Human Mesenchymal Stem Cell Derived Exosomes Alleviate Type 2 Diabetes Mellitus by Reversing Peripheral Insulin Resistance and Relieving β-Cell Destruction

Sun, Yaoxiang; Shi, Hui; Yin, Siqi; Ji, Chenfeng; Xu, Zu-De; Zhang, Bin; Wu, Peipei; Shi, Ying‐Hong; Mao, Fei; Yan, Yongmin; Xu, Wenrong; Qian, Hui

doi:10.1021/acsnano.7b07643

Cited by 304 publications

(211 citation statements)

References 64 publications

(146 reference statements)

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“…The cargo is often representative of their cell of origin [3]; this is thought to be why EVs derived from umbilical cord mesenchymal stromal cells (UCMSCs) have shown similar immunosuppressive effects to the UCMSCs themselves [2,5]. Indeed it has been shown in vitro that UCMSC-EVs can inhibit T-cell proliferation [6], and also in animal studies, where UCMSC-EVs are found to ameliorate hyperglycaemia in rats with type 2 diabetes mellitus [7], reduce neuroinflammation in a rat brain injury model [8] and improve acute respiratory distress symptoms in rats [9]. The evidence that UCMSCs and their EVs can suppress immune responses is appealing; however, in order to harness the full immunomodulatory properties of UCMSCs and their EVs, the best conditions for growing these cells must be established.…”

Section: Introductionmentioning

confidence: 99%

Pro-Inflammatory Priming of Umbilical Cord Mesenchymal Stromal Cells Alters the Protein Cargo of Their Extracellular Vesicles

Hyland

Mennan

Wilson

et al. 2020

Cells

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Umbilical cord mesenchymal stromal cells (UCMSCs) have shown an ability to modulate the immune system through the secretion of paracrine mediators, such as extracellular vesicles (EVs). However, the culture conditions that UCMSCs are grown in can alter their secretome and thereby affect their immunomodulatory potential. UCMSCs are commonly cultured at 21% O 2 in vitro, but recent research is exploring their growth at lower oxygen conditions to emulate circulating oxygen levels in vivo. Additionally, a pro-inflammatory culture environment is known to enhance UCMSC anti-inflammatory potential. Therefore, this paper examined EVs from UCMSCs grown in normal oxygen (21% O 2 ), low oxygen (5% O 2 ) and pro-inflammatory conditions to see the impact of culture conditions on the EV profile. EVs were isolated from UCMSC conditioned media and characterised based on size, morphology and surface marker expression. EV protein cargo was analysed using a proximity-based extension assay. Results showed that EVs had a similar size and morphology. Differences were found in EV protein cargo, with pro-inflammatory primed EVs showing an increase in proteins associated with chemotaxis and angiogenesis. This showed that the UCMSC culture environment could alter the EV protein profile and might have downstream implications for their functions in immunomodulation.

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Section: Introductionmentioning

confidence: 99%

Pro-Inflammatory Priming of Umbilical Cord Mesenchymal Stromal Cells Alters the Protein Cargo of Their Extracellular Vesicles

Hyland

Mennan

Wilson

et al. 2020

Cells

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“…In a type 2 diabetes rat model, intravenous infusion of hucMSC-EXs decreased the level of blood glucose and promoted glucose uptake, glycolysis, and glycogen storage [32]. 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: 98%

Section: Diabetesmentioning

confidence: 99%

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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“…Regarding T2D, treatment of obese mice with exosomes released by adipose tissue MSCs (AT‐MSCs) improved insulin sensitivity, reduced obesity, and alleviated hepatic steatosis by transferring active signal transducer and activator of transcription 3 (STAT3) and directing the alternative M2 activation of macrophages . Treatment with exosomes isolated from human umbilical cord MSCs (hucMSCs) was also able to increase insulin sensitivity and β‐cell survival in a rat model of T2D by combined high‐fat diet (HFD) feeding and STZ injection . Exosomes isolated from MSCs can also be used in the treatment of T1D, as they are immunomodulatory and favour cell survival.…”

Section: Exosomes As Therapy For Diabetesmentioning

confidence: 99%

Exosomes and diabetes

Castaño

Novials

Párrizas

2019

Diabetes Metabolism Res

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Summary Diabetes is a group of metabolic diseases characterized by elevated blood glucose levels that drive the development of life‐threatening complications. Diabetes results from a situation of insufficient insulin action, either by deficient production of the hormone by the pancreas, or by the development of insulin resistance in peripheral tissues such as liver, muscle, or the adipose depots. Communication between organs is thus central to the maintenance of glucose homoeostasis. Recently, several studies are evidencing that small vesicles called exosomes released by, amongst other, the adipose tissue can regulate gene expression in other tissues, hence modulating interorgan crosstalk. Therefore, exosomes participate in the development of diabetes and its associated complications. Their study holds the potential of providing us with novel biomarkers for the early diagnosis and stratification of patients at risk of developing diabetes, hence allowing the timely implementation of more personalized therapies. On the other hand, the molecular dissection of the pathways initiated by exosomes under situations of metabolic stress could help to gain a deeper knowledge of the pathophysiology of diabetes and its associated metabolic diseases.

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Human Mesenchymal Stem Cell Derived Exosomes Alleviate Type 2 Diabetes Mellitus by Reversing Peripheral Insulin Resistance and Relieving β-Cell Destruction

Cited by 304 publications

References 64 publications

Pro-Inflammatory Priming of Umbilical Cord Mesenchymal Stromal Cells Alters the Protein Cargo of Their Extracellular Vesicles

Pro-Inflammatory Priming of Umbilical Cord Mesenchymal Stromal Cells Alters the Protein Cargo of Their Extracellular Vesicles

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

Exosomes and diabetes

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