Neuroprotective effect of placenta-derived mesenchymal stromal cells: role of exosomes.
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ABSTRACT:
SUBMITTER: Kumar P
PROVIDER: S-EPMC6463921 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The skin is the largest organ of the human body and its main functions include providing protection from external harmful agents, regulating body temperature, and homeostatic maintenance. Skin injuries can damage this important barrier and its functions so research focuses on approaches to accelerate wound healing and treat inflammatory skin diseases. Due to their regenerative and immunomodulatory properties, mesenchymal stromal cells (MSCs) have been reported to play a significant role in skin repair and regeneration. However, it seems that the secretome of these cells and exosomes in particular may be responsible for their functions in skin regeneration and the immunomodulation field. The present review aims to gather the available information about the role of MSC-derived exosomes for both in vitro and in vivo models of different skin conditions and to highlight the need for further research in order to overcome any limitations for clinical translation.
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Project description:BackgroundThe therapeutic potential of mesenchymal stem cells (MSCs) may be attributed partly to humoral factors such as growth factors, cytokines, and chemokines. Human term placental tissue-derived MSCs (PlaMSCs), or conditioned medium left over from cultures of these cells, have been reported to enhance angiogenesis. Recently, the exosome, which can transport a diverse suite of macromolecules, has gained attention as a novel intercellular communication tool. However, the potential role of the exosome in PlaMSC therapeutic action is not well understood. The purpose of this study was to evaluate PlaMSC-derived exosome angiogenesis promotion in vitro and in vivo.MethodsMSCs were isolated from human term placental tissue by enzymatic digestion. Conditioned medium was collected after 48-h incubation in serum-free medium (PlaMSC-CM). Angiogenic factors present in PlaMSC-CM were screened by a growth factor array. Exosomes were prepared by ultracentrifugation of PlaMSC-CM, and confirmed by transmission electron microscopy, dynamic light scattering, and western blot analyses. The proangiogenic activity of PlaMSC-derived exosomes (PlaMSC-exo) was assessed using an endothelial tube formation assay, a cell migration assay, and reverse transcription-PCR analysis. The in-vivo angiogenic activity of PlaMSC-exo was evaluated using a murine auricle ischemic injury model.ResultsPlaMSC-CM contained both angiogenic and angiostatic factors, which enhanced endothelial tube formation. PlaMSC-exo were incorporated into endothelial cells; these exosomes stimulated both endothelial tube formation and migration, and enhanced angiogenesis-related gene expression. Laser Doppler blood flow analysis showed that PlaMSC-exo infusion also enhanced angiogenesis in an in-vivo murine auricle ischemic injury model.ConclusionsPlaMSC-exo enhanced angiogenesis in vitro and in vivo, suggesting that exosomes play a role in the proangiogenic activity of PlaMSCs. PlaMSC-exo may be a novel therapeutic approach for treating ischemic diseases.
| S-EPMC5627451 | biostudies-literature
Project description:BackgroundMesenchymal stromal cells (MSCs) are a promising therapy for preventing chronic Graft-Versus-Host Disease (cGVHD) due to their potent immunomodulatory properties. However, the safety concerns regarding the use of MSCs remain unsolved, and conflicting effects are observed due to the heterogeneity of MSCs. Recently, exosomes were shown to mediate the paracrine effects of MSCs, making it a potential candidate for cell-free therapies. The aim of this study is to investigate the efficacy and safety of MSCs-derived exosomes (MSCs-exo) in an established cGVHD mouse model.MethodsBone marrow (BM)-derived MSCs were cultured, and the supernatants of these cultures were collected to prepare exosomes using ultracentrifugation. Exosomes from human dermal fibroblasts (Fib-exo) were used as a negative control. The cGVHD model was established, and tail vein injections of MSCs-exo or Fib-exo were administered once per week for 6?weeks. The symptoms and signs of cGVHD were monitored, and histopathological changes were detected by hematoxylin and eosin and Masson staining. The effects of MSCs-exo on Th17, Th1, and Treg were evaluated by flow cytometry, qPCR, and Luminex. In addition, human peripheral blood mononuclear cells (PBMCs) were stimulated and treated with MSCs-exo in vitro. IL-17-expressing Th17 and IL-10-expressing Treg were evaluated by flow cytometry, qPCR, and ELISA.ResultsWe found that MSCs-exo effectively prolonged the survival of cGVHD mice and diminished the clinical and pathological scores of cGVHD. Fibrosis in the skin, lung, and liver was significantly ameliorated by MSCs-exo application. In MSCs-exo treated mice, activation of CD4+ T cells and their infiltration into the lung were reduced. Of note, MSCs-exo exhibited potent immunomodulatory effects via the inhibition of IL-17-expressing pathogenic T cells and induction of IL-10-expressing regulatory cells during cGVHD. The expressions of Th17 cell-relevant transcription factors and pro-inflammatory cytokines was markedly reduced after MSCs-exo treatment. In vitro, MSCs-exo blocked Th17 differentiation and improved the Treg phenotype in PBMCs obtained from healthy donors and patients with active cGVHD, further indicating the regulatory effect of MSCs-exo on GVHD effector T cells.ConclusionsOur data suggested that MSCs-exo could improve the survival and ameliorate the pathologic damage of cGVHD by suppressing Th17 cells and inducing Treg. This finding provides a novel alternative approach for the treatment of cGVHD.
| S-EPMC6286548 | biostudies-literature
Project description:Exosomes are nanovesicles secreted by virtually all cells. Exosomes mediate the horizontal transfer of various macromolecules previously believed to be cell-autonomous in nature, including nonsecretory proteins, various classes of RNA, metabolites, and lipid membrane-associated factors. Exosomes derived from mesenchymal stem/stromal cells (MSCs) appear to be particularly beneficial for enhancing recovery in various models of disease. To date, there have been more than 200 preclinical studies of exosome-based therapies in a number of different animal models. Despite a growing number of studies reporting the therapeutic properties of MSC-derived exosomes, their underlying mechanism of action, pharmacokinetics, and scalable manufacturing remain largely outstanding questions. Here, we review the global trends associated with preclinical development of MSC-derived exosome-based therapies, including immunogenicity, source of exosomes, isolation methods, biodistribution, and disease categories tested to date. Although the in vivo data assessing the therapeutic properties of MSC-exosomes published to date are promising, several outstanding questions remain to be answered that warrant further preclinical investigation.
| S-EPMC7004029 | biostudies-literature
Project description:Studies in which mesenchymal stromal cells (MSC) from the placenta are compared with multiple MSC types from other sources are rare. The chorionic plate of the human placenta is mainly composed of fetal blood vessels embedded in fetal stroma tissue, lined by trophoblastic cells and organized into chorionic villi (CV) structures.We comprehensively characterized human MSC collected from postnatal human chorionic villi of placenta (CV-MSC) by analyzing their growth and proliferation potential, differentiation, immunophenotype, extracellular matrix production, telomere length, aging phenotype, and plasticity.Immunophenotypic characterization of CV-MSC confirmed the typical MSC marker expression as defined by the International Society for Cellular Therapy. The surface marker profile was consistent with increased potential for proliferation, vascular localization, and early myogenic marker expression. CV-MSC retained multilineage differentiation potential and extracellular matrix remodeling properties. They have undergone reduced telomere loss and delayed onset of cellular senescence as they aged in vitro compared to three other MSC sources. We present evidence that increased human telomerase reverse transcriptase gene expression could not explain the exceptional telomere maintenance and senescence onset delay in cultured CV-MSC. Our in-vitro tumorigenesis detection assay suggests that CV-MSC are not prone to undergo malignant transformation during long-term in-vitro culture. Besides SOX2 expression, no other pluripotency features were observed in early and late passages of CV-MSC.Our work brings forward two remarkable characteristics of CV-MSC, the first being their extended life span as a result of delayed replicative senescence and the second being a delayed aged phenotype characterized by improved telomere length maintenance. MSC from human placenta are very attractive candidates for stem cell-based therapy applications.
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Project description:Mesenchymal stromal cells (MSCs) are a major component of the tumour microenvironment. A plethora of elegant studies focusing on tumour-derived MSCs have shown that they, unlike normal MSCs in other tissue, exhibit a strong ability to promote tumour progression. However, the mechanisms underlying the conversion of normal MSCs into tumour-associated MSCs are unknown. We report here a critical role of tumour cell-derived exosomes in endowing bone marrow-derived MSCs (BM-MSCs) with a tumour-favourable phenotype. Tumour cell-derived exosomes affected neither the growth factor production nor the immunosuppressive property of MSCs; rather, they endowed MSCs with a strong ability to promote macrophage infiltration into B16-F0 melanoma or EL-4 lymphoma. Ablation of macrophages by clodronate liposome administration reversed the tumour-promoting effect of MSCs educated by tumour cell-derived exosomes (TE-MSCs) on the tumour growth. By comparing the chemokine profile of BM-MSCs with that of TE-MSCs, we found that TE-MSCs produced a large amount of CCR2 ligands, CCL2 and CCL7, which are responsible for macrophage recruitment. CCR2-specific inhibitor was found to block the tumour-promoting effect of TE-MSCs. Thus, our investigations demonstrated that tumour cell-derived exosomes confer BM-MSCs the ability to enhance tumour growth. Therefore, we uncovered a novel mechanism underlying the conversion of normal MSCs to tumour-associated MSCs.
| S-EPMC5116561 | biostudies-literature
Project description:Fetal membranes (FM) derived mesenchymal stromal/stem cells (MSCs) are higher in number, expansion and differentiation abilities compared with those obtained from adult tissues, including bone marrow. Upon systemic administration, ex vivo expanded FM-MSCs preferentially home to damaged tissues promoting regenerative processes through their unique biological properties. These characteristics together with their immune-privileged nature and immune suppressive activity, a low infection rate and young age of placenta compared to other sources of SCs make FM-MSCs an attractive target for cell-based therapy and a valuable tool in regenerative medicine, currently being evaluated in clinical trials. In the present study we investigated the permissivity of FM-MSCs to all members of the human Herpesviridae family, an issue which is relevant to their purification, propagation, conservation and therapeutic use, as well as to their potential role in the vertical transmission of viral agents to the fetus and to their potential viral vector-mediated genetic modification. We present here evidence that FM-MSCs are fully permissive to infection with Herpes simplex virus 1 and 2 (HSV-1 and HSV-2), Varicella zoster virus (VZV), and Human Cytomegalovirus (HCMV), but not with Epstein-Barr virus (EBV), Human Herpesvirus-6, 7 and 8 (HHV-6, 7, 8) although these viruses are capable of entering FM-MSCs and transient, limited viral gene expression occurs. Our findings therefore strongly suggest that FM-MSCs should be screened for the presence of herpesviruses before xenotransplantation. In addition, they suggest that herpesviruses may be indicated as viral vectors for gene expression in MSCs both in gene therapy applications and in the selective induction of differentiation.
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Project description:The oral cavity as the second most various microbial community in the body contains a broad spectrum of microorganisms which are known as the oral microbiome. The oral microbiome includes different types of microbes such as bacteria, fungi, viruses, and protozoa. Numerous factors can affect the equilibrium of the oral microbiome community which can eventually lead to orodental infectious diseases. Periodontitis, dental caries, oral leukoplakia, oral squamous cell carcinoma are some multifactorial infectious diseases in the oral cavity. In defending against infection, the immune system has an essential role. Depending on the speed and specificity of the reaction, immunity is divided into two different types which are named the innate and the adaptive responses but also there is much interaction between them. In these responses, different types of immune cells are present and recent evidence demonstrates that these cell types both within the innate and adaptive immune systems are capable of secreting some extracellular vesicles named exosomes which are involved in the response to infection. Exosomes are 30-150 nm lipid bilayer vesicles that consist of variant molecules, including proteins, lipids, and genetic materials and they have been associated with cell-to-cell communications. However, some kinds of exosomes can be effective on the pathogenicity of various microorganisms and promoting infections, and some other ones have antimicrobial and anti-infective functions in microbial diseases. These discrepancies in performance are due to the origin of the exosome. Exosomes can modulate the innate and specific immune responses of host cells by participating in antigen presentation for activation of immune cells and stimulating the release of inflammatory factors and the expression of immune molecules. Also, mesenchymal stromal/stem cells (MSCs)-derived exosomes participate in immunomodulation by different mechanisms. Ease of expansion and immunotherapeutic capabilities of MSCs, develop their applications in hundreds of clinical trials. Recently, it has been shown that cell-free therapies, like exosome therapies, by having more advantages than previous treatment methods are emerging as a promising strategy for the treatment of several diseases, in particular inflammatory conditions. In orodental infectious disease, exosomes can also play an important role by modulating immunoinflammatory responses. Therefore, MSCs-derived exosomes may have potential therapeutic effects to be a choice for controlling and treatment of orodental infectious diseases.
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Project description:BM mesenchymal stromal cells (BM-MSCs) support multiple myeloma (MM) cell growth, but little is known about the putative mechanisms by which the BM microenvironment plays an oncogenic role in this disease. Cell-cell communication is mediated by exosomes. In this study, we showed that MM BM-MSCs release exosomes that are transferred to MM cells, thereby resulting in modulation of tumor growth in vivo. Exosomal microRNA (miR) content differed between MM and normal BM-MSCs, with a lower content of the tumor suppressor miR-15a. In addition, MM BM-MSC-derived exosomes had higher levels of oncogenic proteins, cytokines, and adhesion molecules compared with exosomes from the cells of origin. Importantly, whereas MM BM-MSC-derived exosomes promoted MM tumor growth, normal BM-MSC exosomes inhibited the growth of MM cells. In summary, these in vitro and in vivo studies demonstrated that exosome transfer from BM-MSCs to clonal plasma cells represents a previously undescribed and unique mechanism that highlights the contribution of BM-MSCs to MM disease progression.
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Project description:Due to their robust immunomodulatory capabilities, mesenchymal stem/stromal cells (MSCs) have been used as a cellular therapy for a number of human diseases. Part of the mechanism of action of MSCs is the production of extracellular vesicles (EVs) that contain proteins, nucleic acids, and lipids that transmit signals to recipient cells that change their biologic behavior. This review briefly summarizes the development of MSCs as a treatment for human diseases as well as describes our present understanding of exosomes; how they exert their effects on target cells, and how they are differentiated from other EVs. The current treatment paradigm for acute radiation syndrome (ARS) is discussed, and how MSCs and MSC derived exosomes are emerging as treatment options for treating patients after radiation exposure. Other conditions such as graft-versus-host disease and cardiovascular disease/stroke are discussed as examples to highlight the immunomodulatory and regenerative capacity of MSC-exosomes. Finally, a consideration is given to how these cell-based therapies could possibly be deployed in the event of a catastrophic radiation exposure event.
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