Exosomes have great potential to be drug delivery vehicles due to their natural material transportation properties, intrinsic long-term circulatory capability, and excellent biocompatibility, which are suitable for delivering a variety of chemicals, proteins, nucleic acids, and gene therapeutic agents. However, an effective method of loading specific protein agents into exosomes for absorption by target cells is still lacking. The application potential of exosome is still limited. In this review, we discussed the methods for loading specific treating molecules (proteins, nucleic acids and small chemicals) into exosomes, the design strategies for cell and tissue targeting, and the factors for exosome formation. This review can be used as a reference for further research as well as for the development of therapeutic exosomes.

Design strategies and application progress of therapeutic exosomes.

Background/aims Recent studies have indicated that exosomes secreted from adipose-derived stem cells (ADSCs) have important effects in the treatment of ischemic injury. However, the treatment mechanism is unclear. This study aimed to investigate whether ADSC-derived exosomes enriched with microRNA (miR)-30d-5p have a protective effect on acute ischemic stroke (AIS). Methods In the current study, inflammatory factors and miR-30d-5p expression were assessed in 70 subjects with AIS and 35 healthy controls. Exosomes were characterized by transmission electron microscopy and further examined using nanoparticle tracking analyses. A rat model of AIS and an in vitro model of oxygen- and glucose-deprived (OGD) primary microglia were established to study the protective mechanism of exosomes from miR-30d-5p-overexpressing ADSCs in ischemia-induced nerve injury. Results The results showed that following AIS, the expression of inflammatory cytokines increased, while the anti-inflammatory cytokines IL-4, IL-10, and miR-30d-5p decreased both in patients and in animal models. Moreover, in vitro studies demonstrated that suppression of autophagy significantly reduced the OGD-induced inflammatory response. In addition, exosome treatment was more effective in suppressing the inflammatory response by reversing OGD-induced and autophagy-mediated microglial polarization to M1. Furthermore, in vivo studies showed that exosomes derived from ADSCs significantly decreased the cerebral injury area of infarction by suppressing autophagy and promoting M2 microglia/macrophage polarization. Conclusions Our results suggest that miR-30d-5p-enhanced ADSC-derived exosomes prevent cerebral injury by inhibiting autophagy-mediated microglial polarization to M1.

/pdf/exosomes-from-mir-30d-5p-adscs-reverse-acute-ischemic-stroke-4e6x0dirq5.pdf

Exosomes from MiR-30d-5p-ADSCs Reverse Acute Ischemic Stroke-Induced, Autophagy-Mediated Brain Injury by Promoting M2 Microglial/Macrophage Polarization.

Mesenchymal stem cells (MSCs) are on the cusp of regenerative medicine due to their differentiation capacity, favorable culture conditions, ability to be manipulated in vitro, and strong immunomodulatory activity. Recent studies indicate that the pleiotropic effects of MSCs, especially their immunomodulatory potential, can be largely attributed to paracrine factors. Exosomes, vesicles that are 30-150 nanometers in diameter that function in cell-cell communication, are one of the key paracrine effectors. MSC-derived exosomes are enriched with therapeutic miRNAs, mRNAs, cytokines, lipids, and growth factors. Emerging evidences support the compelling possibility of using MSC-derived exosomes as a new form of therapy for treating several different kinds of disease such as heart, kidney, immune diseases, neural injuries, and neurodegenerative disease. This review provides a summary of current knowledge and discusses engineering of MSC-derived exosomes for their use in translational medicine.

Current Knowledge and Future Perspectives on Mesenchymal Stem Cell-Derived Exosomes as a New Therapeutic Agent.

Exosomes from adipose-derived mesenchymal stem cells ameliorate cardiac damage after myocardial infarction by activating S1P/SK1/S1PR1 signaling and promoting macrophage M2 polarization

Exosomes are extracellular membranous nanovesicles that mediate local and systemic intercellular communication by transporting proteins or nucleic acids (DNA and RNA) into target cells, thus altering the behaviors of recipient cells. Recent studies have revealed that these vesicles play a critical role in many biological functions, such as cell proliferation, immune regulation, nerve regeneration, and cancer. Adipose-derived stem cells (ADSCs) are now considered a multipotent and abundant tool in the field of cell therapy and regenerative medicine. ADSCs can produce and secrete many exosomes, which inherit multiple functions of cells. Therefore, in this review, we will introduce the characteristics of exosomes derived from ADSCs (ADSC-Exos), describe their functions in different biological processes, summarize the latest research achievements, describe their limitations in cell-free therapy, and provide further insights into their clinical application potential for the treatment of certain diseases.

/pdf/the-functions-and-clinical-application-potential-of-exosomes-3u6uxig108.pdf

The functions and clinical application potential of exosomes derived from adipose mesenchymal stem cells: a comprehensive review.

Background/Aims: Recent studies have indicated that exosomes play an important role in adipose-derived stem cell (ADSC) transplant-mediated ischaemic heart disease therapy. However, the treatment effect is not obvious. The aim of this study is to investigate whether ADSC-derived exosomes enriched with microRNA (miR)-126 have a more protective effect on acute myocardial infarction (AMI). Methods: Exosomes were characterized by transmission electron microscopy, and the exosome particles were further examined using nanoparticle tracking analyses. A rat model of myocardial infarction and in vitro model of hypoxia-induced H9c2 myocardial cell injury were established to study the protective mechanism of exosomes from miR-126-overexpressing ADSCs. Results: The in vitro results showed that exosomes derived from miR-126-overexpressing ADSCs decreased H9c2 myocardial cell injury by reducing inflammation factor expression during hypoxia induction. The miR-126-enriched exosomes also decreased the expression of fibrosis-related proteins of H9c2 cells under hypoxic conditions. Matrigel® and Transwell® assays showed that miR-126-enriched exosomes significantly promoted microvascular generation and migration, respectively. In vivo studies confirmed that exosomes derived from ADSCs significantly decreased the myocardial injury area of infarction, especially after miR-126-enriched exosome treatment. Cardiac fibrosis and inflammatory cytokine expression were also decreased after treatment with miR-126-enriched exosomes. However, blood vessel formation was promoted in the infarction region of AMI rats. Conclusions: The results suggested that the expression of miR-126-enhanced ADSC-derived exosomes prevented myocardial damage by protecting myocardial cells from apoptosis, inflammation, fibrosis, and increased angiogenesis.

/pdf/exosomes-from-mir-126-overexpressing-adscs-are-therapeutic-ytk1qyby6w.pdf

Exosomes from MiR-126-Overexpressing Adscs Are Therapeutic in Relieving Acute Myocardial Ischaemic Injury.

Polydatin is a traditional Chinese medicine that provides myocardial protection after acute myocardial infarction (AMI) The study aim was to investigate the myocardial protection polydatin in H9c2 myocardial cells cultured in a hypoxic atmosphere and in a rat AMI model induced by ligating the left anterior descending coronary artery and treated with polydatin 100 mg/kg/day for 30 days The involvement of Nrf2 in mediating the effects of polydatin was investigated in H9c2 cells following Nrf2 knockdown by transfection of siRNA Polydatin suppressed hypoxia-induced H9c2 cell apoptosis and reactive oxygen species (ROS) generation by promoting Nrf2/HO-1 signaling Nrf2 knockdown reversed the protective effects of polydatin against hypoxia-induced myocardial cell injury The in vivo results were consistent with polydatin suppression of apoptosis and ROS generation in myocardial tissue by promotion of Nrf2/HO-1 signaling In conclusion, polydatin effectively inhibited hypoxia- and AMI-induced myocardial damage by promotion of Nrf2/HO-1 signaling

Polydatin protects against acute myocardial infarction-induced cardiac damage by activation of Nrf2/HO-1 signaling

Sepsis is a life-threatening condition. Polydatin (PD), a small natural compound from Polygonum cuspidatum, possesses antioxidant and anti-inflammatory properties. However, the protective mechanism of PD on sepsis-induced acute myocardial damage is still unclear. The aim of this study was to investigate the effect and mechanism of action of PD on lipopolysaccharide (LPS)-induced H9c2 cells and in a rat model of sepsis, and explored the role of PD-upregulated sirtuin (SIRT)6. LPS-induced H9c2 cells were used to simulate sepsis. Cecal ligation and puncture (CLP)-induced sepsis in rats were used to verify the protective effect of PD. ELISA, western blotting, immunofluorescence, immunohistochemistry, and flow cytometry were used to study the protective mechanism of PD against septic myocardial injury. PD pretreatment suppressed LPS-induced H9c2 cell apoptosis by promotion of SIRT6-mediated autophagy. Downregulation of SIRT6 or inhibition of autophagy reversed the protective effect of PD on LPS-induced apoptosis. PD pretreatment also suppressed LPS-induced inflammatory factor expression. CLP-induced sepsis in rats showed that PD pretreatment decreased CLP-induced myocardial apoptosis and serum tumor necrosis factor-α, interleukin (IL)-1β, and IL-6 expression. 3-Methyladenine (autophagy inhibitor) pretreatment prevented the protective effect of PD on septic cardiomyopathy. SIRT6 expression was increased with PD treatment, which confirmed that PD attenuates septic cardiomyopathy by promotion of SIRT6-mediated autophagy. All these results indicate that PD has potential therapeutic effects that alleviate septic myocardial injury by promotion of SIRT6-mediated autophagy.

Polydatin Alleviates Septic Myocardial Injury by Promoting SIRT6-Mediated Autophagy.

The mechanism underlying sepsis‑induced cardiomyopathy (SICM) remains unclear. The aim of the present study was therefore to illuminate the mechanisms and effects of apelin on SICM, using both patient clinical features and a sepsis rat model. A total of 73 adult patients with or without sepsis were analyzed. Male rats were used to generate the sepsis model through cecal ligation and puncture (CLP). The clinical analysis results demonstrated that sepsis induced cardiac dysfunction, including a decrease of left ventricular end‑diastolic dimension, fractional shortening, ejection fraction, left ventricular end‑systolic dimension, and stroke volume, compared with healthy controls. In addition, the results demonstrated that white blood cell count and inflammatory cytokine expression increased in sepsis patients compared with healthy controls. ELISA analyses revealed that apelin was upregulated following sepsis. The animal model study demonstrated that rats treated with apelin had significantly reduced mortality and suppressed sepsis‑induced myocardial damage and inflammatory responses, through suppression of activation of the Toll‑like receptor 4 (TLR4) and NLR family pyrin domain containing 3 (NLRP3) signaling pathways. Taken together, the present results suggested that apelin had a protective effect against sepsis‑induced cardiac impairment by attenuating TLR4 and NLRP3 signaling‑mediated inflammatory responses.

/pdf/apelin-protects-against-sepsis-induced-cardiomyopathy-by-37fycorb4g.pdf

Apelin protects against sepsis‑induced cardiomyopathy by inhibiting the TLR4 and NLRP3 signaling pathways.

Sepsis is a common complication of severe wound injury and infection, with a very high mortality rate. The P2Y12 receptor inhibitor, cangrelor, is an antagonist anti-platelet drug. In our study, we investigated the protective mechanisms of cangrelor in CLP-induced pulmonary injury in sepsis, using C57BL/6 mouse models. TdT-mediated dUTP Nick-End Labeling (TUNEL) and Masson staining showed that apoptosis and fibrosis in lungs were alleviated by cangrelor treatment. Cangrelor significantly promoted surface expression of CD40L on platelets and inhibited CLP-induced neutrophils in Bronchoalveolar lavage fluid (BALF) (p < 0.001). We also found that cangrelor decreased the inflammatory response in the CLP mouse model and inhibited the expression of inflammatory cytokines, IL-1β (p  < 0.01), IL-6 (p < 0.05), and TNF-α (p < 0.001). Western blotting and RT-PCR showed that cangrelor inhibited the increased levels of G-protein-coupled receptor 17 (GPR17) induced by CLP (p < 0.001). Our study indicated that cangrelor repressed the levels of GPR17, followed by a decrease in the inflammatory response and a rise of neutrophils in BALF, potentially reversing CLP-mediated pulmonary injury during sepsis.

/pdf/cangrelor-ameliorates-clp-induced-pulmonary-injury-in-sepsis-r1ded7ryft.pdf

Dongfeng Guo

Papers

Exosomes from MiR-126-Overexpressing Adscs Are Therapeutic in Relieving Acute Myocardial Ischaemic Injury.

Polydatin protects against acute myocardial infarction-induced cardiac damage by activation of Nrf2/HO-1 signaling

Polydatin Alleviates Septic Myocardial Injury by Promoting SIRT6-Mediated Autophagy.

Apelin protects against sepsis‑induced cardiomyopathy by inhibiting the TLR4 and NLRP3 signaling pathways.

Cangrelor ameliorates CLP-induced pulmonary injury in sepsis by inhibiting GPR17.