Ultrasonically targeted destruction of SDF-1 nanobubbles carrying mesenchymal stem cells improves renal tubulointerstitial fibrosis.

[BACKGROUND AND PURPOSE] Renal tubulointerstitial fibrosis (RTF) is an irreversible pathological change that occurs during the end-stage of chronic kidney disease. As a promising new approach, stem cell therapy offers the potential to reverse or ameliorate RTF by promoting cell proliferation in target tissues or through the secretion of relevant substances. However, mesenchymal stem cells (MSCs) that home to renal tissues have reduced proliferation and vitality and a short retention time in the kidneys, which are key factors affecting therapeutic outcomes. Additionally, in vivo real-time tracking of MSCs is not well developed, which significantly obscures our understanding of their potential mechanisms. Nanobubbles (NBs), used as a non-invasive method for auxiliary drug or gene delivery, possess excellent ultrasound imaging capabilities and enhance the penetration of drugs or genes into target tissues under the effect of ultrasound-targeted microbubble destruction (UTMD). Therefore, in this study, aimed to synthesize NBs(stromal cell-derived factor 1 [SDF-1])-MSCs.

[METHODS] We synthesized NBs containing SDF-1 and harvested MSCs from the bone marrow of Sprague-Dawley rats. Subsequently, NBs(SDF-1) were co-cultured with MSCs to produce SDF-1-loaded nanobubble-tagged MSCs. The NBs(SDF-1)-MSCs were injected into adult male rats to investigate their potential for renal visualization and tracking and to assess their efficacy in promoting MSCs homing to the kidneys for RTF treatment under UTMD. We evaluated the effects of NBs(SDF-1)-MSCs on fluorescence ultrasound dual-modality imaging, as well as their ability to enhance MSCs proliferation, vitality, and retention time in vitro and in vivo. Additionally, we explored the therapeutic effects of NBs(SDF-1)-MSCs in rats treated with doxorubicin.

[RESULTS] Using in vivo animal models, dual-modality ultrasound imaging, and immunofluorescence testing, we demonstrated that NBs(SDF-1)-MSCs could be tracked in the kidneys for up to 7 days. Protein blotting, quantitative real-time PCR, immunofluorescence, and immunohistochemistry analyses revealed that ultrasound targeted microbubble destruction greatly enhanced the homing of these stem cells to the kidneys, ameliorating chronic kidney disease by mitigating renal tubular fibrosis via the Tumor necrosis factor-β 1(TGF-β)/B-cell lymphoma/leukemia 2 (Bcl2) signaling pathway.

[CONCLUSION] In this study, we developed a method for in vivo real-time tracking of MSCs loaded with NBs(SDF-1) using dual-modality fluorescence ultrasound imaging, highlighting the therapeutic potential of stem cells and presenting a new therapeutic strategy for treating RTF.