Human mesenchymal‐stem‐cells‐derived exosomes are important in enhancing porcine islet resistance to hypoxia

Nie, Wei; Ma, Xiaoqian; Yang, Cejun; Chen, Zeyi; Rong, Pengfei; Wu, Minghua; Jiang, Jian‐Hui; Tan, Mei Lan; Yi, Shounan; Wang, Wei

doi:10.1111/xen.12405

Cited by 40 publications

(39 citation statements)

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“…Previous reports have illustrated that one of the potential mechanisms that contribute to the protective effect of MSCs is paracrine effects. As shown in our previous studies, exosomes derived from human MSCs protect NICCs from hypoxia‐induced apoptosis, but the mechanism mediating this process remains unclear. MSCs have been reported to secrete various cytokines, including interleukin‐6 (IL‐6), hepatocyte growth factor (HGF) and others .…”

Section: Introductionmentioning

confidence: 81%

“…MSCs were then isolated from umbilical cords, using a recently published protocol, and cultured with alpha‐MEM medium (GE Healthcare) supplemented with 5% (v/v) UltraGROTM‐Advanced cell culture supplement (Helios BioScience) and 2 mmol/L L‐glutamine (GlutaMAXI, Thermo Fisher) at 37°C and 5% CO 2 . The supernatant of passage 3‐5 huc‐MSCs was collected as conditioned medium (huc‐MSC‐CM) as previously described . Briefly, the human umbilical cord‐derived MSCs, at passage 3‐5, were seeded into 100‐mm tissue culture dishes and cultured with complete medium containing serum in incubators under normoxic conditions (20% O 2 , 5% CO 2 and 37°C).…”

Section: Methodsmentioning

confidence: 99%

“…Three‐ to five‐day‐old pigs, designated pathogen‐free (DPF), of either sex were obtained from Hunan Xeno Life Science. NICCs were isolated from a donor pancreas as described previously and cultured with the previously described medium . After one day of incubation (on day 0), NICCs were rinsed twice with phosphate‐buffered saline (PBS).…”

Section: Methodsmentioning

confidence: 99%

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Human mesenchymal stem cells–derived conditioned medium inhibits hypoxia‐induced death of neonatal porcine islets by inducing autophagy

Tan²,

et al. 2019

Xenotransplantation

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Background The dysfunction of islet grafts is generally attributed to hypoxia‐induced damage. Mesenchymal stem cells (MSCs) are currently thought to effectively protect cells from various risk factors via regulating autophagy. In our study, we investigated if human umbilical cord‐derived MSCs could ameliorate hypoxia‐induced apoptosis in porcine islets by modulating autophagy, and we explored the underlying mechanisms. Methods Neonatal porcine islet cell clusters (NICCs) were cultured with human umbilical cord‐derived MSC conditioned medium (huc‐MSC‐CM) and RPMI‐1640 medium (control) under hypoxic conditions (1% O2) in vitro. NICCs were treated with 3‐methyladenine (3‐MA) and chloroquine (CQ) to examine the role of huc‐MSC‐CM in regulating autophagy. Finally, the levels of several cytokines secreted by huc‐MSCs were detected by ELISAs, and the corresponding inhibitors were applied to investigate which cytokine mediates the protective effects of huc‐MSC‐CM. The effects of huc‐MSC‐CM on NICCs viability and autophagy were examined using AO/PI staining, flow cytometry analysis, transmission electron microscopy (TEM) and confocal fluorescence microscopy analysis. The insulin secretion of NICCs was tested with an insulin immunoradiometric assay kit. Results Compared to the control, the huc‐MSC‐CM treatment improved the viability of NICCs, inhibited apoptosis, increased autophagic activity and the levels of PI3K class III and phosphorylated Akt, while the ratio of phosphorylated mTOR/mTOR was reduced. These changes were reversed by CQ and 3‐MA treatments. High concentrations of IL‐6 were detected in hu‐MSC‐CM. Furthermore, recombinant IL‐6 pre‐treatment exerted similar effects as huc‐MSC‐CM, and these effects were reversed by a specific inhibitor of IL‐6 (Sarilumab). Conclusions Our results demonstrated that huc‐MSC‐CM improved islet viability and function by increasing autophagy through the PI3K/Akt/mTOR pathway under hypoxic conditions. Additionally, IL‐6 plays an important role in the function of huc‐MSC‐CM.

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Section: Introductionmentioning

confidence: 81%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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Human mesenchymal stem cells–derived conditioned medium inhibits hypoxia‐induced death of neonatal porcine islets by inducing autophagy

Tan²,

et al. 2019

Xenotransplantation

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“…Additionally, hucMSC-EX treatment relieved the destroyed islets, activated the insulin-signaling pathway, and ameliorated insulin resistance in the rats [32]. Similarly, Nie et al found that hucMSC-EXs could protect islet cells from hypoxia-induced injury in vitro, prolong islet cell survival, and improve its function, thus increasing the efficiency of islet transplantation [33].…”

Section: Diabetesmentioning

confidence: 93%

Therapeutic Advances of Stem Cell-Derived Extracellular Vesicles in Regenerative Medicine

Yin

Liu

Shi

et al. 2020

Cells

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Extracellular vesicles (EVs), which are the main paracrine components of stem cells, mimic the regenerative capacity of these cells. Stem cell-derived EVs (SC-EVs) have been used for the treatment of various forms of tissue injury in preclinical trials through maintenance of their stemness, induction of regenerative phenotypes, apoptosis inhibition, and immune regulation. The efficiency of SC-EVs may be enhanced by selecting the appropriate EV-producing cells and cell phenotypes, optimizing cell culture conditions for the production of optimal EVs, and further engineering the EVs produced to transport therapeutic and targeting molecules. Cells 2020, 9, 707 2 of 28 storage, immune rejection, gene mutation, and tumorigenesis or tumor promotion in vivo limit its application. Stem cell derived-EVs (SC-EVs), as the main paracrine executor, overcome most limitations of stem cell applications. SC-EVs have allowed major advances in preclinical or clinical studies.In this review, the potential therapeutic applications of SC-EVs in regenerative medicine are discussed and the underlying molecular mechanisms are explored. Some of the possibilities for improving their secretion and altering their components to improve their efficacy toward diverse indications and diseases are summarized. Stem Cell-Derived EVs in the Treatment of Damaged TissueNumerous preclinical trials have reported that SC-EVs can carry active molecules, such as proteins, lipids, and nucleic acids, and good therapeutic effects against various diseases regarding different systems, including the nervous system, respiratory system, circulatory system, digestive system, urinary system, and others, have been observed. Neurological SystemBrain trauma is a common event that can cause nerve damage and disability. EXs derived from human adipose mesenchymal stem cells (AdMSC-EXs) can significantly increase the number of neurons, reduce inflammation, improve sensory and cognitive function, and produce better effects than AdMSCs alone in rats that have incurred traumatic brain injury (TBI) [6]. Kim et al. indicated that systemic administration of CD63+CD81+ EVs produced by human bone marrow-derived stem cells (BMSC-EVs) decreased neuroinflammation 12 h after a TBI in a mouse model of TBI induced by a controlled cortical impact device [7]. They also found that BMSC-EV infusion preserved the pattern separation and spatial learning abilities of mice, which were demonstrated respectively by an object-based behavioral test and a water maze test [7].Stroke is the sudden rupture or occlusion of cerebral blood vessels that interrupts the blood supply. It is the main cause of death and disability in Chinese adults. Preclinical studies have shown that SC-EVs seem to be a promising candidate for stroke treatment. Xin et al. showed that infusion of BMSC-EXs enhanced oligodendrogenesis and neurogenesis, remodeled synapses, reduced the incidence of stroke, and accelerated the recovery of neurological functions in a rat model of stroke induced by transient middle cerebral artery occl...

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“…To better understand how MSCs protect islet cells, Nie et al evaluated the contribution of MSC‐secreted factors. MSC‐conditioned media (CM) and exosomes reduced cellular apoptosis leading to enhanced cell survival . Additionally, CM and exosomes activated transcriptional programs in islet cells associated with hypoxia tolerance, including hypoxia‐inducible factor 1 alpha (Hif1‐alpha).…”

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confidence: 99%

Xenotransplantation literature update, September/October 2018

Taylor

Levy

Burlak

2018

Xenotransplantation

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Damage from hypoxia is a significant hurdle for effect islet transplantation. Past studies have shown that porcine islet cells are protected from hypoxic damage when cultured with human mesenchymal stem cells (MSCs). To better understand how MSCs protect islet cells, Nie et al evaluated the contribution of MSC-secreted factors. MSC-conditioned media (CM) and exosomes reduced cellular apoptosis leading to enhanced cell survival. 1 Additionally, CM and exosomes activated transcriptional programs in islet cells associated with hypoxia tolerance, including hypoxia-inducible factor 1 alpha (Hif1-alpha). The review article by Smith et al 2 focuses on cellular encapsulation to protect recipients from antigenic donor grafts. They discuss new discoveries, issues, and strategies for wrapping up the donor cells, including an overview of device characteristics. 2 of 2 | TAYLOR eT AL. Non-Gal antigens in porcine cells have long been of interest for engineering an optimal porcine donor graft to use in clinical xenotransplantation. The review written by Byrne et al provides detailed and supportive information on a critical non-Gal antigen, B4GalNT2, and illustrates that when deleted, porcine cells are targeted less by the immune system. 10 2 | IMMUNE SUPPRE SS ION Corneal transplants using porcine tissues are a promising solution to a global need for corneal tissue to correct blindness. Descemet's membrane endothelial keratoplasty (DMEK) is an innovative transplantation technique that benefits from low rejection rates and requisite immunosuppression and results in superior vision recovery compared to other surgical techniques. Indeed, in current issue, Kim et al 11 demonstrate that immunosuppression with the common agent tacrolimus can lead to asymptomatic thrombotic microangiopathy that can lead to a number of problems including organ damage. Minimizing the need for immunosuppression by improved graft quality, genetics, and preparation may therefore enhance tissue survival long term. Liu et al 12 tested the feasibility of porcine xenografts using the DMEK technique. Here, the group used two techniques, mechanical stripping and liquid bubble, to prepare the ultra-thin DMEK prior to transplantation. The data, including a comparison of endothelial growth, were promising and indicate that corneal xenografts using DMEK are a viable future option. The authors plan next to test the xeno-DMEK in a non-human primate model. Successful xenotransplantation currently requires immunosuppression. Unfortunately, the immunosuppression regimen may be lethal, by a yet unidentified mechanism, though often linked with anti-CD154 antibody treatment. Ock et al 13 used a non-human primate model (cynomolgus macaques) to evaluate the transcriptional changes prior to and after the standard immunosuppression protocol for porcine cardiac xenotransplantation (alpha-1,3-galactosyltransferase KO pigs). The regimen included cobra venom factor, anti-thymocyte globulin, and rituximab, in the presence or absence of anti-CD154 antibodies. The authors identified a...

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Human mesenchymal‐stem‐cells‐derived exosomes are important in enhancing porcine islet resistance to hypoxia

Abstract: This study found that hu-MSC-CM could protect NICCs from hypoxia-induced dysfunction, and exosomes played an important role in hypoxic resistance, suggesting a potential strategy to improve islet transplantation outcomes.

Cited by 40 publications

References 53 publications

Human mesenchymal stem cells–derived conditioned medium inhibits hypoxia‐induced death of neonatal porcine islets by inducing autophagy

Human mesenchymal stem cells–derived conditioned medium inhibits hypoxia‐induced death of neonatal porcine islets by inducing autophagy

Therapeutic Advances of Stem Cell-Derived Extracellular Vesicles in Regenerative Medicine

Xenotransplantation literature update, September/October 2018

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