PCNA proteins, which are indictors for tubular cell dedifferentiation and cell proliferation, respectively, was employed. TUNEL staining was used to detect cell apoptosis. In contrast to the rats treated with vehicle or with RNase-MVs, the rats receiving MV treatment displayed more PCNA- and vimentin-positive stained tubular cells and fewer TUNEL-positive cells on kidney tissue sections. Magnification, ×40.
Mentions: PCNA staining and vimentin staining in tubule cells were adopted as indicators for cell proliferation and dedifferentiation, respectively. At 48 h, MV administration greatly accelerated tubular cell dedifferentiation, in parallel with an increased number of proliferating tubular cells (P<0.05, Fig. 2). Additionally, tubular cell apoptosis was remarkably inhibited (P<0.05, Fig. 2). As expected, RNase pretreatment abolished these MV effects (P<0.05, Fig. 2). Tubular cell dedifferentiation is known to initiate cell growth and to protect cells against apoptosis [8], and our finding is consistent with this notion.

Bottom Line: In a rat model of unilateral AKI, the administration of MVs promoted kidney recovery.RNase treatment abrogated all MV effects.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.

View Article: PubMed Central - PubMed

Affiliation: Department of Urology, Shanghai Children's Medical Center, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.

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.

No MeSH data available.


Related in: MedlinePlus