Stem Cell Research & Therapy | |
Serum-free medium and hypoxic preconditioning synergistically enhance the therapeutic effects of mesenchymal stem cells on experimental renal fibrosis | |
Masataka Nagao1  Shigehiro Doi2  Takao Masaki2  Ryo Kanai2  Naoki Ishiuchi3  Ayumu Nakashima4  Satoshi Maeda5  Shinya Takahashi6  | |
[1] Department of Forensic Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8553, Hiroshima, Hiroshima, Japan;Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Hiroshima, Japan;Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Hiroshima, Japan;Center for Cause of Death Investigation Research, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8553, Hiroshima, Hiroshima, Japan;Department of Forensic Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8553, Hiroshima, Hiroshima, Japan;Department of Nephrology, Hiroshima University Hospital, 1-2-3 Kasumi, Minami-ku, 734-8551, Hiroshima, Hiroshima, Japan;Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8553, Hiroshima, Hiroshima, Japan;Department of Stem Cell Biology and Medicine, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8553, Hiroshima, Hiroshima, Japan;TWOCELLS Company, Limited, 16-35 Hijiyama-honmachi, Minami-ku, 732-0816, Hiroshima, Japan;Department of Surgery, Graduate School of Biomedical & Health Sciences, Hiroshima University, 1-2-3 Kasumi, Minami-ku, 734-8553, Hiroshima, Hiroshima, Japan; | |
关键词: Mesenchymal stem cells; Hypoxic preconditioning; Serum-free conditions; Hepatocyte growth factor; Renal fibrosis; | |
DOI : 10.1186/s13287-021-02548-7 | |
来源: Springer | |
【 摘 要 】
BackgroundMesenchymal stem cells (MSCs) repair injured tissue in a paracrine manner. To enhance their therapeutic properties, preconditioning with various factors has been researched. We have previously showed that MSCs cultured in serum-free medium (SF-MSCs) promote their immunosuppressive ability, thereby enhancing their anti-fibrotic effect. Here, we examined whether serum-free medium and hypoxic preconditioning synergistically enhance the therapeutic effects of MSCs on renal fibrosis in rats with ischemia–reperfusion injury (IRI).MethodsSF-MSCs were incubated under 1% O2 conditions (hypo-SF-MSCs) or 21% O2 conditions (normo-SF-MSCs) for 24 h before collection. After IRI procedure, hypo-SF-MSCs or normo-SF-MSCs were injected through the abdominal aorta. At 7 or 21 days post-injection, the rats were killed and their kidneys were collected to evaluate inflammation and fibrosis. In in vitro experiments, we investigated whether hypo-SF-MSCs enhanced secretion of anti-fibrotic humoral factors using transforming growth factor (TGF)-β1-stimulated HK-2 cells incubated with conditioned medium from hypo-SF-MSCs or normo-SF-MSCs.ResultsNormo-SF-MSCs showed attenuation of senescence, which increased their proliferative capacity. Although no significant difference in cellular senescence was found between normo-SF-MSCs and hypo-SF-MSCs, hypo-SF-MSCs further increased their proliferative capacity compared with normo-SF-MSCs. Additionally, administration of hypo-SF-MSCs more strongly ameliorated renal fibrosis than that of normo-SF-MSCs. Moreover, although hypo-SF-MSCs strongly attenuated infiltration of inflammatory cells compared with the control rats, which were treated with PBS, this attenuation was almost equal between normo-SF-MSCs and hypo-SF-MSCs. In vitro experiments revealed that hypo-SF-MSCs more significantly inhibited transforming growth factor (TGF)-β/Smad signaling compared with normo-SF-MSCs. Moreover, hypoxic preconditioning increased hepatocyte growth factor (HGF) secretion even under serum-free conditions, whereas knockdown of HGF in hypo-SF-MSCs attenuated inhibition of TGF-β/Smad signaling.ConclusionsThese results indicate that administration of ex vivo-expanded, hypoxia-preconditioned SF-MSCs may be a useful cell therapy to prevent renal fibrosis.
【 授权许可】
CC BY
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