Hypoxia-preconditioned mesenchymal stem cells prevent renal fibrosis and inflammation in ischemia-reperfusion rats

Abstract

Background Mesenchymal stem cells (MSCs) have been reported to promote the regeneration of injured tissue via their paracrine abilities, which are enhanced by hypoxic preconditioning. In this study, we examined the therapeutic efficacy of hypoxia-preconditioned MSCs on renal fibrosis and inflammation in rats with ischemia-reperfusion injury (IRI). Methods MSCs derived from rats and humans were incubated in 1% O2 conditions (1%O2 MSCs) for 24 h. After IRI, 1%O2 MSCs or MSCs cultured under normoxic conditions (21%O2 MSCs) were injected through the abdominal aorta. At 7 or 21 days post-injection, the rats were sacrificed and their kidneys were analyzed. In in vitro experiments, we examined whether 1%O2 MSCs enhanced the ability to produce anti-fibrotic humoral factors using transforming growth factor (TGF)-β1-stimulated HK-2 cells incubated with conditioned medium from MSCs. Results Administration of rat 1%O2 MSCs (1%O2 rMSCs) attenuated renal fibrosis and inflammation more significantly than rat 21%O2 MSCs. Notably, human 1%O2 MSCs (1%O2 hMSCs) also attenuated renal fibrosis to the same extent as 1%O2 rMSCs. Flow cytometry showed that 1%O2 hMSCs did not change human leukocyte antigen expression. Further in vitro experiments revealed that conditioned medium from 1%O2 MSCs further suppressed TGF-β1-induced fibrotic changes in HK-2 cells compared with 21%O2 MSCs. Hypoxic preconditioning enhanced vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) secretion. Interestingly, VEGF knockdown in 1%O2 MSCs attenuated HGF secretion and the inhibition of TGF-β1-induced fibrotic changes in HK-2 cells. In addition, VEGF knockdown in 1%O2 hMSCs reduced the anti-fibrotic effect in IRI rats. Conclusions Our results indicate that hypoxia-preconditioned MSCs are useful as an allogeneic transplantation cell therapy to prevent renal fibrosis and inflammation.

Interferon-γ enhances the therapeutic effect of mesenchymal stem cells on experimental renal fibrosis

“…PGE2 has been reported to induce the polarization of immunosuppressive M2 macrophages that produce anti-inflammatory cytokines and inhibit the persistence of inflammation 27 , 28 . In addition, we previously reported that MSCs promoted macrophage differentiation from an M1 pro-inflammatory phenotype to an immunosuppressive M2 phenotype, and that the administration of ex vivo-expanded MSCs suppressed the progression of fibrosis 29 , 30 . Taken together, this suggests that IFN-γ-preconditioned MSCs have a strong immunosuppressive effect and therefore might ameliorate renal fibrosis.…”

Localization and Maintenance of Engrafted Mesenchymal Stem Cells Administered via Renal Artery in Kidneys with Ischemia-Reperfusion Injury

“…We recently reported that MSCs from EGFP-positive rats persisted for 21 days post-IRI [14]. We further traced MSCs from EGFP-positive rats in IRI kidneys and found they were sparsely detected on day 42 post-IRI (Figure 4A).…”

Hypoxic preconditioning induces epigenetic changes and modifies swine mesenchymal stem cell angiogenesis and senescence in experimental atherosclerotic renal artery stenosis

“…MSCs mode of action involves a strong paracrine component resulting from active factors secreted in response to the local microenvironment [ 15 , 52 ]. Previous studies have applied HPC to MSCs as a strategy to enhance stem cell survival in vitro, proliferation, and repair capacity [ 53 – 55 ]. Indeed, restoring MSC paracrine effects through HPC may improve immunomodulatory, angiogenic, antiapoptotic effects, and promote activation of local quiescent stem cells [ 56 ].…”