Targeted delivery of neural progenitor cell-derived extracellular vesicles for anti-inflammation after cerebral ischemia

ObjectiveStudies have shown that the therapeutic effects of mesenchymal stem cells (MSCs) are mediated in a paracrine manner, mainly through extracellular vesicles such as exosomes. Here, we designed a study to investigate whether exosomes derived from adipose-derived mesenchymal stem cells (ADMSC-Exos) had protective effects in a rat model of radiation-induced brain injury and in microglia.MethodsMale adult Sprague-Dawley (SD) rats were randomly divided into three groups: the control group, the radiation group (30 Gy), and the radiation + exosomes group (30 Gy + 100 ug exosomes). Meanwhile, microglia were divided into four groups: the control group, the radiation group (10 Gy), the radiation + exosomes group (10 Gy + 4 ug exosomes), and radiation + exosomes + EX527 group (10 Gy + 4 ug exosomes + 100 nM EX527). Tissue samples and the levels of oxidative stress and inflammatory factors in each group were compared.ResultsStatistical analysis showed that after irradiation, ADMSC-Exos intervention in vivo significantly reduced the levels of caspase-3, malondialdehyde (MDA), 8-hydroxydeoxyguanosine (8-OHdG), tumor necrosis factor-α (TNF-α), interleukin-4 (IL-4), and promoted the recovery of superoxide dismutase (SOD), catalase (CAT), IL-4, and IL-10. Moreover, ADMSC-Exos intervention inhibited microglial infiltration and promoted the expression of SIRT1. Furthermore, the results in vitro showed that the above effects of ADMSC-Exos could be reversed by SIRT-1 inhibitor EX527.ConclusionThis study demonstrated that ADMSC-Exos exerted protective effects against radiation-induced brain injury by reducing oxidative stress, inflammation and microglial infiltration via activating the SIRT1 pathway. ADMSC-Exos may serve as a promising therapeutic tool for radiation-induced brain injury.

Section: Discussionmentioning

confidence: 99%

Exosomes Derived From Adipose-Derived Mesenchymal Stem Cells Ameliorate Radiation-Induced Brain Injury by Activating the SIRT1 Pathway

Liu

Yang

Zhao

et al. 2021

“…As a member of the secreted extracellular matrix protein family, lactadherin is a small multifunctional glycoprotein that binds phosphatidylserine (PS)-enriched cell surfaces in a receptor-independent manner (Kamińska et al, 2018). Since the C1 and C2 domains (referred to as C1C2) readily selfassociates onto the EV membrane, Tian et al (2021) generated a recombinant fusion protein containing the arginine-glycineaspartic acid (RGD)-4C peptide fused to C1C2-the PSbinding domains of lactadherin. It was verified the RGD-EV targeted the lesion region of the ischemic brain after intravenous administration, and resulted in a strong suppression of the inflammatory response (Tian et al, 2021).…”

Section: Genetic Engineeringmentioning

confidence: 99%

“…Since the C1 and C2 domains (referred to as C1C2) readily selfassociates onto the EV membrane, Tian et al (2021) generated a recombinant fusion protein containing the arginine-glycineaspartic acid (RGD)-4C peptide fused to C1C2-the PSbinding domains of lactadherin. It was verified the RGD-EV targeted the lesion region of the ischemic brain after intravenous administration, and resulted in a strong suppression of the inflammatory response (Tian et al, 2021). To overcome pre-existing immunity to commonly used human adenovirus serotype 5 (Ad5), Bliss et al (2020) engineered targeting exosomes through fusion of Ag to the C1C2 domain of lactadherin, and revealed that exosomes induce substantially increasing Ag-specific humoral immunity post intramuscular and intranasal vaccination, improving the immunological potency of both ChAdOx1 and Ad5.…”

Section: Genetic Engineeringmentioning

confidence: 99%

Exosomes, a New Star for Targeted Delivery

Chen

Wang

Zeng

et al. 2021

165

125

Exosomes are cell-secreted nanoparticles (generally with a size of 30–150 nm) bearing numerous biological molecules including nucleic acids, proteins and lipids, which are thought to play important roles in intercellular communication. As carriers, exosomes hold promise as advanced platforms for targeted drug/gene delivery, owing to their unique properties, such as innate stability, low immunogenicity and excellent tissue/cell penetration capacity. However, their practical applications can be limited due to insufficient targeting ability or low efficacy in some cases. In order to overcome these existing challenges, various approaches have been applied to engineer cell-derived exosomes for a higher selectivity and effectiveness. This review presents the state-of-the-art designs and applications of advanced exosome-based systems for targeted cargo delivery. By discussing experts’ opinions, we hope this review will inspire the researchers in this field to develop more practical exosomal delivery systems for clinical applications.

“…Targeting proteins can also be incorporated onto EVs after their isolation from cell culture. Tian et al (2021) recently showed that fusion proteins that bind the phosphatidylserine component of the EV lipid membrane can be used to target EVs to ischemic brain tissue after systemic injection, relieving inflammation. The targeting protein was attached to EVs by simple incubation.…”

Section: Evs As a Novel Class Of Therapeuticmentioning

confidence: 99%

From Mesenchymal Stromal Cells to Engineered Extracellular Vesicles: A New Therapeutic Paradigm

Johnson

Shojaee²,

Crow³

et al. 2021

Mesenchymal stromal cells (MSCs) are multipotent cells obtained from many tissues including bone marrow, adipose tissue, umbilical cord, amniotic fluid, and placenta. MSCs are the leading cell source for stem cell therapy due to their regenerative and immunomodulatory properties, their low risk of tumorigenesis and lack of ethical constraints. However, clinical applications of MSCs remain limited. MSC therapeutic development continues to pose challenges in terms of preparation, purity, consistency, efficiency, reproducibility, processing time and scalability. Additionally, there are issues with their poor engraftment and survival in sites of disease or damage that limit their capacity to directly replace damaged cells. A key recent development in MSC research, however, is the now widely accepted view that MSCs primarily exert therapeutic effects via paracrine factor secretion. One of the major paracrine effectors are extracellular vesicles (EVs). EVs represent a potential cell-free alternative to stem cell therapy but are also rapidly emerging as a novel therapeutic platform in their own right, particularly in the form of engineered EVs (EEVs) tailored to target a broad range of clinical indications. However, the development of EVs and EEVs for therapeutic application still faces a number of hurdles, including the establishment of a consistent, scalable cell source, and the development of robust GMP-compliant upstream and downstream manufacturing processes. In this review we will highlight the clinical challenges of MSC therapeutic development and discuss how EVs and EEVs can overcome the challenges faced in the clinical application of MSCs.