Int J Mol Sci. 2023;24(21):ijms242115726.

Efficacy of Mesenchymal-Stromal-Cell-Derived Extracellular Vesicles in Ameliorating Cisplatin Nephrotoxicity, as Modeled Using Three-Dimensional, Gravity-Driven, Two-Layer Tubule-on-a-Chip (3D-MOTIVE Chip).

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제1저자 권은정 · 교신저자 박석우, 김세중

PMID 37958709 PMC10647511 DOI 10.3390/ijms242115726 IF 5.6 신장내과

소속 (4)

Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam 13620, Republic of Korea.
Osong Medical Innovation Foundation, Cheongju-si 28161, Republic of Korea.
Department of School of Interdisciplinary Bioscience and Bioengineering, Pohang University of Science and Technology, Pohang 37673, Republic of Korea.
Department of Internal Medicine, Seoul National University College of Medicine, Seoul 03080, Republic of Korea.

Abstract

Mesenchymal stromal cell (MSC)-derived extracellular vesicles (EVs) are known to have a therapeutic effect on nephrotoxicity. As animal models require significant time and resources to evaluate drug effects, there is a need for a new experimental technique that can accurately predict drug effects in humans. We evaluated the therapeutic effect of MSC-derived EVs in cisplatin nephrotoxicity using a three-dimensional, gravity-driven, two-layer tubule-on-a-chip (3D-MOTIVE chip). In the 3D-MOTIVE chip, 10 μM cisplatin decreased the number of attached cells compared to the vehicle. Conversely, annexin V and reactive oxygen species (ROS) were increased. Cell viability was increased 2.8-fold and 2.5-fold after treatment with EVs at 4 and 8 µg/mL, respectively, compared to the cisplatin-induced nephrotoxicity group. Cell attachment was increased 2.25-fold by treatment with 4 µg/mL EVs and 2.02-fold by 8 µg/mL EVs. Annexin V and ROS levels were decreased compared to those in the cisplatin-induced nephrotoxicity group. There were no significant differences in annexin V and ROS levels according to EV concentration. In sum, we created a cisplatin-induced nephrotoxicity model on a 3D-MOTIVE chip and found that MSC-derived EVs could restore cell viability. Thus, MSC-derived EVs may have the potential to ameliorate cisplatin-induced nephrotoxicity.

Keywords

3D-MOTIVE chipacute kidney injurydrug efficacyextracellular vesicles (EVs)tubule-on-a-chip

Figures

**Figure 1** Schematic illustration of the experimental tools and schedule. (A) Design of the 3-dimensional, gravity-driven, 2-layer tubule-on-a-chip. (B) Actual image of a 3D-MOTIVE chip. (C) Cisplatin nephrotoxicity experimental schedule for 4 days using a 3D-MOTIVE chip.

**Figure 2** Cell viability of MSC-derived EVs in cisplatin-induced nephrotoxic model. (A) Confocal microscopic images (20×) of cells treated with a combination of cisplatin (10 μM) and EVs (4 µg/mL or 8 µg/mL) followed by staining with calcein AM and Hoechst33342. Scale bar, 50 μM. (B,C). Fluorescence intensity was measured (* p < 0.05 vs. control in Student’s t-test, # p < 0.05 vs. cisplatin in one-way ANOVA, data are presented as mean ± SE; n = 4–5).

**Figure 3** Tubular function and apoptosis in the cisplatin-induced nephrotoxic model by MSC-derived EVs. (A) Confocal microscopy images (20×) of cells treated with a combination of cisplatin and Evs followed by staining with calcein AM, TMRM, annexin V, and Hoechst 33342. Fluorescent dye scale bar, 50 μM. (B–D) Fluorescence intensity was measured (* p < 0.05 vs. control in Student’s t-test, # p < 0.05 vs. cisplatin in one-way ANOVA, data are presented as mean ± SE; n = 3–5).

**Figure 4** ROS generation of MSC-derived EVs. (A) Confocal microscopy images (20×) of cells treated with a combination of cisplatin and EVs, followed by incubation with DCF-DA, and staining with Hoechst 33342. Fluorescent dye scale bar, 50 μM. (B) Fluorescence intensity was measured (* p < 0.05 vs. control in Student’s t-test, # p < 0.05 vs. cisplatin in one-way ANOVA, data are presented as mean ± SE; n = 4).

그림 출처: PubMed Central 공개 논문 (PMC10647511)

Conflict of interest statement

The authors declare no conflict of interest.

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