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The ability to differentiate into cells of different lineage, such as muscle, bone, cartilage and fat, is the chief value of adult mesenchymal stem cells (MSCs) which can be used with the final aim to regenerate damaged tissue. Due to potential use, as well as importance in tissue development, a number of questions have been raised regarding the molecular mechanisms of MSC differentiation. As one of the crucial mediators in organism development, transforming growth factor beta (TGF-beta) superfamily directs MSCs commitment in the selection of differentiation pathways. In this review we aim to give an overview of the current knowledge on the mechanisms of MSCs differentiation, on the involvement of TGF-beta superfamily in MSCs differentiation with additional insight into the mutual regulation of microRNAs and TGF-beta in MSCs differentiation. Particular focus has been given to the signaling and transcriptional networks governing the differentiation processes.

Accumulation of dysfunctional white adipose tissues increases risks for cardiometabolic diseases in obesity. In addition to white, brown or brite adipose tissues are also present in adult humans and increasing their amount may be protective. Therefore, understanding factors regulating the amount and function of each adipose depot is crucial for developing therapeutic targets for obesity and its associated metabolic diseases. The transforming growth factor beta (TGFβ) superfamily, which consists of TGFβ, BMPs, GDFs, and activins, controls multiple aspects of adipose biology. This review focuses on the recent development in understanding the role of TGFβ superfamily in the regulation of white, brite and brown adipocyte differentiation, adipose tissue fibrosis, and adipocyte metabolic and endocrine functions. TGFβ family and their antagonists are produced locally within adipose tissues and their expression levels are altered in obesity. We also discuss their potential contribution to adipose tissue dysfunction in obesity.

During pregnancy, there is increased expression of some cytokines at the fetal–maternal interface; and the clarification of their roles in trophoblast–endometrium interactions is crucial to understanding the mechanism of placentation. This review addresses the up-to-date reported mechanisms by which the members of the transforming growth factor beta superfamily regulate trophoblast proliferation, differentiation, and invasion of the decidua, which are the main phases of placentation. The available information shows that these cytokines regulate placentation in somehow a synergistic and an antagonistic manner; and that dysregulation of their levels can lead to aberrant placentation. Nevertheless, prospective studies are needed to reconcile some conflicting reports; and identify some unknown mediators involved in the actions of these cytokines before their detailed mechanistic regulation of human placentation could be fully characterized. The TGF beta superfamily are expressed in the placenta, and regulate the process of placentation through the activation of several signaling pathways.

The hypothesis that, in contrast to other Transforming growth factor-beta (TGFβ) superfamily ligands, the dose-response curve of Anti-Mullerian hormone (AMH) is unmodulated was tested by examining whether known TGFB superfamily modulators affect AMH signalling, using a P19/BRE luciferase reporter assay. AMHC and AMHN,C activated the reporter with an EC50 of approximately 0.5 nM. Follistatins (FS) produced concentration-dependent increases in AMHC- and AMHN,C-inidiated reporter activity, with FS288 being more potent than FS315; however, the maximum bioactivity of AMH was not altered by either follistatin. Thirteen other TGFB regulators (Chordin, Chordin-like 1, Chordin-like 2, Differential screening-selected gene aberrative in neuroblastoma [DAN], Decorin, Endoglin, Follistatin-like 1, Follistatin-like 3, Follistatin-like 4, Noggin, α2 macroglobulin, TGFβ receptor 3, Von Willebrand factor C domain-containing 2) had little or no effect. Surface plasmon resonance analysis showed no significant association between FS288 and AMHC, suggesting that FS288 indirectly regulates AMH signalling. Activin A, a direct target of FS288, did not itself induce reporter activity in P19 cells, but did prevent the FS288-induced increase in AMH signalling. Hence, local concentrations of FS288 and Activin A may influence the response of some cell types to AMH. This article is protected by copyright. All rights reserved

PEKCAN, MERT/0000-0003-3084-125X WOS: 000504519700013 PubMed: 31677486 The aim of this study was to investigate some of the growth and transcriptional factors originating from oocytes and granulosa cells in follicular fluid and to identify the relationships between the basic blood metabolite-metabolic hormones and intrafollicular lipo-polysaccharide (LPS) concentrations. Thirty cows included in the study were allocated into 2 groups comprising 15 cows with healthy preovulatory follicles (cyclic cows) and 15 cows with confirmed cystic follicles. The ovaries and uteri of all cows were assessed by transrectal ultrasonographic examination. Blood serum samples were collected at 15, 25, 35, 45, and 55 d after calving for analysis of nonesterified fatty acids, beta-hydroxybutyrate, insulin, glucose, IGF-1, ACTH, and cortisol. Ovaries and uteri were examined using transrectal ultrasound. Vaginal discharge was evaluated on the same days. Follicular fluid was also aspirated on days 35-55 from the healthy preovulatory follicles and cystic follicles using a transvaginal ovum pickup method. The densitometric levels of inhibin-a, growth and differentiation factor (GDF-9), bone morphogenetic protein (BMP-6), and GATA-4 and GATA-6 proteins were analyzed by the Western blotting technique; the concentrations of antimullerian hormone (AMH), IGF-I, estradiol-17 beta (E2), and progesterone (P4) were determined by ELISA; and the concentrations of LPS in the follicular fluid were measured by the Limulus amebocyte lysate test. The serum insulin, ACTH, and cortisol concentrations were higher in cystic cows than cyclic cows, but serum IGF-I concentrations were lower in cystic cows. The IGF-1 concentrations of cystic follicular fluids were lower, whereas AMH levels were significantly greater than those of healthy preovulatory follicular fluids. The cystic follicles had significantly lower expression levels of GDF-9, BMP-6, GATA-4, and GATA-6; in contrast, inhibin-alpha expression and LPS concentrations were significantly higher than in healthy preovulatory follicles. The proportion of pathologic vaginal discharge within 25 d postpartum in cystic cows were higher than in the cyclic group. In conclusion, it is suggested that intrafollicular dysregulation of the transforming growth factor-beta superfamily, growth, and transcriptional factors is affected by high intrafollicular LPS concentrations and systemic metabolic changes and these disturbances may be responsible for the generation of ovarian cysts. (C) 2019 Elsevier Inc. All rights reserved. Scientific and Technological Research Council of Turkey, Turkey (TUBITAK)Turkiye Bilimsel ve Teknolojik Arastirma Kurumu (TUBITAK) [1090643] This work was supported by the Scientific and Technological Research Council of Turkey, Turkey (TUBITAK) (Project number: 1090643).

BACKGROUND: The regeneration of cartilage has always been a challenge for tissue engineering. Constantly renewed insights into the role of transforming growth factor-beta (TGF-β) supergene family of proteins, which are vital in several fundamental biological processes in cartilage health and regeneration, has opened up new prospects for the treatment of cartilage-related diseases. In this study, the aim was to investigate what the effect of three different growth factors from the TGF-β supergene family specifically [bone morphogenetic protein 2 (BMP-2); TGF-β3; osteogenic protein 1 (OP-1)], alone but especially in varying combinations including application durations, would have on the induction of chondrogenesis in muscle tissue of rats. METHODS: Abdominal muscle tissue from rats was utilized. To monitor what the effect of morphogen presence would have on chondrogenesis, the “withdrawal study”, assessed two modes of stimulation. These were a continuous application of relevant morphogens and their combinations for the entire duration of the in vitro culture or a single application only for 48h. The detections were performed on day 7, 14 and 30 using immunohistochemistry (IHC), histological staining (alcian blue staining) and quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR). Aggrecan was treated as the target antigen in the IHC. The relative gene expression levels were analyzed to confirm the survival of the model and the chondrogenesis, including vascular endothelial growth factor A (VEGF-A), collagen type IV alpha 1 (Col4α1), sex-determining region Y (SRY)-box 9 (SOX9), aggrecan (ACAN), collagen type II alpha 1 (Col2α1), collagen type X alpha 1 (Col10α1), collagen type I alpha 1 (Col1α1) and alkaline phosphatase (ALP). RESULTS: The results of the qRT-PCR showed that the up-regulation in gene expression for the continuous experimental groups was more significant than that of the single 48h stimulation groups. The group with BMP-2 alone continuously presented the highest relative expression levels on day 7, in terms of the chondrogenic-related genes. Positive reactions were observed in the alcian blue staining and IHC with semi-quantitative histomorphometrical analysis showing a correlation to that of the gene expression patterns. CONCLUSIONS: Muscle tissue was proven to be a viable model in this chondrogenic induction study. The application of members of the TGF-β supergene family, alone or in combinations, induced chondrogenesis in this tissue model, with results suggesting that hyaline cartilage chondrogenesis was being developed based on the Col2α1 expression patterns. Although it was attempted to get a more economic-efficiency induction scheme using the withdraw-study in this project, it was shown that single stimulation of a growth factor was insufficient to evoke the relevant response, strongly suggesting that a continuous stimulation is necessary. However, the results in this regard have to be interpreted with care as it is clear that a single morphogen has a limited spatial and temporal effect where the presence of the appropriate corresponding complementary soluble signal(s) needs to be present at the correct time to ensure a proper and sustained biological reaction of specific pathways with time. This was exemplified by BMP-2 that on its own was able to initiate chondrogenesis, yet when added in combination with TGF-β3 and/or OP-1 was inhibited. However, while the BMP-2 initially stimulated chondrogenesis, it could not maintain the relevant reaction in the middle and late stages of chondrogenic induction, where TGF-β3 and OP-1 were necessary to maintain the cartilage tissue engineering reaction. Although limitations still exist, the experiments provide a crucial realization in the TGF-β supergene family tissue engineering prospect and deliver novel awareness and strategies in producing engineered hyaline cartilage for future clinical applications.

During mammalian ovarian development transforming growth factor-beta (TGFbeta) superfamily members and their inhibitors are critical paracrine regulators, yet the intraovarian functions of these proteins have received less attention in fish. Using quantitative real-time RT-PCR, changes in ovarian mRNA expression of six TGFbeta members and two inhibitors were investigated in rainbow trout across a wide range of fish ovarian stages (i.e., early perinucleous stage through acquisition of maturational competence). Transcript changes for insulin-like growth factor 1 and 2, and five enzymes associated with steroidogenesis, as well as plasma levels of three sex steroids were also measured to provide a framework of established intraovarian regulators in trout. Expression of bone morphogenetic protein 4 (bmp4), bone morphogenetic protein7 (bmp7), and growth differentiation factor 9 (gdf9) peaked during pre-vitellogenic stages and steadily decreased through advancing stages implicating these genes in early ovarian development. A dramatic increase in inhibin beta(A) and decrease in follistatin expression occurred during early to mid-vitellogenic stages, which corresponded with increased 17beta-estradiol plasma levels suggesting a vitellogenic role for ovarian activin A. Follicles that were competent to respond to the maturation-inducing hormone had decreased levels of inhibin beta(B) and increased expression of bambi (bmp and activin membrane-bound inhibitor) suggesting their roles in maturation processes. Furthermore, bmp4, bmp7 and gdf9 are primarily expressed in the oocyte whereas the inhibin subunits, follistatin, and bambi are primarily expressed in the somatic follicle cells. These results support TGFbeta superfamily members and their inhibitors have wide-ranging and disparate roles in regulating ovarian development in fish.

Primordial follicle formation and the subsequent transition of follicles to the primary and secondary stages encompass the early events during folliculogenesis in mammals. These processes establish the ovarian follicle pool and prime follicles for entry into subsequent growth phases during the reproductive cycle. Perturbations during follicle formation can affect the size of the primordial follicle pool significantly, and alterations in follicle transition can cause follicles to arrest at immature stages or result in premature depletion of the follicle reserve. Determining the molecular events that regulate primordial follicle formation and early follicle growth may lead to the development of new fertility treatments. Over the last decade, many of the growth factors and signaling proteins that mediate the early stages of folliculogenesis have been identified using mouse genetic models, in vivo injection studies, and ex vivo organ culture approaches. These studies reveal important roles for the transforming growth factor beta (TGF-beta) superfamily of proteins in the ovary. This article reviews these roles for TGF-beta family proteins and focuses in particular on work from our laboratories on the functions of activin in early folliculogenesis.

Meningiomas are central nervous system tumors with a high recurrence rate. In the absence of effective chemotherapies, inoperable, recurrent and metastatic tumors remain a therapeutic challenge. Members of the TGF- super-family play an integral role in the development, progression and metastases of many malignancies yet may be underappreciated participants in the biology of meningiomas. This paper reviews the common abnormalities in TGF- or BMP signaling in neoplasias with a focus on meningiomas. Sites of potential targeting for new chemotherapies are also noted.

The process of transformation of growing bovine follicles into cysts is still a mystery. Local expression of proteins or factors, including transforming growth factor β, growth factors, and transcription factors, plays a central role in mammals. Therefore, in abattoir-derived cystic ovarian follicles and follicular fluid, the role of some transforming growth factor β superfamily proteins, insulinlike growth factor-1 (IGF-1) and GATA-4 and GATA-6, were investigated. The relationship between intrafollicular lipopolysaccharide (LPS) and etiopathogenesis of ovarian cysts was also assessed. Data on the preovulatory follicle and the largest follicle (F1) were compared. The number of intrafollicular LPS-positive samples and LPS concentrations were higher in cysts. Immunohistochemical staining was mildly positive for IGF-1, inhibin alpha, and GATA-4 in thecal cells. Staining for anti-Mullerian hormone (AMH), growth differentiation factor-9, bone morphogenetic protein-6 (BMP-6), and GATA-6 was insufficient for their quantitation, and oocytes could not be stained for any of the proteins tested in the cystic follicles. Expression of BMP-6, inhibin alpha, and IGF-1 was moderately higher in granulosa cells of F1 follicles, and all the proteins were moderately expressed in granulosa cells in preovulatory follicles. However, loss of GATA-6 staining was significant in F1 follicles. Intrafollicular progesterone, IGF-1, and AMH concentrations in cysts and F1 follicles were significantly higher than those in preovulatory follicles. Western blot analyses revealed that follicular fluid inhibin-α was strongly expressed, whereas expression of growth differentiation factor-9, BMP-6, GATA-4 and GATA-6 was lower in cysts than in preovulatory follicles. Also, high intrafollicular AMH concentration and low BMP-6 expression were closely associated with cystic degeneration and atresia. In conclusion, immunohistochemical loss of BMP-6 and GATA-6 in the granulosa cells together with high intrafollicular LPS levels may play important roles in disruption of the ovulatory mechanism and steroidogenic reactions in type 2 cyst. Also, high intrafollicular AMH concentration along with low BMP-6 expression may be used as indicators of the bovine degenarative ovarian follicles.

Embryonic limb outgrowth is accomplished by the proliferation of mesodermal cells in the progress zone. In this region, mesodermal cells are maintained in an undifferentiated and proliferating state by the action of the apical ectodermal ridge (AER). Differentiation of these cells into individual skeletal elements occurs when the cells are displaced proximally and leave the influence of the AER as a consequence of the accumulation of cells in that region. Here we review the evidence obtained in the last few years showing that members of the transforming growth factor beta (TGFbeta) subfamily and bone morphogenetic proteins (BMPs) act as proximal signals in the autopod regulating the fate of the progress zone cells towards chondrogenesis or apoptosis. Our findings show that apoptosis is regulated by BMPs while chondrogenesis requires the interaction of TGFbetas and BMPs. Fibroblast growth factors (FGFs) produced by the AER exert an opposite function to both TGFbetas and BMPs, maintaining the progress zone cells in an undifferentiated state.

Two new mammalian members (growth/differentiation factor 3 (GDF-3) and GDF-9) of the transforming growth factor-beta superfamily were identified using degenerate oligonucleotides corresponding to conserved regions among known family members. By Northern analysis, GDF-3 transcripts were detected primarily in adult bone marrow, spleen, thymus, and adipose tissue. In contrast, GDF-9 transcripts were detected only in the ovary. Based on their cDNA sequences, the predicted GDF-3 and GDF-9 polypeptides each contain a potential signal sequence for secretion, a putative tetrabasic proteolytic processing site, and a COOH-terminal region that shows significant homology to the known members of the transforming growth factor-beta superfamily. In the COOH-terminal region, GDF-3 and GDF-9 are most homologous to Xenopus Vg-1 (57%) and human bone morphogenetic protein 4 (34%), respectively. Unlike all previously described members of this superfamily, both GDF-3 and GDF-9 lack the conserved cysteine residue that is believed to form the sole disulfide linkage between subunits in other family members. These findings raise new possibilities regarding subunit interactions among members of this superfamily.

Human endometrium is unique since it is the only tissue in the body that bleeds at regular intervals. In addition, abnormal endometrial bleeding is one of the most common manifestations of gynecological diseases, and is a prime indication for hysterectomy. Here, we report on a novel human gene, endometrial bleeding associated factor (ebaf), whose strong expression in endometrium was associated with abnormal endometrial bleeding. In normal human endometrium, this gene was transiently expressed before and during menstrual bleeding. In situ hybridization showed that the mRNA of ebaf was expressed in the stroma without any significant mRNA expression in the endometrial glands or endothelial cells. The predicted protein sequence of ebaf showed homology with and structural features of the members of TGF-beta superfamily. Fluorescence in situ hybridization showed that the ebaf gene is located on human chromosome 1 at band q42.1. Thus, ebaf is a novel member of the TGF-beta superfamily and an endometrial tissue factor whose expression is associated with normal menstrual and abnormal endometrial bleeding.