Currently, the most effective therapy for acute liver failure and advanced cirrhosis is liver transplantation. However, this procedure has several limitations, including lack of donors, surgical ...complications, immunological suppression, and high medical costs. The alternative approaches that circumvent the use of a whole liver, such as stem cell transplantation, have been suggested as an effective alternate therapy for hepatic diseases. Mesenchymal stem cells (MSCs), also known as multipotent mesenchymal stromal cells, are self-renewing cells that can be found in almost all postnatal organs and tissues, including liver. During the past decade, great progress has been made in the field of MSC-dependent liver regeneration and immunomodulation. Because of their potential for differentiation into hepatocytes as well as their immunomodulatory characteristics, MSCs are considered as promising therapeutic agents for the therapy of acute liver failure and cirrhosis. In this concise review, we have summarized therapeutic potential of MSCs in the treatment of acute liver failure and cirrhosis, emphasizing their regenerative and immunomodulatory characteristics after engraftment in the liver. We have also presented several outstanding problems including conflicting data regarding MSCs engraftment in the liver and unwanted mesenchymal lineage differentiation in vivo which limits MSC therapy as a mainstream treatment approach for liver regeneration. It can be concluded that efficient and safe MSC-based therapy for acute and chronic liver failure remains a challenging issue that requires more investigation and continuous cooperation between clinicians, researchers, and patients.
Mesenchymal stem cells (MSCs) are self-renewable, rapidly proliferating, multipotent stem cells which reside in almost all post-natal tissues. MSCs possess potent immunoregulatory properties and, in ...juxtacrine and paracrine manner, modulate phenotype and function of all immune cells that participate in tissue repair and regeneration. Additionally, MSCs produce various pro-angiogenic factors and promote neo-vascularization in healing tissues, contributing to their enhanced repair and regeneration. In this review article, we summarized current knowledge about molecular mechanisms that regulate the crosstalk between MSCs and immune cells in tissue repair and regeneration.
There is growing evidence that mesenchymal stem cell (MSC)-based immunosuppression was mainly attributed to the effects of MSC-derived extracellular vesicles (MSC-EVs). MSC-EVs are enriched with ...MSC-sourced bioactive molecules (messenger RNA (mRNA), microRNAs (miRNAs), cytokines, chemokines, immunomodulatory factors) that regulate phenotype, function and homing of immune cells. In this review article we emphasized current knowledge regarding molecular mechanisms responsible for the therapeutic effects of MSC-EVs in attenuation of autoimmune and inflammatory diseases. We described the disease-specific cellular targets of MSC-EVs and defined MSC-sourced molecules, which were responsible for MSC-EV-based immunosuppression. Results obtained in a large number of experimental studies revealed that both local and systemic administration of MSC-EVs efficiently suppressed detrimental immune response in inflamed tissues and promoted survival and regeneration of injured parenchymal cells. MSC-EVs-based anti-inflammatory effects were relied on the delivery of immunoregulatory miRNAs and immunomodulatory proteins in inflammatory immune cells (M1 macrophages, dendritic cells (DCs), CD4+Th1 and Th17 cells), enabling their phenotypic conversion into immunosuppressive M2 macrophages, tolerogenic DCs and T regulatory cells. Additionally, through the delivery of mRNAs and miRNAs, MSC-EVs activated autophagy and/or inhibited apoptosis, necrosis and oxidative stress in injured hepatocytes, neurons, retinal cells, lung, gut and renal epithelial cells, promoting their survival and regeneration.
Osteoarthritis (OA) is a chronic, prevalent, debilitating joint disease characterized by progressive cartilage degradation, subchondral bone remodeling, bone marrow lesions, meniscal damage, and ...synovitis. Innate immune cells (natural killer cells, macrophages, and mast cells) play the most important pathogenic role in the early inflammatory response, while cells of adaptive immunity (CD4 + Th1 lymphocytes and antibody producing B cells) significantly contribute to the development of chronic, relapsing course of inflammation in OA patients. Conventional therapy for OA is directed toward symptomatic treatment, mainly pain management, and is not able to promote regeneration of degenerated cartilage or to attenuate joint inflammation. Since articular cartilage, intra-articular ligaments, and menisci have no ability to heal, regeneration of these tissues remains one of the most important goals of new therapeutic approaches used for OA treatment.
Due to their capacity for differentiation into chondrocytes and due to their immunomodulatory properties, mesenchymal stem cells (MSCs) have been the most extensively explored as new therapeutic agents in the cell-based therapy of OA. Simple acquisition, rapid proliferation, maintenance of differentiation potential after repeated passages in vitro, minor immunological rejection due to the low surface expression of major histocompatibility complex antigens, efficient engraftment and long-term coexistence in the host are the main characteristics of MSCs that enable their therapeutic use in OA.
In this review article, we emphasized current knowledge and future perspectives regarding molecular and cellular mechanisms responsible for beneficial effects of autologous and allogeneic MSCs in the treatment of OA.
Mesenchymal stem cell (MSC)-derived exosomes (MSC-Exo) are nano-sized extracellular vesicles enriched with MSC-sourced neuroprotective and immunomodulatory microRNAs, neural growth factors, and ...anti-inflammatory cytokines, which attenuate neuro-inflammation, promote neo-vascularization, induce neurogenesis, and reduce apoptotic loss of neural cells. Accordingly, a large number of experimental studies demonstrated MSC-Exo-dependent improvement of cognitive impairment in experimental animals. In this review article, we summarized current knowledge about molecular and cellular mechanisms that were responsible for MSC-Exo-based restoration of cognitive function, emphasizing therapeutic potential of MSC-Exos in the treatment of neurocognitive disorders.
Therapeutic agents that are able to prevent or attenuate inflammation and ischemia-induced injury of neural and retinal cells could be used for the treatment of neural and retinal diseases. Exosomes ...derived from adipose tissue-sourced mesenchymal stem cells (AT-MSC-Exos) are extracellular vesicles that contain neurotrophins, immunoregulatory and angio-modulatory factors secreted by their parental cells. AT-MSC-Exos are enriched with bioactive molecules (microRNAs (miRNAs), enzymes, cytokines, chemokines, immunoregulatory, trophic, and growth factors), that alleviate inflammation and promote the survival of injured cells in neural and retinal tissues. Due to the nano-sized dimension and bilayer lipid envelope, AT-MSC-Exos easily bypass blood-brain and blood-retinal barriers and deliver their cargo directly into the target cells. Accordingly, a large number of experimental studies demonstrated the beneficial effects of AT-MSC-Exos in the treatment of neural and retinal diseases. By delivering neurotrophins, AT-MSC-Exos prevent apoptosis of injured neurons and retinal cells and promote neuritogenesis. AT-MSC-Exos alleviate inflammation in the injured brain, spinal cord, and retinas by delivering immunoregulatory factors in immune cells, suppressing their inflammatory properties. AT-MSC-Exos may act as biological mediators that deliver pro-angiogenic miRNAs in endothelial cells, enabling re-vascularization of ischemic neural and retinal tissues. Herewith, we summarized current knowledge about molecular mechanisms which were responsible for the beneficial effects of AT-MSC-Exos in the treatment of neural and retinal diseases, emphasizing their therapeutic potential in neurology and ophthalmology.
Mesenchymal stem cells (MSCs) are self-renewable, multipotent stem cells that regulate the phenotype and function of all immune cells that participate in anti-tumor immunity. MSCs modulate the ...antigen-presenting properties of dendritic cells, affect chemokine and cytokine production in macrophages and CD4+ T helper cells, alter the cytotoxicity of CD8+ T lymphocytes and natural killer cells and regulate the generation and expansion of myeloid-derived suppressor cells and T regulatory cells. As plastic cells, MSCs adopt their phenotype and function according to the cytokine profile of neighboring tumor-infiltrated immune cells. Depending on the tumor microenvironment to which they are exposed, MSCs may obtain pro- and anti-tumorigenic phenotypes and may enhance or suppress tumor growth. Due to their tumor-homing properties, MSCs and their exosomes may be used as vehicles for delivering anti-tumorigenic agents in tumor cells, attenuating their viability and invasive characteristics. Since many factors affect the phenotype and function of MSCs in the tumor microenvironment, a better understanding of signaling pathways that regulate the cross-talk between MSCs, immune cells and tumor cells will pave the way for the clinical use of MSCs in cancer immunotherapy. In this review article, we summarize current knowledge on the molecular and cellular mechanisms that are responsible for the MSC-dependent modulation of the anti-tumor immune response and we discuss different insights regarding therapeutic potential of MSCs in the therapy of malignant diseases.
Mesenchymal stem cell (MSC)-sourced secretome, defined as the set of MSC-derived bioactive factors (soluble proteins, nucleic acids, lipids and extracellular vesicles), showed therapeutic effects ...similar to those observed after transplantation of MSCs. MSC-derived secretome may bypass many side effects of MSC-based therapy, including unwanted differentiation of engrafted MSCs. In contrast to MSCs which had to be expanded in culture to reach optimal cell number for transplantation, MSC-sourced secretome is immediately available for treatment of acute conditions, including fulminant hepatitis, cerebral ischemia and myocardial infarction. Additionally, MSC-derived secretome could be massively produced from commercially available cell lines avoiding invasive cell collection procedure. In this review article we emphasized molecular and cellular mechanisms that were responsible for beneficial effects of MSC-derived secretomes in the treatment of degenerative and inflammatory diseases of hepatobiliary, respiratory, musculoskeletal, gastrointestinal, cardiovascular and nervous system. Results obtained in a large number of studies suggested that administration of MSC-derived secretomes represents a new, cell-free therapeutic approach for attenuation of inflammatory and degenerative diseases. Therapeutic effects of MSC-sourced secretomes relied on their capacity to deliver genetic material, growth and immunomodulatory factors to the target cells enabling activation of anti-apoptotic and pro-survival pathways that resulted in tissue repair and regeneration.
Interleukin (IL)‐1 receptor antagonist (IL‐1Ra), a naturally occurring antagonist of IL‐1α/IL‐1β signaling pathways, has been attributed to the immunosuppressive effects of mesenchymal stem cells ...(MSCs). MSCs, in IL‐1Ra‐dependent manner, suppressed production of IL‐1β in dermal macrophages, induced their polarization in anti‐inflammatory M2 phenotype, attenuated antigen‐presenting properties of dendritic cells (DCs), and promoted expansion of immunosuppressive T regulatory cells in the skin, which resulted in enhanced repair of the nonhealing wounds. Reduced activation of inflammasome and suppressed production of IL‐1β in macrophages were mainly responsible for beneficial effects of MSC‐derived IL‐1Ra in alleviation of acute lung injury, dry eye syndrome, and corneal injury. Through the production of IL‐1Ra, MSCs reduced migration of DCs to the draining lymph nodes and attenuated generation of inflammatory Th1 and Th17 cells that resulted in alleviation of fulminant hepatitis and rheumatoid arthritis. MSCs, in IL‐1Ra‐dependent manner, reduced liver fibrosis by suppressing production of Type I collagen in hepatic stellate cells. IL‐1Ra was, at least partially, responsible for enhanced proliferation of hepatocytes and chondrocytes in MSC‐treated animals with partial hepatectomy and osteoarthritis. Despite of these beneficial effects, IL‐1Ra‐dependent inhibition of IL‐1α/IL‐1β‐signaling significantly increased risk of infections. Therefore, future experimental and clinical studies should delineate potential side effects of MSC‐derived IL‐1Ra before IL‐1Ra‐overexpressing MSCs could be used as a potentially new therapeutic agent for the treatment of acute and chronic inflammatory diseases.
Mesenchymal stem cells (MSC) are, due to their immunosuppressive and regenerative properties, used as new therapeutic agents in cell-based therapy of inflammatory and degenerative diseases. A large ...number of experimental and clinical studies revealed that most of MSC-mediated beneficial effects were attributed to the effects of MSC-sourced exosomes (MSC-Exos). MSC-Exos are nano-sized extracellular vesicles that contain MSC-derived bioactive molecules (messenger RNA (mRNA), microRNAs (miRNAs)), enzymes, cytokines, chemokines, and growth factors) that modulate phenotype, function and homing of immune cells, and regulate survival and proliferation of parenchymal cells. In this review article, we emphasized current knowledge about molecular and cellular mechanisms that were responsible for MSC-Exos-based beneficial effects in experimental models and clinical trials. Additionally, we elaborated on the challenges of conventional MSC-Exos administration and proposed the use of new bioengineering and cellular modification techniques which could enhance therapeutic effects of MSC-Exos in alleviation of inflammatory and degenerative diseases.
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