Abstract
IntroductionMicroparticles (MPs) derived from kidney-derived mesenchymal stem cells (KMSCs) have recently been reported to ameliorate rarefaction of peritubular capillaries (PTC) in ischemic kidneys via delivery of proangiogenic effectors. This study aimed to investigate whether KMSC-derived MPs show anti-fibrotic effects by ameliorating endothelial-to-mesenchymal transition (EndoMT) in human umbilical vein endothelial cells (HUVEC) in vitro and by preserving PTC in kidneys with unilateral ureteral obstruction (UUO) in vivo.MethodsMPs isolated from the supernatants of KMSC were co-cultured with HUVEC to assess their in vitro biologic effects on endothelial cells. Mice were treated with MPs via the tail vein after UUO injury to assess their anti-fibrotic and PTC sparing effects. Renal tubulointerstitial damage and inflammatory cell infiltration were examined with Masson’s trichrome, F4/80 and α-smooth muscle actin (α-SMA) staining and PTC rarefaction index was determined by CD31 staining.ResultsKMSC-derived MPs significantly ameliorated EndoMT and improved in vitro proliferation of TGF-β1 treated HUVEC. In vivo administration of KMSC-derived MPs significantly inhibited EndoMT of PTC endothelial cells and improved PTC rarefaction in UUO kidneys. Furthermore, administration of KMSC-derived MPs inhibited inflammatory cell infiltration as well as tubulointerstitial fibrosis in UUO mice as demonstrated by decreased F4/80 and α-SMA-positive cells and Masson’s trichrome staining, respectively.ConclusionsOur results suggest that KMSC-derived MPs ameliorate PTC rarefaction via inhibition of EndoMT and protect against progression of renal damage by inhibiting tubulointerstitial fibrosis.
Highlights
Microparticles (MPs) derived from kidney-derived mesenchymal stem cells (KMSCs) have recently been reported to ameliorate rarefaction of peritubular capillaries (PTC) in ischemic kidneys via delivery of proangiogenic effectors
KMSC-derived MPs attenuate transforming growth factor-β1 (TGF-β1)-induced endothelial-to-mesenchymal transition (EndoMT) of human umbilical vein endothelial cells (HUVEC) in vitro First, we confirmed the incorporation of MPs which were pre-incubated with PKH26 dye for 30 minutes at 37°C into cultured HUVEC by immunofluorescence microscopy analysis (Figure 1A)
To investigate the effects of KMSC-derived MPs on EndoMT, cultured HUVEC were treated with a predetermined concentration of TGF-β1
Summary
Microparticles (MPs) derived from kidney-derived mesenchymal stem cells (KMSCs) have recently been reported to ameliorate rarefaction of peritubular capillaries (PTC) in ischemic kidneys via delivery of proangiogenic effectors. This study aimed to investigate whether KMSC-derived MPs show anti-fibrotic effects by ameliorating endothelial-to-mesenchymal transition (EndoMT) in human umbilical vein endothelial cells (HUVEC) in vitro and by preserving PTC in kidneys with unilateral ureteral obstruction (UUO) in vivo. Unilateral ureteral obstruction (UUO) is a well-established in vivo model of tubulointerstitial scarring It involves virtually all renal intrinsic and infiltrating cells and is characterized by alterations in their phenotype and accumulation of excessive extracellular matrix proteins [1,2,3,4]. Another histologic alteration frequently noted in UUO is rarefaction of peritubular capillaries (PTC) that are essential for providing nutrients and oxygen to the surrounding tubules and interstitial cells [5,6]. PTC rarefaction derived via EndoMT may play an important role in the process of kidney fibrosis in UUO [8]
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