Sirtuins: Subtle Regulators Involved in Convoluted Mechanisms of Pregnancy.

Sirtuins are Class III protein deacetylases with seven conserved isoforms. In general, Sirtuins are highly activated in starving cells in response to stringent conditions, in which levels of NAD+ are increased. Each member of the Sirtuin family is prominently involved in the regulation of myriad fundamental biological processes including inflammation, proliferation, cell survival, DNA repair and metabolism. Sirtuins can also interact with various signaling pathways and factors such as hypoxia-inducible factors (HIFs), mitogen-activated protein kinases (MAPKs), nuclear factor-κB (NF-κB) and the Notch pathway, yet these interactions are demonstrated to be rather complicated. Therefore, deficiency in each member of the Sirtuin family results in severe developmental defects and irregularities both in animals and humans. Currently, a rapidly expanding body of evidence supports that Sirtuins can improve the pregnancy outcome. In fact, each Sirtuin isoform plays distinct yet fundamental roles in controlling folliculogenesis, oocyte meiotic maturation, oocyte aging, trophoblast functions, feto-maternal inflammation and placental angiogenesis and oxidative stress. Consequently, alterations in Sirtuin levels can be a pivotal intermediary step in the pathogenesis of several pregnancy disorders such as fetal growth retardation, preeclampsia and the HELLP syndrome. Furthermore, Sirtuins also appear to be involved in the regulation of parturition and pregnancy complications caused by maternal obesity and diabetes. In this review, we shall first address Sirtuin regulation and functions including their interactions with the most important signaling pathways involved in pregnancy. Then, we will focus on the pivotal roles of Sirtuins in female reproductive functions, normal pregnancy, parturition and pregnancy complications.

Harnessing the inherent power of chimeric antigen receptor (CAR)-expressing regulatory T cells (CAR-Tregs) to treat autoimmune-related disorders.

Over the past years, adoptive cell therapy with regulatory T lymphocytes (Tregs) has captured the attention of many scientists and clinicians as a novel promising approach for treating a wide range of immune-mediated disorders. In particular, the robust immunosuppressive properties of these cells have been demonstrated to make them uniquely valuable for the treatment of autoimmune diseases. More recently, it has been brought to light that adoptive transfer of chimeric antigen receptor (CAR) Tregs (CAR-Tregs) can also serve a protective role against autoimmune-related disorders. Interestingly, a growing body of evidence indicates that the beneficial and therapeutic effects of antigen-specific CAR-Tregs surpass those of polyclonal Tregs in treating autoimmune conditions. Therefore, harnessing and adapting CAR technology to generate more specific and effective CAR-Tregs, both in terms of tissue localization and antigen recognition, may lay the foundations for the development of far more potent immunotherapeutic strategies for autoimmune-related disorders. Herein, we first highlight the major immunosuppressive abilities of CAR-Tregs and further summarize the current findings on their potential applications in treating autoimmune-related disorders. Then, we will attempt to address the practical challenges in the clinical use of CAR-Treg therapies.

Emerging therapeutic potential of regulatory T (Treg) cells for rheumatoid arthritis: New insights and challenges.

Rheumatoid arthritis (RA) is an autoimmune-related disorder characterized by chronic inflammation. Although the etiopathogenesis of RA still remains to be clarified, it is supposed that the breakdown of immune self-tolerance may contribute to the development of RA. Thus, restoring of immune tolerance at the site of inflammation is the ultimate goal of RA treatment. Regulatory T cells (Treg cells) are the main suppressive cells that maintain tolerance and inhibit immunity against auto-antigen. Of note, recent studies demonstrated the efficacy of adoptive transfer of Treg cells in the modulation of the unwanted immune response, which makes them an ideal candidate to maintain immune homeostasis and restore antigen-specific tolerance in the case of RA and other autoimmune diseases. This review intends to submit recent finding of Treg cells-based therapies in RA with a focus on strategies applied to improve the therapeutic value of Treg cells to restore immune tolerance.

A Rapid Qualitative Review of Sarcoidosis: Clinical Manifestations, Immunopathogenesis, Diagnosis and Treatment.

Sarcoidosis is a worldwide inflammatory disorder of unknown etiology that is characterized by the formation of non-caseating immune granulomas in involved organs,most commonly in the lungs and eyes. Although clinical manifestations of sarcoidosis depend on the organs involved, the most common symptoms include fatigue, fever, weight loss, eye pain, dyspnea, and chest pain. Sarcoidosis usually undergoes spontaneous regression, yet its chronic form progressively threatens the involved organs through the induction of fibrotic damage. Despite decades of medical research, the etiology of sarcoidosis still remains unclear. Nevertheless, a combination of contributors, including genetic factors, environmental exposures, and microbial agents, is believed to trigger the inflammatory state observed in this disease. Furthermore, a highly polarized Th1 and Th17 response with diminished immunomodulatory mechanisms constitute the most significant immunological event associated with this disorder. Indeed, sarcoid granulomas, which consist of highly activated antigen-presenting cells (APCs) and lymphocytes, maintain a robust specialized niche to facilitate antigen presentation and exaggerated immune responses. Both the unknown etiology and multisystem nature of the disease have hampered the development of specific therapeutics and definitive diagnostic assays for sarcoidosis. Consequently, its diagnosis and treatment still represent a challenging task for clinicians. In this article, we aim to summarize contemporary findings of sarcoidosis and its etiology, pathogenesis, and treatment.

Mesenchymal stem cell therapy attenuates complement C3 deposition and improves the delicate equilibrium between angiogenic and anti-angiogenic factors in abortion-prone mice.

Immunological disorders are one of the main causes of recurrent spontaneous abortions (RSA). A rapidly expanding body of evidence indicates that excessive activation of the complement system is critically involved in the development of miscarriages. In the CBA/J × DBA/2 murine model of recurrent miscarriage, exaggerated and unrestrained complement activation is reported to be the underlying cause of angiogenic factor imbalance and persistent inflammation. We have previously shown that mesenchymal stem cell (MSC) therapy can significantly reduce the abortion rate in abortion-prone mice through regulating the feto-maternal immune response. In the present study, we hypothesized that MSCs might improve the balance of angiogenic factors at the feto-maternal unit of CBA/J × DBA/2 mice by restraining complement activation and deposition. To explore this hypothesis, autologous adipose tissue-derived mesenchymal stem cells (AD-MSCs) were administered intra-peritoneally to abortion-prone mice on the 4.5th day of gestation. Control mice received PBS as vehicle. On day 13.5 of pregnancy, deposition of the complement component C3 and expression levels of Crry, CFD (adipsin), VEGF, PlGF and FLT-1 were measured at the feto-maternal interface by immunohistochemistry and real-time PCR, respectively. Decidual cells were also cultured in RPMI 1640 medium for 48 h and VEGF and sFLT-1 protein levels were quantified in supernatants using enzyme-linked immunosorbent assay (ELISA). Our results indicated that MSC therapy significantly reduced C3 deposition and adipsin transcription in the fetal-maternal interface of abortion-prone mice. Furthermore, administration of MSCs robustly upregulated the mRNA expression levels of Crry, VEGF, PlGF and FLT-1 in the placenta and decidua of CBA/J × DBA/2 mice. Consistently, the in vitro results demonstrated that decidual cells obtained from MSC-treated dams produced increased concentrations of VEGF in culture supernatants, with concomitant decreased levels of sFLT-1 protein. Here, we show for the first time that adoptive transfer of MSCs rectifies the disturbed balance of angiogenic factors observed at the feto-maternal unit of CBA/J × DBA/2 mice, in part at least, through inhibiting excessive complement activation and promoting the production of angiogenic factors. Collectively, these alterations seem to play a pivotal role in reducing the abortion rate and improving the intrauterine condition for the benefit of the fetus.

A comprehensive review of Sirtuins: With a major focus on redox homeostasis and metabolism.

Sirtuins are Class III protein deacetylases with seven conserved isoforms. In general, Sirtuins are highly activated under cellular stress conditions in which NAD+ levels are increased. Nevertheless, regulation of Sirtuins extends far beyond the influences of cellular NAD+/NADH ratio and a rapidly expanding body of evidence currently suggests that their expression and catalytic activity are highly kept under control at multiple levels by various factors and processes. Owing to their intrinsic ability to enzymatically target various intracellular proteins, Sirtuins are prominently involved in the regulation of fundamental biological processes including inflammation, metabolism, redox homeostasis, DNA repair and cell proliferation and senescence. In fact, Sirtuins are well established to regulate and reprogram different redox and metabolic pathways under both pathological and physiological conditions. Therefore, alterations in Sirtuin levels can be a pivotal intermediary step in the pathogenesis of several disorders. This review first highlights the mechanisms involved in the regulation of Sirtuins and further summarizes the current findings on the major functions of Sirtuins in cellular redox homeostasis and bioenergetics (glucose and lipid metabolism).

Therapeutic potential of mesenchymal stem cell-derived extracellular vesicles as novel cell-free therapy for treatment of autoimmune disorders.

Over the past decades, new light has been shed on the efficiency of Mesenchymal Stem Cells (MSCs) in the treatment of autoimmune diseases. The therapeutic functions of MSCs partly stem from their well-recognized ability to efficiently modulate immune responses and it is well substantiated that MSC secretory components, in particular extracellular vesicles (EVs), play a critical role in this immunomodulation. In fact, almost any cell type can generate and release EVs under both pathological and physiological conditions and these nano-sized particles are believed to greatly contribute to homeostasis and cell-cell communication through transportation of a wide variety of biomolecules including nucleic acid, signaling lipids, regulatory proteins, transcription factors, cytokines, and growth factors. Lamentably, despite exhibiting promising results in both animal experiments and clinical trials, MSC therapy is still largely restricted to the experimental stage due to its critical pitfalls and drawbacks such as safety issues, poor cell survival, immune rejection and high cost. On the other hand, MSC-derived EVs, which ideally reflect the exact biophysical features of MSCs, are considered to be much safer and more effective than MSCs themselves. Therefore, introducing alternative approaches based on MSC-derived EVs can offer appreciable promise in overcoming the limitations and practical challenges observed in cell-based therapy and thus the extracellular vesicles of MSCs may also provide a far more potent therapeutic strategy for immune-related disorders. In this review, we first focus on the properties of MSC-derived EVs and then we shall provide valuable insight regarding their beneficial therapeutic opportunities to further compare this alternative approach with conventional MSC therapy. Finally, we will attempt to summarize the current findings on the influences of MSC-derived EVs on autoimmune disorders, offering a potential alternative avenue towards treatment of autoimmune diseases.

The effects of 17 Beta-Estradiol primed mesenchymal stem cells on the biology of co-cultured neutrophil.

OBJECTIVES: Mesenchymal stem cells (MSCs) can influence immune effector cells. It is proved that MSCs respond to various Toll-like receptor (TLR) ligands, which could ultimately result in changes in their immunomodulatory effects. Neutrophils play an essential role in the first line defense system and their function can be regulated by MSCs. Estrogen is a female hormone that contributes to sex differences in several immune-related diseases. With regard to the stated facts, this research aims to elucidate the effects of estrogen treatment on the ability of TLR4-primed MSCs to regulate neutrophil functions. METHODS: Following isolation and characterization, MSCs were stimulated with LPS as a TLR4 ligand and subsequently incubated with different concentrations (0, 10, 20 and 40 nM) of estrogen for 48 hrs. Then, MSCs were co-cultured with neutrophils to investigate the vitality and function of the co-cultured neutrophils. RESULTS: Our results indicated that TLR4-primed MSCs could decrease the viability and neutral red uptake potential of co-cultured neutrophils. Furthermore, neutrophils co-cultured with TLR4-primed MSCs exhibited a decrease in the respiratory burst intensity after being challenged with opsonized yeast. Interestingly, treating TLR4-primed MSCs with estrogen reversed the observed alterations in neutrophil functions. CONCLUSION: It appears that estrogen can alter the interaction between MSCs and neutrophils.

Mesenchymal stem cells alter the frequency and cytokine profile of natural killer cells in abortion-prone mice.

Natural killer cells, which play a pivotal role in the establishment and maintenance of normal pregnancy, are the most abundant leukocytes at the fetomaternal interface that their subsets frequencies and cytokine profile are influential factors in the preservation of the decidual tolerogenic microenvironment. Any imbalance in NK cells' frequency and functions could be associated with pregnancy failure. Mesenchymal stem cells (MSCs) are shown to have immunomodulatory effects on NK cells and their cytokine profile. The purpose of this study is to evaluate the impact of MSCs therapy on the cytokine profiles and subpopulations of NK cells in a murine model of recurrent pregnancy loss. Adipose-derived MSCs were injected intraperitoneally to the abortion-prone mice on Day 4.5 of gestation. The abortion rate was determined after MSCs administration and the frequency and cytokine profiles of the different subsets of NK cells were determined using the flow cytometry. Our results showed that, in abortion-prone mice, the frequency of CD49b+ NK cells was significantly higher than normal pregnant mice that decreased after therapy. We also demonstrated that MSCs downregulated the production of IFN-γ and upregulated IL-4 and IL-10 production by uNK cells. These findings indicate that MSCs can decrease the infiltration of CD49b+ NK cells to the fetomaternal interface and modulate the cytokine profile of NK cells from inflammatory to tolerogenic profile and thereby improve the tolerogenic microenvironment at the fetomaternal interface in benefit of pregnancy maintenance.