Re-establishing immune tolerance in multiple sclerosis: focusing on novel mechanisms of mesenchymal stem cell regulation of Th17/Treg balance.

The T-helper 17 (Th17) cell and regulatory T cell (Treg) axis plays a crucial role in the development of multiple sclerosis (MS), which is regarded as an immune imbalance between pro-inflammatory cytokines and the maintenance of immune tolerance. Mesenchymal stem cell (MSC)-mediated therapies have received increasing attention in MS research. In MS and its animal model experimental autoimmune encephalomyelitis, MSC injection was shown to alter the differentiation of CD4+T cells. This alteration occurred by inducing anergy and reduction in the number of Th17 cells, stimulating the polarization of antigen-specific Treg to reverse the imbalance of the Th17/Treg axis, reducing the inflammatory cascade response and demyelination, and restoring an overall state of immune tolerance. In this review, we summarize the mechanisms by which MSCs regulate the balance between Th17 cells and Tregs, including extracellular vesicles, mitochondrial transfer, metabolic reprogramming, and autophagy. We aimed to identify new targets for MS treatment using cellular therapy by analyzing MSC-mediated Th17-to-Treg polarization.

Melatonin restores the declining maturation quality and early embryonic development of oocytes in aged mice.

With increase in women's age, the reproductive capability of female mammals decreases dramatically caused by age-related oxidative stress, coinciding with the decline in the ovarian reserve, and the quality and quantity of oocytes, which is the main determinant of female fertility. Melatonin, as an effective antioxidant and antiaging substance, is secreted by the pineal gland and been found in the follicular fluid as well, which has been turned out to enable to protect oocytes from oxidative stress during ovulation. However, the beneficial effects of melatonin on meiotic maturation in vitro and early embryo development of aged oocytes are still not fully understood. Thus, the aim of this study is to explore the potential mechanism of melatonin to improve the oocytes maturation and early embryonic development. The results suggested that oocyte quality decreased with age, whereas 10-6 M melatonin supplementation can significantly prompt the maturation quality of oocytes, the rate of fertilization and the formation rate of blastocyst. Mechanistic investigation indicated that melatonin supplementation not only restored the function of mitochondria by reducing reactive oxygen species (ROS) generation and early apoptosis, but also increased the level of ATP and total GSH through enhancing the mRNA expression levels of SIRT1, SIRT3, GPX4, SOD1 and SOD2. In conclusion, melatonin could alleviate the impairment of age-related oxidative stress to meiotic maturation and early embryonic development of oocytes. This study may provide a potential remediation strategy to improve the quality of oocytes from aged women and the efficiency of assisted reproductive technologies.

Crosstalk between dendritic cells and regulatory T cells: Protective effect and therapeutic potential in multiple sclerosis.

Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system related to autoimmunity and is characterized by demyelination, neuroinflammation, and neurodegeneration. Cell therapies mediated by dendritic cells (DCs) and regulatory T cells (Tregs) have gradually become accumulating focusing in MS, and the protective crosstalk mechanisms between DCs and Tregs provide the basis for the efficacy of treatment regimens. In MS and its animal model experimental autoimmune encephalomyelitis, DCs communicate with Tregs to form immune synapses and complete a variety of complex interactions to counteract the unbalanced immune tolerance. Through different co-stimulatory/inhibitory molecules, cytokines, and metabolic enzymes, DCs regulate the proliferation, differentiation and function of Tregs. On the other hand, Tregs inhibit the mature state and antigen presentation ability of DCs, ultimately improving immune tolerance. In this review, we summarized the pivotal immune targets in the interaction between DCs and Tregs, and elucidated the protective mechanisms of DC-Treg cell crosstalk in MS, finally interpreted the complex cell interplay in the manner of inhibitory feedback loops to explore novel therapeutic directions for MS.

Rational synthesis and lithium storage properties of hierarchical nanoporous TiO2(B) assemblies with tailored crystallites and architectures.

In comparison to the common anatase, rutile and brookite phases, the bronze phase TiO2 (TiO2(B)) is rarely prepared, and obtaining unique TiO2(B) structures, especially those with complex configurations remains a great challenge. This work presents a completely new synthetic approach for fabricating hierarchical nanoporous TiO2(B) assemblies with tailored crystallites and architectures via the reaction between tetrabutyl titanate and normal fatty acids. Three different kinds of normal fatty acids, i.e., pentanoic acid, hexanoic acid, and nonanoic acid were utilized as the sole solvent. After a simple solvothermal treatment, nanoporous TiO2(B) microspheres constructed by [001]-elongated ultrathin nanorods, randomly aggregated ultrafine nanocrystals, and crystallographically oriented nanocrystals were successfully produced separately. Further investigation revealed that the morphology of the hierarchical assemblies could be modified by using foreign substrates to adjust the growth dynamics of TiO2(B) crystals. As a good illustration, by introducing graphene nanosheets into the tetrabutyl titanate-pentanoic acid system, nanosized [001]-elongated-ultrathin-nanorod-constructed nanoporous TiO2(B) assemblies were obtained, which exhibited superior performance as an anode in Li-ion batteries. This work can not only shed new light on TiO2(B) crystallization, but also provide an effective solution for the rational design of complex TiO2(B) micro-/nanoarchitectures for desired applications.

Silencing MAP3K1 expression inhibits the proliferation of goat hair follicle stem cells.

The Yangtze River Delta White Goat is the only goat breed in the world that can produce superior-quality brush hair. Previous studies have shown that some genes are expressed differentially in the skin tissues between the goats produced superior-quality and normal-quality brush hair. Studies also have shown that different gene play varied roles in regulating the proliferation and apoptosis of hair follicle stem cells. However, the biological function of MAP3K1 (mitogen-activated protein kinase kinase kinase 1) gene in hair follicle stem cells is not fully understood. This study aims to investigate the role of MAP3K1 knockdown during the proliferation and apoptosis of hair follicle stem cells. RT-qPCR and Western blot were used to detect mRNA gene and protein expression level, CCK-8 and EdU assays were used to detect cell proliferation, and cell cycle and apoptosis were detected by flow cytometry. The results showed that the MAP3K1 expression level was significantly higher in the skin tissue of produced superior-quality brush hair than that in produced normal-quality brush hair. Moreover, functional studies indicated that si-MAP3K1 significantly inhibits the proliferation of hair follicle stem cells that came from a superior goat and promotes its apoptosis. Based on aforementioned assays, we speculated that MAP3K1 might play a regulatory effect in superior-quality brush hair traits.

miR-31-5p promotes proliferation and inhibits apoptosis of goat hair follicle stem cells by targeting RASA1/MAP3K1 pathway.

The Yangtze River Delta white goat is a sole goat species that can naturally produce superior-quality brush hair. It's worth to mention that study the developmental mechanism of goat hair follicle stem cells is vital for future breed preservation and molecular breeding. In this study, we successfully isolated hair follicle stem cells from the skin tissue of fetal sheep neck spine, and harvested superior-quality and normal-quality brush hair goat tissue. The expression of miR-31-5p in goat hair follicle stem cells was verified by qPCR and Western blot. The effects of overexpression or inhibition of miR-31-5p on the proliferation and apoptosis of hair follicle stem cells were detected by EdU, CCK-8, flow cytometry, etc. miR-31-5p can significantly improve cell proliferation and inhibit cell apoptosis by targeting RASA1 and upregulating MAP3K1 level, whereas miR-31-5p knockdown led to an opposite effect. These results reveal a miR-31-5p-associated regulatory network between miR-31-5p and RASA1/MAP3K1 during the progression of superiorquality brush hair traits.

miR-149-5p Regulates Goat Hair Follicle Stem Cell Proliferation and Apoptosis by Targeting the CMTM3/AR Axis During Superior-Quality Brush Hair Formation.

The Yangtze River Delta white goat is a unique goat species that can produce superior quality brush hair. CKLF-like MARVEL transmembrane domain-containing 3 (CMTM3), which influences the transcriptional activity of androgen receptor (AR), was identified as a candidate gene related to superior-quality brush hair formation. CMTM3 is generally expressed at low levels, but miR-149-5p is highly expressed in the skin tissues of these goats. The mechanism by which CMTM3 regulates the proliferation and apoptosis of goat hair follicle stem cells has not been elucidated. Here, RT-qPCR, western blotting, 5-ethynyl-2'-deoxyuridine (EdU), cell cycle, apoptosis, and dual-luciferase assays were used to investigate the role and regulatory mechanism of CMTM3 and miR-149-5p. Functional studies showed that CMTM3 overexpression inhibited proliferation and induced apoptosis in cultured hair follicle stem cells, whereas silencing CMTM3 markedly facilitated cell proliferation and deterred apoptosis in cultured hair follicle stem cells. Then, using bioinformatic predictions and the aforementioned assays, including dual-luciferase assays, RT-qPCR, and western blotting, we confirmed that miR-149-5p targets CMTM3 and preliminarily investigated the interaction between CMTM3 and AR in goat hair follicle stem cells. Furthermore, miR-149-5p overexpression significantly accelerated the proliferation and attenuated the apoptosis of hair follicle stem cells. Conversely, miR-149-5p inhibition suppressed the proliferation and induced the apoptosis of hair follicle stem cells. These results reveal a miR-149-5p-related regulatory framework for the miR-149-5p/CMTM3/AR axis during superior quality brush hair formation, in which CMTM3 plays a negative role.