Abstract
IntroductionMesenchymal stem cells (MSCs) play a central role in the remediation of cell and tissue damage. Erythropoietin (EPO) may enhance the beneficial influence of MSCs during recovery from tissue and organ injuries. Microvesicles (MVs) released from MSCs contribute to the restoration of kidney damage. We studied the influence of EPO on MVs derived from MSCs, and the protective effects of these factors in subjects with chronic kidney disease (CKD).MethodsThe MVs derived from untreated MSCs (MSC-MVs) or from MSCs incubated in different concentrations of EPO (1, 10, 100, and 500 IU/ml EPO-MVs) were used to treat renal injury of unilateral ureteral obstruction (UUO) in vivo, and transforming growth factor-β1 (TGF-β1)-induced fibrosis in a human renal proximal tubular epithelial (HK2) cell line in vitro. Western blot and reverse transcription polymerase chain reaction (RT-PCR) analyses were used to evaluate the expression of epithelial and mesenchymal markers in the renal tissue and HK2 cells. Flow cytometry was used to assess apoptosis within the HK2 cells, and microRNA (miRNA) microarray assays were used to determine the expression profiles of miRNA in the MSC-MVs and EPO-MVs.ResultsCompared to MSC-MVs (untreated), there was a significant increase in the number of EPO-MVs derived from MSCs treated with 1–100 IU/ml EPO, and these EPO-MVs had a greater benefit in UUO mice on days 7 and 14. Moreover, the EPO-MVs had a better restorative effect following TGF-β1-induced fibrosis in HK2 cells at 24 h and 48 h. The flow cytometry results revealed that both types of MVs, especially EPO-MVs, play an important anti-apoptotic role in HK2 cells treated with TGF-β1. The miRNA profiles of the MVs revealed that EPO-MVs changed 212 miRNAs (fold-change ≥ 1.5), including miR-299, miR-499, miR-302, and miRNA-200, and that 70.28 % of these changes involved upregulation. The changed miRNA in EPO-MVs may have contributed to their enhanced protective effects following renal injury compared to MSC-MVs.ConclusionsThere was a dose-dependent increase in the level of EPO-MVs within the range of 1–100 IU/ml EPO. Although both MSC-MVs and EPO-MVs protect the kidney from fibrosis-related damage, there is a superior effect of EPO-MVs.Electronic supplementary materialThe online version of this article (doi:10.1186/s13287-015-0095-0) contains supplementary material, which is available to authorized users.
Highlights
Mesenchymal stem cells (MSCs) play a central role in the remediation of cell and tissue damage
Compared to MSC-derived MVs (MSC-MVs), there was a significant increase in the number of EPO on MVs derived from MSCs (EPO-MVs) derived from MSCs treated with 1–100 IU/ml EPO, and these EPO-MVs had a greater benefit in ureteral obstruction (UUO) mice on days 7 and 14
The changed miRNA in EPO-MVs may have contributed to their enhanced protective effects following renal injury compared to MSC-MVs
Summary
Mesenchymal stem cells (MSCs) play a central role in the remediation of cell and tissue damage. We studied the influence of EPO on MVs derived from MSCs, and the protective effects of these factors in subjects with chronic kidney disease (CKD). In addition to the ability of MSCs to differentiate in the kidney, the beneficial effects of these factors in the cells of injured tissues have been attributed to their paracrine effects, which indirectly improve renal function via the reduction of disease-related inflammation and fibrosis [4,5,6]. MVs that develop from bone-derived MSCs accelerate recovery following acute kidney injury (AKI) induced by toxic agents [8, 9] or ischemia–reperfusion [10], and induce functional improvements in patients with CKD [11] via miRNA- and mRNA-dependent mechanisms. In high concentrations under highly homogeneous preparation conditions, MVs provide focused stimulation that allows for their interaction with target cells and, in turn, positive reparative effects on damaged organs [12]
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