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Extracellular Vesicles Derived from Induced Pluripotent Stem Cells Promote Renoprotection in Acute Kidney Injury Model.

ABSTRACT: Induced pluripotent stem cells (iPSC) have been the focus of several studies due to their wide range of application, including in cellular therapy. The use of iPSC in regenerative medicine is limited by their tumorigenic potential. Extracellular vesicles (EV) derived from stem cells have been shown to support renal recovery after injury. However, no investigation has explored the potential of iPSC-EV in the treatment of kidney diseases. To evaluate this potential, we submitted renal tubule cells to hypoxia-reoxygenation injury, and we analyzed cell death rate and changes in functional mitochondria mass. An in vivo model of ischemia-reperfusion injury was used to evaluate morphological and functional alterations. Gene array profile was applied to investigate the mechanism involved in iPSC-EV effects. In addition, EV derived from adipose mesenchymal cells (ASC-EV) were also used to compare the potential of iPSC-EV in support of tissue recovery. The results showed that iPSC-EV were capable of reducing cell death and inflammatory response with similar efficacy than ASC-EV. Moreover, iPSC-EV protected functional mitochondria and regulated several genes associated with oxidative stress. Taken together, these results show that iPSC can be an alternative source of EV in the treatment of different aspects of kidney disease.

SUBMITTER: Collino F

PROVIDER: S-EPMC7072760 | biostudies-literature | 2020 Feb

REPOSITORIES: biostudies-literature

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Extracellular Vesicles Derived from Induced Pluripotent Stem Cells Promote Renoprotection in Acute Kidney Injury Model.

Collino Federica F Lopes Jarlene A JA Tapparo Marta M Tortelote Giovane G GG Kasai-Brunswick Taís H TH Lopes Gustavo M C GMC Almeida Douglas B DB Skovronova Renata R Wendt Camila H C CHC Miranda Kildare R de KR Bussolati Benedetta B Vieyra Adalberto A Lindoso Rafael Soares RS

Cells 20200217 2

Induced pluripotent stem cells (iPSC) have been the focus of several studies due to their wide range of application, including in cellular therapy. The use of iPSC in regenerative medicine is limited by their tumorigenic potential. Extracellular vesicles (EV) derived from stem cells have been shown to support renal recovery after injury. However, no investigation has explored the potential of iPSC-EV in the treatment of kidney diseases. To evaluate this potential, we submitted renal tubule cells ...[more]

PMID: 32079274

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Project description:Although cell survival post-transplantation is very low, emerging evidence using stem cell therapy for myocardial repair points toward a primary role of paracrine signaling mechanisms as the basis for improved cardiac function, decreased fibrosis, and increased angiogenesis. Recent studies have demonstrated that extracellular vesicles (EVs) such as exosomes secreted by stem cells stimulate angiogenesis, provide cytoprotection, and modulate apoptosis. However, the angiogenic potential of EVs secreted from human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CM), a terminally differentiated cell type, has not been elucidated yet. Therefore, the main objective of this study is to isolate, characterize, and evaluate the in vitro angiogenic potential of EVs collected from hiPSC-CM conditioned media. The hiPSC-CM were cultured for 2 weeks and EVs were isolated from cell culture medium. Isolated EVs were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis, and immunoblotting. Furthermore, the angiogenic potential of these EVs was evaluated by tube formation, wound-healing, and cell-proliferation assays in bovine aortic endothelial cells (BAEC). In addition, gene expression levels of growth factors was evaluated in hiPSC-derived endothelial cells (hiPSC-EC) treated with hiPSC-CM-derived EV (CM-EVs) to assess their role in promoting angiogenesis. TEM imaging of CM-EVs showed a presence of a double-membrane bound structure, which is a characteristic of EV. Nanoparticle tracking analysis further confirmed the size and shape of the secreted particles to be consistent with EVs. Furthermore, EV-specific markers (CD63 and HSP70) were enriched in these particles as illustrated by immunoblotting. Most importantly, BAEC treated with 100 μg/ml of CM-EVs showed significant increases in tube formation, wound closure, and cell proliferation as compared to control (no-EVs). Finally, treatment of hiPSC-EC with CM-EVs induced increased expression of pro-angiogenic growth factors by the endothelial cells. Overall, our results demonstrated that EVs isolated from hiPSC-CM enhance angiogenesis in endothelial cells. This acellular/cell-free approach constitutes a potential translational therapeutic to induce angiogenesis in patients with myocardial infarction.

Project description:Limitations in the current therapeutic strategies for the prevention of progression of chronic kidney disease (CKD) to end stage renal disease has been a drawback to improving patient recovery. It is therefore imperative that a solution is found to alleviate this problem and improve the health and well-being of patients overall. Aristolochic acid (AA) induced nephropathy, a type of nephrotoxic CKD is characterised by cortical tubular injury, inflammation, leading to interstitial fibrosis. Extracellular vesicles derived from human bone marrow mesenchymal stem cells (MSC-EVs) display therapeutic properties in various disease models including kidney injury. In the current study, we intended to investigate the ability of MSC-EVs on ameliorating tubular injury and interstitial fibrosis in a mouse model of aristolochic acid nephropathy (AAN). The chronic model of AAN is comprised of an intraperitoneal injection of AA in NSG mice, followed by a three-day incubation period and then inoculation of MSC-EVs intravenously. This routine was performed on a weekly basis for four consecutive weeks, accompanied by the monitoring of body weight of all mice. Blood and tissue samples were collected post sacrifice. All animals administered with AA developed kidney injury and renal fibrosis. A gradual loss of body weight was observed, together with a deterioration in kidney function. Although no significant recovery was observed in weight loss following treatment with MSC-EVs, a significant reduction in: blood creatinine and blood urea nitrogen (BUN), tubular necrosis, and interstitial fibrosis was observed. In addition, infiltration of CD45 positive immune cells, fibroblasts, and pericytes which were elevated in the interstitium post AA induced injury, were also significantly reduced by MSC-EVs. Kidneys were also subjected to molecular analyses to evaluate the regulation of pro-fibrotic genes. MSC-EVs significantly reduced AA induction of the pro-fibrotic genes α-Sma, Tgfb1 and Col1a1. A downregulation in pro-fibrotic genes was also observed in fibroblasts activated by AA injured mTECs in vitro. Furthermore, meta-analyses of miRNAs downregulated by MSC-EVs, such as miR21, revealed the regulation of multiple pathways involved in kidney injury including fibrosis, inflammation, and apoptosis. These results therefore suggest that MSC-EVs could play a regenerative and anti-fibrotic role in AAN through the transfer of biologically active cargo that regulates the disease both at a protein and genetic level.

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Dataset Information

Extracellular Vesicles Derived from Induced Pluripotent Stem Cells Promote Renoprotection in Acute Kidney Injury Model.

Publications

Extracellular Vesicles Derived from Induced Pluripotent Stem Cells Promote Renoprotection in Acute Kidney Injury Model.

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