Embryonic Stem Cell-Derived Extracellular Vesicles Maintain ESC Stemness by Activating FAK.
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ABSTRACT:
SUBMITTER: Hur YH
PROVIDER: S-EPMC8005871 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Background: Embryonic stem cells (ES) have a great potential for cell-based therapies in a regenerative medicine. However, the ethical and safety issues limit its clinical application. ES-derived extracellular vesicles (ES-EVs) have been reported suppress cellular senescence. Mesenchymal stem cells (MSCs) are widely used for clinical cell therapy. In this study, we investigated the beneficial effects of ES-EVs on aging MSCs to further enhancing their therapeutic effects. Methods: In vitro, we explored the rejuvenating effects of ES-EVs on senescent MSCs by senescence-associated β-gal (SA-β-gal) staining, immunostaining, and DNA damage foci analysis. The therapeutic effect of senescent MSC pre-treated with ES-EVs was also evaluated by using mouse cutaneous wound model. Results: We found that ES-EVs significantly rejuvenated the senescent MSCs in vitro and improve the therapeutic effects of MSCs in a mouse cutaneous wound model. In addition, we also identified that the IGF1/PI3K/AKT pathway mediated the antisenescence effects of ES-EVs on MSCs. Conclusions: Our results suggested that ES cells derived-extracellular vesicles possess the antisenescence properties, which significantly rejuvenate the senescent MSCs and enhance the therapeutic effects of MSCs. This strategy might emerge as a novel therapeutic strategy for MSCs clinical application.
| S-EPMC6815953 | biostudies-literature
Project description:BackgroundEmbryonic stem cell-derived extracellular vesicles (ESC-EVs) possess therapeutic potential for a variety of diseases and are considered as an alternative of ES cells. Acute kidney injury (AKI) is a common acute and severe disease in clinical practice, which seriously threatens human life and health. However, the roles and mechanisms of ESC-EVs on AKI remain unclear.MethodsIn this study, we evaluated the effects of ESC-EVs on physiological repair and pathological repair using murine ischemia-reperfusion injury-induced AKI model, the potential mechanisms of which were next investigated. EVs were isolated from ESCs and EVs derived from mouse fibroblasts as therapeutic controls. We then investigated whether ESC-EVs can restore the structure and function of the damaged kidney by promoting physiological repair and inhibiting the pathological repair process after AKI in vivo and in vitro.ResultsWe found that ESC-EVs significantly promoted the recovery of the structure and function of the damaged kidney. ESC-EVs increased the proliferation of renal tubular epithelial cells, facilitated renal angiogenesis, inhibited the progression of renal fibrosis, and rescued DNA damage caused by ischemia and reperfusion after AKI. Finally, we found that ESC-EVs play a therapeutic effect by activating Sox9+ cells.ConclusionsESC-EVs significantly promote the physiological repair and inhibit the pathological repair after AKI, enabling restoration of the structure and function of the damaged kidney. This strategy might emerge as a novel therapeutic strategy for ESC clinical application.
| S-EPMC8254253 | biostudies-literature
Project description:Aging is associated with high prevalence of chronic degenerative diseases that take a large part of the increasing burden of morbidities in a growing demographic of elderly people. Aging is a complex process that involves cell autonomous and cell non-autonomous mechanisms where senescence plays an important role. Senescence is characterized by the loss of proliferative potential, resistance to cell death by apoptosis and expression of a senescence-associated secretory phenotype (SASP). SASP includes pro-inflammatory cytokines and chemokines, tissue-damaging proteases, growth factors; all contributing to tissue microenvironment alteration and loss of tissue homeostasis. Emerging evidence suggests that the changes in the number and composition of extracellular vesicles (EVs) released by senescent cells contribute to the adverse effects of senescence in aging. In addition, age-related alterations in mesenchymal stem/stromal cells (MSCs) have been associated to dysregulated functions. The loss of functional stem cells necessary to maintain tissue homeostasis likely directly contributes to aging. In this review, we will focus on the characteristics and role of EVs isolated from senescent MSCs, the potential effect of MSC-derived EVs in aging and discuss their therapeutic potential to improve age-related diseases.
| S-EPMC7047768 | biostudies-literature
Project description:Mesenchymal stem/stromal cells (MSCs) have distinct capability for renal repair, but may have safety concerns. MSC-derived extracellular vesicles emerged as a novel noncellular alternative. Using a porcine model of metabolic syndrome and renal artery stenosis we tested whether extracellular vesicles attenuate renal inflammation, and if this capacity is mediated by their cargo of the anti-inflammatory cytokine interleukin (IL) 10. Pigs with metabolic syndrome were studied after 16 weeks of renal artery stenosis untreated or treated four weeks earlier with a single intrarenal delivery of extracellular vesicles harvested from adipose tissue-derived autologous MSCs. Lean and sham metabolic syndrome animals served as controls (seven each). Five additional pigs with metabolic syndrome and renal artery stenosis received extracellular vesicles with pre-silenced IL10 (IL10 knock-down). Single-kidney renal blood flow, glomerular filtration rate, and oxygenation were studied in vivo and renal injury pathways ex vivo. Retention of extracellular vesicles in the stenotic kidney peaked two days after delivery and decreased thereafter. Four weeks after injection, extracellular vesicle fragments colocalized with stenotic-kidney tubular cells and macrophages, indicating internalization or fusion. Extracellular vesicle delivery attenuated renal inflammation, and improved medullary oxygenation and fibrosis. Renal blood flow and glomerular filtration rate fell in metabolic syndrome and renal artery stenosis compared to metabolic syndrome, but was restored in pigs treated with extracellular vesicles. These renoprotective effects were blunted in pigs treated with IL10-depleted extracellular vesicles. Thus, extracellular vesicle-based regenerative strategies might be useful for patients with metabolic syndrome and renal artery stenosis.
| S-EPMC5483390 | biostudies-literature
Project description:Mesenchymal stem cells (MSCs) are multipotent stem cells that have attracted increasing interest in the field of regenerative medicine. Previously, the differentiation ability of MSCs was believed to be primarily responsible for tissue repair. Recent studies have shown that paracrine mechanisms play an important role in this process. MSCs can secrete soluble molecules and extracellular vesicles (EVs), which mediate paracrine communication. EVs contain large amounts of proteins and nucleic acids, such as mRNAs and microRNAs (miRNAs), and can transfer the cargo between cells. The cargoes are similar to those in MSCs and are not susceptible to degradation due to the protection of the EV bimolecular membrane structure. MSC-EVs can mimic the biological characteristics of MSCs, such as differentiation, maturation, and self-renewal. Due to their broad biological functions and their ability to transfer molecules between cells, EVs have been intensively studied by an increasing number of researchers with a focus on therapeutic applications, especially those of EVs secreted by MSCs. In this review, we discuss MSC-derived EVs and their therapeutic potential in tissue regeneration.
| S-EPMC7444208 | biostudies-literature
Project description:Spinal cord injury (SCI) can cause severe irreversible motor dysfunction and even death. Neural stem cell (NSC) transplantation can promote functional recovery after acute SCI in experimental animals, but numerous issues, including low-transplanted cell survival rate, cell de-differentiation, and tumor formation need to be resolved before routine clinical application is feasible. Recent studies have shown that transplanted stem cells facilitate regeneration through release of paracrine factors. Small extracellular vesicles (sEVs), the smallest known membrane-bound nanovesicles, are involved in complex intercellular communication systems and are an important vehicle for paracrine delivery of therapeutic agents. However, the application of NSC-derived small extracellular vesicles (NSC-sEVs) to SCI treatment has not been reported. We demonstrate that NSC-sEVs can significantly reduce the extent of SCI, improve functional recovery, and reduce neuronal apoptosis, microglia activation, and neuroinflammation in rats. Furthermore, our study suggests that NSC-sEVs can regulate apoptosis and inflammatory processes by inducing autophagy. In brief, NSC-sEVs increased the expression of the autophagy marker proteins LC3B and beclin-1, and promoted autophagosome formation. Following NSC-sEV infusion, the SCI area was significantly reduced, and the expression levels of the proapoptotic protein Bax, the apoptosis effector cleaved caspase-3, and the pro-inflammatory cytokines TNF-α, IL-1β, and IL-6 were significantly reduced, whereas the expression level of the anti-apoptotic protein Bcl-2 was upregulated. In the presence of the autophagy inhibitor 3MA, however, these inhibitory effects of NSC-sEVs on apoptosis and neuroinflammation were significantly reversed. Our results show for the first time that NSC-sEV treatment has the potential to reduce neuronal apoptosis, inhibit neuroinflammation, and promote functional recovery in SCI model rats at an early stage by promoting autophagy.
| S-EPMC6472377 | biostudies-literature
Project description:The onset and progression of human inflammatory joint diseases are strongly associated with the activation of resident synovium/infrapatellar fat pad (IFP) pro-inflammatory and pain-transmitting signaling. We recently reported that intra-articularly injected IFP-derived mesenchymal stem/stromal cells (IFP-MSC) acquire a potent immunomodulatory phenotype and actively degrade substance P (SP) via neutral endopeptidase CD10 (neprilysin). Our hypothesis is that IFP-MSC robust immunomodulatory therapeutic effects are largely exerted via their CD10-bound small extracellular vesicles (IFP-MSC sEVs) by attenuating synoviocyte pro-inflammatory activation and articular cartilage degradation. Herein, IFP-MSC sEVs were isolated from CD10High- and CD10Low-expressing IFP-MSC cultures and their sEV miRNA cargo was assessed using multiplex methods. Functionally, we interrogated the effect of CD10High and CD10Low sEVs on stimulated by inflammatory/fibrotic cues synoviocyte monocultures and cocultures with IFP-MSC-derived chondropellets. Finally, CD10High sEVs were tested in vivo for their therapeutic capacity in an animal model of acute synovitis/fat pad fibrosis. Our results showed that CD10High and CD10Low sEVs possess distinct miRNA profiles. Reactome analysis of miRNAs highly present in sEVs showed their involvement in the regulation of six gene groups, particularly those involving the immune system. Stimulated synoviocytes exposed to IFP-MSC sEVs demonstrated significantly reduced proliferation and altered inflammation-related molecular profiles compared to control stimulated synoviocytes. Importantly, CD10High sEV treatment of stimulated chondropellets/synoviocyte cocultures indicated significant chondroprotective effects. Therapeutically, CD10High sEV treatment resulted in robust chondroprotective effects by retaining articular cartilage structure/composition and PRG4 (lubricin)-expressing cartilage cells in the animal model of acute synovitis/IFP fibrosis. Our study suggests that CD10High sEVs possess immunomodulatory miRNA attributes with strong chondroprotective/anabolic effects for articular cartilage in vivo. The results could serve as a foundation for sEV-based therapeutics for the resolution of detrimental aspects of immune-mediated inflammatory joint changes associated with conditions such as osteoarthritis (OA).
| S-EPMC10377825 | biostudies-literature
Project description:BackgroundPrimary human hepatocytes (PHHs) are the ideal candidates for studying critical liver functions such as drug metabolism and toxicity. However, as they are isolated from discarded livers that are unsuitable for transplantation, they possess limited expansion ability in vitro and their enzymatic functions deteriorate rapidly because they are often of poor quality. Therefore, there is a compelling reason to find reliable alternative sources of hepatocytes.MethodsIn this study, we report on efficient and robust differentiation of embryonic stem cells (ESC) from the common marmoset Callithrix jacchus into functional hepatocyte-like cells (HLC) using a simple, and reproducible three-step procedure. ESC-derived HLCs were examined by morphological analysis and tested for their expression of hepatocyte-specific markers using a combination of immunohistochemistry, RT-PCR, and biochemical assays. Primary human hepatocytes were used as controls.ResultsESC-derived HLCs expressed each of the hepatocyte-specific markers tested, including albumin; α-fetoprotein; asialoglycoprotein receptor 1; α-1 antitrypsin; hepatocyte nuclear factors 1α and 4; cytokeratin 18; hepatocyte growth factor receptor; transferrin; tyrosine aminotransferase; alkaline phosphatase; c-reactive protein; cytochrome P450 enzymes CYP1A2, CYP2E1 and CYP3A4; and coagulation factors FVII and FIX. They were functionally competent as demonstrated by biochemical assays in addition to producing urea.ConclusionOur data strongly suggest that marmoset HLCs possess characteristics similar to those of PHHs. They could, therefore, be invaluable for studies on drug metabolism and cell transplantation therapy for a variety of liver disorders. Because of the similarities in the anatomical and physiological features of the common marmoset to that of humans, Callithrix jacchus is an appropriate animal model to study human disease conditions and cellular functions.
| S-EPMC7026140 | biostudies-literature
Project description:Extracellular vesicles (EVs) are cell-derived membrane-bound nanoparticles, which act as shuttles, delivering a range of biomolecules to diverse target cells. They play an important role in maintenance of biophysiological homeostasis and cellular, physiological, and pathological processes. EVs have significant diagnostic and therapeutic potentials and have been studied both in vitro and in vivo in many fields. Mesenchymal stem cells (MSCs) are multipotent cells with many therapeutic applications and have also gained much attention as prolific producers of EVs. MSC-derived EVs are being explored as a therapeutic alternative to MSCs since they may have similar therapeutic effects but are cell-free. They have applications in regenerative medicine and tissue engineering and, most importantly, confer several advantages over cells such as lower immunogenicity, capacity to cross biological barriers, and less safety concerns. In this review, we introduce the biogenesis of EVs, including exosomes and microvesicles. We then turn more specifically to investigations of MSC-derived EVs. We highlight the great therapeutic potential of MSC-derived EVs and applications in regenerative medicine and tissue engineering.
| S-EPMC7463378 | biostudies-literature
Project description:Within the last two decades mesenchymal stem/stromal cells (MSCs) emerged after hematopoietic stem cells as the second most investigated and applied somatic stem cell entity so far. MSCs mediate immunosuppressive as well as pro-regenerative activities. Against the initial assumption, MSCs may not primarily exert their therapeutic functions in a cellular but rather in a paracrine manner. Here, extracellular vesicles (EVs), such as exosomes and microvesicles, have been identified as major mediators of these paracrine effects. Meanwhile, MSC-EVs have been applied to an increasing amount of different animal models and were tested in a patient suffering from steroid-refractory acute graft-versus-host disease (acute GvHD) as well as in a patient cohort with chronic kidney disease. So far, the MSC-EV administration appears to be safe in humans and all tested animal models. Improvements were reported in all settings. Thus, MSC-EVs appear as promising novel therapeutic agents which might help to improve disease associated symptoms in millions of patients. Here, we review some of the milestones in the field, briefly discuss challenges and highlight clinical aspects of acute GvHD and its treatment with MSCs and MSC-EVs.
| S-EPMC5676188 | biostudies-literature