GOFARR Laboratory for Organ Regenerative Research and Cell Therapeutics in Urology, Children's Hospital Los Angeles, Division of Urology, Saban Research Institute, University of Southern California, Los Angeles, California, USA.
Department of Molecular Biotechnology and Health Sciences, University of Torino, Torino, Italy.
Sci Rep. 2017 Dec 4;7(1):16875. doi: 10.1038/s41598-017-17061-2.
Injection of amniotic fluid stem cells (AFSC) delays the course of progression of renal fibrosis in animals with Alport Syndrome, enhancing kidney function and improving survival. The mechanisms responsible for these protective outcomes are still largely unknown. Here, we showed that vascular endothelial growth factor (VEGF) signaling within the glomeruli of Alport mice is strongly elevated early on in the disease, causing glomerular endothelial cell damage. Intraventricular injected AFSC that homed within the glomeruli showed strong modulation of the VEGF activity, particularly in glomerular endothelial cells. To investigate this phenomenon we hypothesized that extracellular vesicles (EVs) produced by the AFSC could be responsible for the observed renoprotection. AFSC derived EVs presented exosomal and stem cell markers on their surface membrane, including VEGFR1 and VEGFR2. EVs were able to modulate VEGF in glomerular endothelial cells by effectively trapping the excess VEGF through VEGFR1-binding preventing cellular damage. In contrast, VEGFR1/sVEGFR1 knockout EVs failed to show similar protection, thus indicating that VEGF trapping is a potentially viable mechanism for AFSC-EV mediated renoprotection. Taken together, our findings establish that EVs secreted by AFSC could target a specific signaling pathway within the glomerulus, thus representing a new potential glomerulus-specific targeted intervention.
羊水干细胞 (AFSC) 的注射可延缓 Alport 综合征动物肾脏纤维化的进展过程，增强肾功能并提高存活率。但导致这些保护作用的机制在很大程度上仍不清楚。在这里，我们发现血管内皮生长因子 (VEGF) 信号在 Alport 小鼠的肾小球中早期被强烈上调，导致肾小球内皮细胞损伤。注射到脑室中的归巢到肾小球中的 AFSC 对 VEGF 活性表现出强烈的调节作用，特别是在肾小球内皮细胞中。为了研究这种现象，我们假设 AFSC 产生的细胞外囊泡 (EV) 可能是观察到的肾脏保护作用的原因。AFSC 衍生的 EV 在其表面膜上呈现出外泌体和干细胞标记物，包括 VEGFR1 和 VEGFR2。EV 能够通过 VEGFR1 结合有效地捕获过多的 VEGF，从而防止细胞损伤，从而调节肾小球内皮细胞中的 VEGF。相比之下，VEGFR1/sVEGFR1 敲除 EV 未能显示出类似的保护作用，因此表明 VEGF 捕获是 AFSC-EV 介导的肾脏保护的一种潜在可行机制。总之，我们的研究结果表明，AFSC 分泌的 EV 可以靶向肾小球中的特定信号通路，因此代表了一种新的潜在的肾小球特异性靶向干预措施。
