Microparticles from kidney-derived mesenchymal stem cells act as carriers of proangiogenic signals and contribute to recovery from acute kidney injury

• Published in: PloS one 2014-02, Vol.9 (2), p.e87853-e87853
• Main Authors: Choi, Hoon Young, Moon, Sung Jin, Ratliff, Brian B, Ahn, Sun Hee, Jung, Ara, Lee, Mirae, Lee, Seol, Lim, Beom Jin, Kim, Beom Seok, Plotkin, Matthew D, Ha, Sung Kyu, Park, Hyeong Cheon
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - genetics; Acute Kidney Injury - metabolism; Acute Kidney Injury - pathology; Angiogenesis; Animals; Anoxic conditions; Apoptosis; Biological effects; Biological Transport; Biology; Bone marrow; CD29 antigen; CD44 antigen; CD73 antigen; Cell Proliferation; Cell-Derived Microparticles - metabolism; Cell-Derived Microparticles - ultrastructure; Disease Models, Animal; Endothelial cells; Endothelial Cells - metabolism; Endothelium; Engraftment; Fibroblast growth factor 2; Fibroblast growth factors; Fibroblasts; Fluorescence; Gene Expression Profiling; Gene Transfer, Horizontal; Human Umbilical Vein Endothelial Cells; Humans; Hypoxia; Injuries; Insulin-like growth factor I; Integrins; Internal medicine; Ischemia; Kidneys; Male; Medicine; Membranes; Mesenchymal stem cells; Mesenchymal Stromal Cells - metabolism; Mesenchyme; Metabolism; Mice; Microparticles; Microscopy; Microvasculature; Neovascularization, Physiologic; Nephrology; Physiology; Political aspects; Rarefaction; Recovery (Medical); Renal function; Reperfusion; Reperfusion Injury - genetics; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; Rodents; Signal Transduction; Splicing; Stem cell transplantation; Stem cells; Studies; Umbilical vein; Vascular endothelial growth factor; Veins & arteries
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0087853

We recently demonstrated the use of in vitro expanded kidney-derived mesenchymal stem cells (KMSC) protected peritubular capillary endothelial cells in acute renal ischemia-reperfusion injury. Herein, we isolated and characterized microparticles (MPs) from KMSC. We investigated their in vitro biologic effects on human endothelial cells and in vivo renoprotective effects in acute ischemia-reperfusion renal injury. MPs were isolated from the supernatants of KMSC cultured in anoxic conditions in serum-deprived media for 24 hours. KMSC-derived MPs demonstrated the presence of several adhesion molecules normally expressed on KMSC membranes, such as CD29, CD44, CD73, α4, 5, and 6 integrins. Quantitative real time PCR confirmed the presence of 3 splicing variants of VEGF-A (120, 164, 188), bFGF and IGF-1 in isolated MPs. MPs labeled with PKH26 red fluorescence dye were incorporated by cultured human umbilical vein endothelial cells (HUVEC) via surface molecules such as CD44, CD29, and α4, 5, and 6 integrins. MP dose dependently improved in vitro HUVEC proliferation and promoted endothelial tube formation on growth factor reduced Matrigel. Moreover, apoptosis of human microvascular endothelial cell was inhibited by MPs. Administration of KMSC-derived MPs into mice with acute renal ischemia was followed by selective engraftment in ischemic kidneys and significant improvement in renal function. This was achieved by improving proliferation, of peritubular capillary endothelial cell and amelioration of peritubular microvascular rarefaction. Our results support the hypothesis that KMSC-derived MPs may act as a source of proangiogenic signals and confer renoprotective effects in ischemic kidneys.