Extracellular Vesicles Secreted by Human Urine-Derived Stem Cells Promote Ischemia Repair in a Mouse Model of Hind-Limb Ischemia

Zhu, Qiangqiang; Li, Qing; Niu, Xiamu; Zhang, Guowei; Ling, Xiaozheng; Zhang, Jieyuan; Wang, Yang; Deng, Zixin

doi:10.1159/000490214

Cited by 53 publications

(45 citation statements)

References 59 publications

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“…One study reported that MSC-derived exosomes can mediate repair of kidney injury 23 , 24 . USCs also secrete exosomes, which were shown to protect against diabetic nephropathy 25 , promote of angiogenesis and wound healing in diabetic wound repair 26 , and promote the angiogenesis and muscle regeneration in hind-limb ischemia 27 . It is well known microRNAs (miRNAs) or small noncoding RNAs in exosomes play important roles in the regulation of target genes 28 .…”

Section: Introductionmentioning

confidence: 99%

Human urine-derived stem cells protect against renal ischemia/reperfusion injury in a rat model via exosomal miR-146a-5p which targets IRAK1

Liu

et al. 2020

Theranostics

126

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Rationale: Ischemia/reperfusion injury (IRI) is a major cause of acute kidney injury (AKI) that is associated with high morbidity and mortality, and for which specific treatments are lacking. In this study, we investigated the protective effect of human urine-derived stem cells (USCs) and their exosomes against IRI-induced AKI to explore the potential of these cells as a new therapeutic strategy. Methods: USCs were derived from fresh human urine. Cell surface marker expression was analyzed by flow cytometry to determine the characteristics of the stem cells. Adult male Sprague-Dawley rats were used to generate a lethal renal IRI model. One dose of USCs (2×10 6 cells/ml) or exosomes (20 µg/1 ml) in the experimental groups or saline (1 ml) in the control group was administered intravenously immediately after blood reperfusion. Blood was drawn every other day for measurement of serum creatinine (sCr) and blood urea nitrogen (BUN) levels. The kidneys were harvested for RNA and protein extraction to examine the levels of apoptosis and tubule injury. In vitro , the hypoxia-reoxygenation (H/R) model in human kidney cortex/proximal tubule cells (HK2) was used to analyze the protective ability of USC-derived exosomes (USC-Exo). Quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR), western blotting, superoxide dismutase activity, and malonaldehyde content analyses were used to evaluate oxidative stress in HK2 cells treated with USC-Exo after H/R. Exosomal microRNA sequencing techniques and bioinformatics analysis were used to search for enriched miRNAs in the exosomes and interacting genes. The interaction between miRNAs and the 3' untranslated region of the target gene was detected using a dual luciferase reporting system. The miRNA mimic and inhibitor were used to regulate the miRNA level in HK2 cells. Results: Treatment with USCs led to reductions in the levels of sCr, BUN, and renal tubular cell apoptosis; inhibited the infiltration of inflammatory cells; and protected renal function in the rat IRI model. Additionally, USC-derived exosomes protected against IRI-induced renal damage. miR-146a-5p was the most abundant miRNA in exosomes obtained from the conditioned medium (CM) of USCs. miR-146a-5p targeted and degraded the 3'UTR of interleukin-1 receptor-associated kinase 1 (IRAK1) mRNA, subsequently inhibited the activation of nuclear factor (NF)-κB signaling, and protected HK2 cells from H/R injury. USC transplantation also upregulated miR-146a-5p expression, downregulated IRAK1 expression and inhibited nuclear translocation of NF-κB p65 in the kidney of the rat IRI model. Conclusions: According to our experimental results, USCs could protect against renal IRI via exosomal miR-146a-5p , which could target the 3'UTR of I...

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Section: Introductionmentioning

confidence: 99%

Human urine-derived stem cells protect against renal ischemia/reperfusion injury in a rat model via exosomal miR-146a-5p which targets IRAK1

Liu

et al. 2020

Theranostics

126

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“…Likewise, EVs isolated from ADMSCs limited the abnormal proliferation and migration of vascular smooth muscle cells, followed by neointimal hyperplasia in the setting of vein graft bypass surgery [164]. Administration of human UCMSC-EVs in a mouse model of hind-limb ischemia ameliorated severe ischemic injury, as revealed by increased limb perfusion and function [165]. With respect to tracheoesophageal diseases such as fistulas, ADMSC-EVs embedded in thermo-responsive hydrogels ensured the targeted delivery of EVs at the site of porcine oesophageal fistula; this, in turn, augmented healing.…”

Section: The Regenerative Effect Of Msc-evs On Various Tissuesmentioning

confidence: 99%

Mesenchymal Stem Cell Derived Extracellular Vesicles for Tissue Engineering and Regenerative Medicine Applications

Tsiapalis

O’Driscoll

2020

Cells

227

164

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Mesenchymal stem cells (MSCs) are being extensively investigated for their potential in tissue engineering and regenerative medicine. However, recent evidence suggests that the beneficial effects of MSCs may be manifest by their released extracellular vesicles (EVs); typically not requiring the administration of MSCs. This evidence, predominantly from pre-clinical in vitro and in vivo studies, suggests that MSC-EVs may exhibit substantial therapeutic properties in many pathophysiological conditions, potentially restoring an extensive range of damaged or diseased tissues and organs. These benefits of MSC EVs are apparently found, regardless of the anatomical or body fluid origin of the MSCs (and include e.g., bone marrow, adipose tissue, umbilical cord, urine, etc). Furthermore, early indications suggest that the favourable effects of MSC-EVs could be further enhanced by modifying the way in which the donor MSCs are cultured (for example, in hypoxic compared to normoxic conditions, in 3D compared to 2D culture formats) and/or if the EVs are subsequently bio-engineered (for example, loaded with specific cargo). So far, few human clinical trials of MSC-EVs have been conducted and questions remain unanswered on whether the heterogeneous population of EVs is beneficial or some specific sub-populations, how best we can culture and scale-up MSC-EV production and isolation for clinical utility, and in what format they should be administered. However, as reviewed here, there is now substantial evidence supporting the use of MSC-EVs in tissue engineering and regenerative medicine and further research to establish how best to exploit this approach for societal and economic benefit is warranted.

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“…Since exosomes are nanosized, they can easily penetrate different bio barriers, including the blood-brain barrier. Hence, exosome-mediated therapy provides treatment of earlier distant foci of disease [61].…”

Section: Extracellular Vesicles Secreted By Udscsmentioning

confidence: 99%

Urine as a Main Effector in Urological Tissue Engineering—A Double-Edged Sword

Abbas

Ali

Uddin

2020

Cells

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In order to reconstruct injured urinary tract tissues, biodegradable scaffolds with autologous seeded cells are explored in this work. However, when cells are obtained via biopsy from individuals who have damaged organs due to infection, congenital disorders, or cancer, this can result in unhealthy engineered cells and donor site morbidity. Thus, neo-organ construction through an alternative cell source might be useful. Significant advancements in the isolation and utilization of urine-derived stem cells have provided opportunities for this less invasive, limitless, and versatile source of cells to be employed in urologic tissue-engineered replacement. These cells have a high potential to differentiate into urothelial and smooth muscle cells. However, urinary tract reconstruction via tissue engineering is peculiar as it takes place in a milieu of urine that imposes certain risks on the implanted cells and scaffolds as a result of the highly cytotoxic nature of urine and its detrimental effect on both growth and differentiation of these cells. Both of these projections should be tackled thoughtfully when designing a suitable approach for repairing urinary tract defects and applying the needful precautions is vital.

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Extracellular Vesicles Secreted by Human Urine-Derived Stem Cells Promote Ischemia Repair in a Mouse Model of Hind-Limb Ischemia

Cited by 53 publications

References 59 publications

Human urine-derived stem cells protect against renal ischemia/reperfusion injury in a rat model via exosomal miR-146a-5p which targets IRAK1

Human urine-derived stem cells protect against renal ischemia/reperfusion injury in a rat model via exosomal miR-146a-5p which targets IRAK1

Mesenchymal Stem Cell Derived Extracellular Vesicles for Tissue Engineering and Regenerative Medicine Applications

Urine as a Main Effector in Urological Tissue Engineering—A Double-Edged Sword

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