PMC:6141714 / 2289-6979 JSONTXT

{"project":"MyTest","denotations":[{"id":"30254638-28620373-35420629","span":{"begin":221,"end":222},"obj":"28620373"},{"id":"30254638-9478893-35420630","span":{"begin":224,"end":225},"obj":"9478893"},{"id":"30254638-11479621-35420631","span":{"begin":432,"end":433},"obj":"11479621"},{"id":"30254638-18190880-35420632","span":{"begin":846,"end":847},"obj":"18190880"},{"id":"30254638-29662485-35420632","span":{"begin":846,"end":847},"obj":"29662485"},{"id":"30254638-29559977-35420632","span":{"begin":846,"end":847},"obj":"29559977"},{"id":"30254638-5330635-35420633","span":{"begin":997,"end":998},"obj":"5330635"},{"id":"30254638-11821508-35420634","span":{"begin":1175,"end":1176},"obj":"11821508"},{"id":"30254638-17709662-35420635","span":{"begin":1553,"end":1554},"obj":"17709662"},{"id":"30254638-28342637-35420636","span":{"begin":1556,"end":1558},"obj":"28342637"},{"id":"30254638-28342637-35420637","span":{"begin":1779,"end":1781},"obj":"28342637"},{"id":"30254638-21394418-35420638","span":{"begin":1969,"end":1971},"obj":"21394418"},{"id":"30254638-1870029-35420639","span":{"begin":2404,"end":2406},"obj":"1870029"},{"id":"30254638-1870029-35420640","span":{"begin":2496,"end":2498},"obj":"1870029"},{"id":"30254638-12147742-35420641","span":{"begin":2591,"end":2593},"obj":"12147742"},{"id":"30254638-15579650-35420642","span":{"begin":2612,"end":2614},"obj":"15579650"},{"id":"30254638-18816169-35420643","span":{"begin":2642,"end":2644},"obj":"18816169"},{"id":"30254638-12475952-35420644","span":{"begin":2656,"end":2658},"obj":"12475952"},{"id":"30254638-24927918-35420645","span":{"begin":2842,"end":2844},"obj":"24927918"},{"id":"30254638-30057627-35420646","span":{"begin":2846,"end":2848},"obj":"30057627"},{"id":"30254638-24561556-35420647","span":{"begin":2960,"end":2962},"obj":"24561556"},{"id":"30254638-11986244-35420648","span":{"begin":3165,"end":3167},"obj":"11986244"},{"id":"30254638-24268069-35420649","span":{"begin":3379,"end":3381},"obj":"24268069"},{"id":"30254638-22118960-35420650","span":{"begin":3548,"end":3550},"obj":"22118960"},{"id":"30254638-19172693-35420651","span":{"begin":3685,"end":3687},"obj":"19172693"},{"id":"30254638-20734355-35420652","span":{"begin":3738,"end":3740},"obj":"20734355"},{"id":"30254638-12542793-35420653","span":{"begin":3814,"end":3816},"obj":"12542793"},{"id":"30254638-21073342-35420654","span":{"begin":3885,"end":3887},"obj":"21073342"},{"id":"30254638-26794657-35420655","span":{"begin":3933,"end":3935},"obj":"26794657"},{"id":"30254638-28581352-35420656","span":{"begin":4040,"end":4042},"obj":"28581352"},{"id":"30254638-24561556-35420657","span":{"begin":4201,"end":4203},"obj":"24561556"},{"id":"30254638-1870029-35420658","span":{"begin":4293,"end":4295},"obj":"1870029"},{"id":"30254638-12147742-35420659","span":{"begin":4297,"end":4299},"obj":"12147742"},{"id":"30254638-15579650-35420659","span":{"begin":4297,"end":4299},"obj":"15579650"},{"id":"30254638-18816169-35420659","span":{"begin":4297,"end":4299},"obj":"18816169"},{"id":"30254638-12475952-35420659","span":{"begin":4297,"end":4299},"obj":"12475952"},{"id":"30254638-26118469-35420660","span":{"begin":4357,"end":4359},"obj":"26118469"},{"id":"30254638-28232595-35420661","span":{"begin":4379,"end":4381},"obj":"28232595"},{"id":"30254638-27809910-35420662","span":{"begin":4425,"end":4427},"obj":"27809910"}],"namespaces":[{"prefix":"_base","uri":"https://www.uniprot.org/uniprot/testbase"},{"prefix":"UniProtKB","uri":"https://www.uniprot.org/uniprot/"},{"prefix":"uniprot","uri":"https://www.uniprot.org/uniprotkb/"}],"text":"Introduction\n\nRationale\nAutoimmune diseases result from defects in the mechanisms of immunological tolerance, culminating in the activation of cellular and humoral mechanisms of the immune response against self-antigens (1, 2). As a result, in autoimmune diseases, a failure occurs in the body's ability to differentiate cells from the body from foreign cells. These diseases may be restricted to a particular organ or be systemic (3). Examples of autoimmune diseases include type I diabetes mellitus, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus and systemic sclerosis. The mechanism and causes of the occurrence of autoimmune diseases are still not well-understood, however, it is believed that the origin of the majority of these diseases is multifactorial, in which both genetic and environmental factors are involved (4–6). Due to the possible occurrence of bone marrow toxicity, caused by the immunosuppressive regimen currently applied in the conventional treatment (7) of these diseases, the use of human mesenchymalstem cells (hMSCs) is being proposed as an alternative to treat these patients. For instance, a study conducted by Joly et al. (8) reported an increase in the mortality rate and the occurrence of severe adverse effects such as sepsis and diabetes mellitus requiring insulin in patients with extensive bullous pemphigoid treated with 1 mg of prednisone per kilogram per day, compared to patients treated with only topical corticosteroids. In addition, despite being effective in the treatment of pemphigus (9, 10), the combination of rituximab and prednisone is associated with the occurrence of many adverse events such as diabetes, endocrine disorders, myopathy and bone disorders, which complicates the treatment of this disease (10). Other autoimmune diseases, such as epidermolysis bullosa acquisita are notoriously difficult to treat by the conventional treatment, as demonstrated in a study conducted by Kim et al. (11). This emphasizes the need for the elaboration of alternative therapies. In this regard, the use of human mesenchymal stem cells (hMSCs) has been studied as an alternative for the treatment of immune-related diseases due their intrinsic immunomodulatory properties.\nMesenchymal stem cells are multipotent cells capable of self renewal and differentiation into several cell lines, including chondrocytes, adipocytes and osteoblasts (12, 13). Despite the fact that this type of stem cells isusually isolated from bone marrow (12), they can also be obtained from several neonatal and adult tissues, including dental pulp (14), umbilical cord (15), orbicularis oris muscle (16), and fat (17). In addition, some studies reported successful differentiation of pluripotent stem cells such as embryonic stem cells and induced pluripotent stem cells into mesenchymal-like cells (18, 19). The therapeutic properties of hMSCs have been attributed to the secretion of factors with paracrine effects (20). Notably, hMSCs have been shown to be capable of supporting the maturation and proliferation of hematopoietic cells, migrating to an area of tissue injury, recruiting tissue-specific progenitor cells (21) and regulating the immune response through the secretion immunomodulatory cytokines and microvesicles containing a variety of bioactive molecules such as enzymes, coding and non-coding RNAs and growth factors (22). Regarding their immunomodulatory potential, hMSCs, when exposed to a pro-inflammatory stimulus, secrete molecules that modulate both innate and adaptive responses (23). These molecules secreted acts, for instance, in the inhibition of thematuration of monocytes in antigen-presenting dendritic cells (24), by promoting a shift from M1 to M2 macrophages (25), by inhibiting the proliferation and activation of B and T lymphocytes (26) and by promoting the clonal expansion of regulatory T lymphocytes (27).\nPositive results from pre-clinical trials (28) and the demonstration of immunomodulatory effects of mesenchymal stem cells in “in vitro” experiments (29) led to a rapid increase in interest for the therapeutic potential of the administration of these cells for the treatment of several immune-related diseases (20). As a consequence, it is currently possible to isolate hMSCs from a variety of tissues (12, 14–17), expand them in culture and administer them locally (30) or intravenously (31) for treatment of immune-related diseases (32).\n\nObjectives\nTherefore, the main objective of this study is to present and summarize, through a systematic review of the literature, in vivo studies in which the efficacy of the administration of hMSCs for the treatment of immune-related diseases was evaluated."}

{"project":"2_test","denotations":[{"id":"30254638-28620373-35420629","span":{"begin":221,"end":222},"obj":"28620373"},{"id":"30254638-9478893-35420630","span":{"begin":224,"end":225},"obj":"9478893"},{"id":"30254638-11479621-35420631","span":{"begin":432,"end":433},"obj":"11479621"},{"id":"30254638-18190880-35420632","span":{"begin":846,"end":847},"obj":"18190880"},{"id":"30254638-29662485-35420632","span":{"begin":846,"end":847},"obj":"29662485"},{"id":"30254638-29559977-35420632","span":{"begin":846,"end":847},"obj":"29559977"},{"id":"30254638-5330635-35420633","span":{"begin":997,"end":998},"obj":"5330635"},{"id":"30254638-11821508-35420634","span":{"begin":1175,"end":1176},"obj":"11821508"},{"id":"30254638-17709662-35420635","span":{"begin":1553,"end":1554},"obj":"17709662"},{"id":"30254638-28342637-35420636","span":{"begin":1556,"end":1558},"obj":"28342637"},{"id":"30254638-28342637-35420637","span":{"begin":1779,"end":1781},"obj":"28342637"},{"id":"30254638-21394418-35420638","span":{"begin":1969,"end":1971},"obj":"21394418"},{"id":"30254638-1870029-35420639","span":{"begin":2404,"end":2406},"obj":"1870029"},{"id":"30254638-1870029-35420640","span":{"begin":2496,"end":2498},"obj":"1870029"},{"id":"30254638-12147742-35420641","span":{"begin":2591,"end":2593},"obj":"12147742"},{"id":"30254638-15579650-35420642","span":{"begin":2612,"end":2614},"obj":"15579650"},{"id":"30254638-18816169-35420643","span":{"begin":2642,"end":2644},"obj":"18816169"},{"id":"30254638-12475952-35420644","span":{"begin":2656,"end":2658},"obj":"12475952"},{"id":"30254638-24927918-35420645","span":{"begin":2842,"end":2844},"obj":"24927918"},{"id":"30254638-30057627-35420646","span":{"begin":2846,"end":2848},"obj":"30057627"},{"id":"30254638-24561556-35420647","span":{"begin":2960,"end":2962},"obj":"24561556"},{"id":"30254638-11986244-35420648","span":{"begin":3165,"end":3167},"obj":"11986244"},{"id":"30254638-24268069-35420649","span":{"begin":3379,"end":3381},"obj":"24268069"},{"id":"30254638-22118960-35420650","span":{"begin":3548,"end":3550},"obj":"22118960"},{"id":"30254638-19172693-35420651","span":{"begin":3685,"end":3687},"obj":"19172693"},{"id":"30254638-20734355-35420652","span":{"begin":3738,"end":3740},"obj":"20734355"},{"id":"30254638-12542793-35420653","span":{"begin":3814,"end":3816},"obj":"12542793"},{"id":"30254638-21073342-35420654","span":{"begin":3885,"end":3887},"obj":"21073342"},{"id":"30254638-26794657-35420655","span":{"begin":3933,"end":3935},"obj":"26794657"},{"id":"30254638-28581352-35420656","span":{"begin":4040,"end":4042},"obj":"28581352"},{"id":"30254638-24561556-35420657","span":{"begin":4201,"end":4203},"obj":"24561556"},{"id":"30254638-1870029-35420658","span":{"begin":4293,"end":4295},"obj":"1870029"},{"id":"30254638-12147742-35420659","span":{"begin":4297,"end":4299},"obj":"12147742"},{"id":"30254638-15579650-35420659","span":{"begin":4297,"end":4299},"obj":"15579650"},{"id":"30254638-18816169-35420659","span":{"begin":4297,"end":4299},"obj":"18816169"},{"id":"30254638-12475952-35420659","span":{"begin":4297,"end":4299},"obj":"12475952"},{"id":"30254638-26118469-35420660","span":{"begin":4357,"end":4359},"obj":"26118469"},{"id":"30254638-28232595-35420661","span":{"begin":4379,"end":4381},"obj":"28232595"},{"id":"30254638-27809910-35420662","span":{"begin":4425,"end":4427},"obj":"27809910"}],"text":"Introduction\n\nRationale\nAutoimmune diseases result from defects in the mechanisms of immunological tolerance, culminating in the activation of cellular and humoral mechanisms of the immune response against self-antigens (1, 2). As a result, in autoimmune diseases, a failure occurs in the body's ability to differentiate cells from the body from foreign cells. These diseases may be restricted to a particular organ or be systemic (3). Examples of autoimmune diseases include type I diabetes mellitus, myasthenia gravis, multiple sclerosis, systemic lupus erythematosus and systemic sclerosis. The mechanism and causes of the occurrence of autoimmune diseases are still not well-understood, however, it is believed that the origin of the majority of these diseases is multifactorial, in which both genetic and environmental factors are involved (4–6). Due to the possible occurrence of bone marrow toxicity, caused by the immunosuppressive regimen currently applied in the conventional treatment (7) of these diseases, the use of human mesenchymalstem cells (hMSCs) is being proposed as an alternative to treat these patients. For instance, a study conducted by Joly et al. (8) reported an increase in the mortality rate and the occurrence of severe adverse effects such as sepsis and diabetes mellitus requiring insulin in patients with extensive bullous pemphigoid treated with 1 mg of prednisone per kilogram per day, compared to patients treated with only topical corticosteroids. In addition, despite being effective in the treatment of pemphigus (9, 10), the combination of rituximab and prednisone is associated with the occurrence of many adverse events such as diabetes, endocrine disorders, myopathy and bone disorders, which complicates the treatment of this disease (10). Other autoimmune diseases, such as epidermolysis bullosa acquisita are notoriously difficult to treat by the conventional treatment, as demonstrated in a study conducted by Kim et al. (11). This emphasizes the need for the elaboration of alternative therapies. In this regard, the use of human mesenchymal stem cells (hMSCs) has been studied as an alternative for the treatment of immune-related diseases due their intrinsic immunomodulatory properties.\nMesenchymal stem cells are multipotent cells capable of self renewal and differentiation into several cell lines, including chondrocytes, adipocytes and osteoblasts (12, 13). Despite the fact that this type of stem cells isusually isolated from bone marrow (12), they can also be obtained from several neonatal and adult tissues, including dental pulp (14), umbilical cord (15), orbicularis oris muscle (16), and fat (17). In addition, some studies reported successful differentiation of pluripotent stem cells such as embryonic stem cells and induced pluripotent stem cells into mesenchymal-like cells (18, 19). The therapeutic properties of hMSCs have been attributed to the secretion of factors with paracrine effects (20). Notably, hMSCs have been shown to be capable of supporting the maturation and proliferation of hematopoietic cells, migrating to an area of tissue injury, recruiting tissue-specific progenitor cells (21) and regulating the immune response through the secretion immunomodulatory cytokines and microvesicles containing a variety of bioactive molecules such as enzymes, coding and non-coding RNAs and growth factors (22). Regarding their immunomodulatory potential, hMSCs, when exposed to a pro-inflammatory stimulus, secrete molecules that modulate both innate and adaptive responses (23). These molecules secreted acts, for instance, in the inhibition of thematuration of monocytes in antigen-presenting dendritic cells (24), by promoting a shift from M1 to M2 macrophages (25), by inhibiting the proliferation and activation of B and T lymphocytes (26) and by promoting the clonal expansion of regulatory T lymphocytes (27).\nPositive results from pre-clinical trials (28) and the demonstration of immunomodulatory effects of mesenchymal stem cells in “in vitro” experiments (29) led to a rapid increase in interest for the therapeutic potential of the administration of these cells for the treatment of several immune-related diseases (20). As a consequence, it is currently possible to isolate hMSCs from a variety of tissues (12, 14–17), expand them in culture and administer them locally (30) or intravenously (31) for treatment of immune-related diseases (32).\n\nObjectives\nTherefore, the main objective of this study is to present and summarize, through a systematic review of the literature, in vivo studies in which the efficacy of the administration of hMSCs for the treatment of immune-related diseases was evaluated."}