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Ultrasound-targeted stromal cell-derived factor-1-loaded microbubble destruction promotes mesenchymal stem cell homing to kidneys in diabetic nephropathy rats.

Wu S, Li L, Wang G, Shen W, Xu Y, Liu Z, Zhuo Z, Xia H, Gao Y, Tan K - Int J Nanomedicine (2014)

Bottom Line: The related bioeffects were also elucidated.In the in vivo study, SDF-1 was successfully released in the targeted kidneys.In conclusion, ultrasound-targeted MB(SDF-1) destruction could promote the homing of MSCs to early DN kidneys and provide a novel potential therapeutic approach for DN kidney repair.

View Article: PubMed Central - PubMed

Affiliation: Department of Ultrasound, Third Military Medical University, Chongqing, People's Republic of China.

ABSTRACT
Mesenchymal stem cell (MSC) therapy has been considered a promising strategy to cure diabetic nephropathy (DN). However, insufficient MSCs can settle in injured kidneys, which constitute one of the major barriers to the effective implementation of MSC therapy. Stromal cell-derived factor-1 (SDF-1) plays a vital role in MSC migration and involves activation, mobilization, homing, and retention, which are presumably related to the poor homing in DN therapy. Ultrasound-targeted microbubble destruction has become one of the most promising strategies for the targeted delivery of drugs and genes. To improve MSC homing to DN kidneys, we present a strategy to increase SDF-1 via ultrasound-targeted microbubble destruction. In this study, we developed SDF-1-loaded microbubbles (MB(SDF-1)) via covalent conjugation. The characterization and bioactivity of MB(SDF-1) were assessed in vitro. Target release in the targeted kidneys was triggered with diagnostic ultrasound in combination with MB(SDF-1). The related bioeffects were also elucidated. Early DN was induced in rats with streptozotocin. Green fluorescent protein-labeled MSCs were transplanted intravenously following the target release of SDF-1 in the kidneys of normal and DN rats. The homing efficacy was assessed by detecting the implanted exogenous MSCs at 24 hours. The in vitro results showed an impressive SDF-1 loading efficacy of 79% and a loading content of 15.8 μg/mL. MB(SDF-1) remained bioactive as a chemoattractant. In the in vivo study, SDF-1 was successfully released in the targeted kidneys. The homing efficacy of MSCs to DN kidneys after the target release of SDF-1 was remarkably ameliorated at 24 hours compared with control treatments in normal rats and DN rats. In conclusion, ultrasound-targeted MB(SDF-1) destruction could promote the homing of MSCs to early DN kidneys and provide a novel potential therapeutic approach for DN kidney repair.

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In vivo detection of implanted exogenous MSCs.Notes: Number of implanted exogenous MSCs in normal and DN kidneys 24 hours after group treatments. (A) The differences of implanted MSCs among groups under a confocal laser scanning microscope. Exogenous MSCs were labeled with GFP and displayed green signals. In normal rats, GFP-labeled MSCs were only occasionally detected in all three groups. In DN rats, GFP-labeled MSCs were rare in control group. UTMD increased the exogenous MSCs and UTMD + SDF-1 greatly improved the homing of exogenous MSCs. The white bar indicates 50 μm. (B) The histogram comparison of the GFP-labeled MSCs among groups, *P<0.05 (P-value of 4.93×10−6, DN + UTMD versus DN + control; P-value of 4.15×10−9, DN + UTMD + SDF-1 versus DN + control) and #P<0.05 (P-value of 3.02×10−5, DN + UTMD + SDF-1 versus DN + UTMD).Abbreviations: MSCs, mesenchymal stem cells; DN, diabetic nephropathy; GFP, green fluorescent protein; UTMD, ultrasound-targeted microbubble destruction; SDF-1, stromal cell-derived factor-1; DAPI, 4′,6-diamidino-2-phenylindole.
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f8-ijn-9-5639: In vivo detection of implanted exogenous MSCs.Notes: Number of implanted exogenous MSCs in normal and DN kidneys 24 hours after group treatments. (A) The differences of implanted MSCs among groups under a confocal laser scanning microscope. Exogenous MSCs were labeled with GFP and displayed green signals. In normal rats, GFP-labeled MSCs were only occasionally detected in all three groups. In DN rats, GFP-labeled MSCs were rare in control group. UTMD increased the exogenous MSCs and UTMD + SDF-1 greatly improved the homing of exogenous MSCs. The white bar indicates 50 μm. (B) The histogram comparison of the GFP-labeled MSCs among groups, *P<0.05 (P-value of 4.93×10−6, DN + UTMD versus DN + control; P-value of 4.15×10−9, DN + UTMD + SDF-1 versus DN + control) and #P<0.05 (P-value of 3.02×10−5, DN + UTMD + SDF-1 versus DN + UTMD).Abbreviations: MSCs, mesenchymal stem cells; DN, diabetic nephropathy; GFP, green fluorescent protein; UTMD, ultrasound-targeted microbubble destruction; SDF-1, stromal cell-derived factor-1; DAPI, 4′,6-diamidino-2-phenylindole.

Mentions: The cytoplasm and nuclei of GFP-labeled MSCs cultured in vitro exhibited bright green fluorescence, and the labeling rate was 72.2% according to flow cytometry. Twenty-four hours after group treatments and the transplantation of GFP-labeled MSCs, implanted exogenous MSCs were scarce in the control and UTMD groups in normal rats, while implanted exogenous MSCs were occasionally visualized in the UTMD + SDF-1 group (Figure 8A). In DN rats, implanted MSCs (number of 3.6±2.1) were rare in the control group. The MSCs significantly increased after UTMD (number of 13.4±3.1), and a much higher amount of implanted MSCs was found in the UTMD + SDF-1 group (number of 23.8±3.6) (Figure 8B). The implanted MSCs were located mainly around the small blood vessels and in the peritubular interstitium. Few MSCs were detected in the glomeruli.


Ultrasound-targeted stromal cell-derived factor-1-loaded microbubble destruction promotes mesenchymal stem cell homing to kidneys in diabetic nephropathy rats.

Wu S, Li L, Wang G, Shen W, Xu Y, Liu Z, Zhuo Z, Xia H, Gao Y, Tan K - Int J Nanomedicine (2014)

In vivo detection of implanted exogenous MSCs.Notes: Number of implanted exogenous MSCs in normal and DN kidneys 24 hours after group treatments. (A) The differences of implanted MSCs among groups under a confocal laser scanning microscope. Exogenous MSCs were labeled with GFP and displayed green signals. In normal rats, GFP-labeled MSCs were only occasionally detected in all three groups. In DN rats, GFP-labeled MSCs were rare in control group. UTMD increased the exogenous MSCs and UTMD + SDF-1 greatly improved the homing of exogenous MSCs. The white bar indicates 50 μm. (B) The histogram comparison of the GFP-labeled MSCs among groups, *P<0.05 (P-value of 4.93×10−6, DN + UTMD versus DN + control; P-value of 4.15×10−9, DN + UTMD + SDF-1 versus DN + control) and #P<0.05 (P-value of 3.02×10−5, DN + UTMD + SDF-1 versus DN + UTMD).Abbreviations: MSCs, mesenchymal stem cells; DN, diabetic nephropathy; GFP, green fluorescent protein; UTMD, ultrasound-targeted microbubble destruction; SDF-1, stromal cell-derived factor-1; DAPI, 4′,6-diamidino-2-phenylindole.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4263441&req=5

f8-ijn-9-5639: In vivo detection of implanted exogenous MSCs.Notes: Number of implanted exogenous MSCs in normal and DN kidneys 24 hours after group treatments. (A) The differences of implanted MSCs among groups under a confocal laser scanning microscope. Exogenous MSCs were labeled with GFP and displayed green signals. In normal rats, GFP-labeled MSCs were only occasionally detected in all three groups. In DN rats, GFP-labeled MSCs were rare in control group. UTMD increased the exogenous MSCs and UTMD + SDF-1 greatly improved the homing of exogenous MSCs. The white bar indicates 50 μm. (B) The histogram comparison of the GFP-labeled MSCs among groups, *P<0.05 (P-value of 4.93×10−6, DN + UTMD versus DN + control; P-value of 4.15×10−9, DN + UTMD + SDF-1 versus DN + control) and #P<0.05 (P-value of 3.02×10−5, DN + UTMD + SDF-1 versus DN + UTMD).Abbreviations: MSCs, mesenchymal stem cells; DN, diabetic nephropathy; GFP, green fluorescent protein; UTMD, ultrasound-targeted microbubble destruction; SDF-1, stromal cell-derived factor-1; DAPI, 4′,6-diamidino-2-phenylindole.
Mentions: The cytoplasm and nuclei of GFP-labeled MSCs cultured in vitro exhibited bright green fluorescence, and the labeling rate was 72.2% according to flow cytometry. Twenty-four hours after group treatments and the transplantation of GFP-labeled MSCs, implanted exogenous MSCs were scarce in the control and UTMD groups in normal rats, while implanted exogenous MSCs were occasionally visualized in the UTMD + SDF-1 group (Figure 8A). In DN rats, implanted MSCs (number of 3.6±2.1) were rare in the control group. The MSCs significantly increased after UTMD (number of 13.4±3.1), and a much higher amount of implanted MSCs was found in the UTMD + SDF-1 group (number of 23.8±3.6) (Figure 8B). The implanted MSCs were located mainly around the small blood vessels and in the peritubular interstitium. Few MSCs were detected in the glomeruli.

Bottom Line: The related bioeffects were also elucidated.In the in vivo study, SDF-1 was successfully released in the targeted kidneys.In conclusion, ultrasound-targeted MB(SDF-1) destruction could promote the homing of MSCs to early DN kidneys and provide a novel potential therapeutic approach for DN kidney repair.

View Article: PubMed Central - PubMed

Affiliation: Department of Ultrasound, Third Military Medical University, Chongqing, People's Republic of China.

ABSTRACT
Mesenchymal stem cell (MSC) therapy has been considered a promising strategy to cure diabetic nephropathy (DN). However, insufficient MSCs can settle in injured kidneys, which constitute one of the major barriers to the effective implementation of MSC therapy. Stromal cell-derived factor-1 (SDF-1) plays a vital role in MSC migration and involves activation, mobilization, homing, and retention, which are presumably related to the poor homing in DN therapy. Ultrasound-targeted microbubble destruction has become one of the most promising strategies for the targeted delivery of drugs and genes. To improve MSC homing to DN kidneys, we present a strategy to increase SDF-1 via ultrasound-targeted microbubble destruction. In this study, we developed SDF-1-loaded microbubbles (MB(SDF-1)) via covalent conjugation. The characterization and bioactivity of MB(SDF-1) were assessed in vitro. Target release in the targeted kidneys was triggered with diagnostic ultrasound in combination with MB(SDF-1). The related bioeffects were also elucidated. Early DN was induced in rats with streptozotocin. Green fluorescent protein-labeled MSCs were transplanted intravenously following the target release of SDF-1 in the kidneys of normal and DN rats. The homing efficacy was assessed by detecting the implanted exogenous MSCs at 24 hours. The in vitro results showed an impressive SDF-1 loading efficacy of 79% and a loading content of 15.8 μg/mL. MB(SDF-1) remained bioactive as a chemoattractant. In the in vivo study, SDF-1 was successfully released in the targeted kidneys. The homing efficacy of MSCs to DN kidneys after the target release of SDF-1 was remarkably ameliorated at 24 hours compared with control treatments in normal rats and DN rats. In conclusion, ultrasound-targeted MB(SDF-1) destruction could promote the homing of MSCs to early DN kidneys and provide a novel potential therapeutic approach for DN kidney repair.

Show MeSH
Related in: MedlinePlus