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Science Translational Medicine May 2020Human genetics, biomarker, and animal studies implicate loss of function in bone morphogenetic protein (BMP) signaling and maladaptive transforming growth factor-β...
Human genetics, biomarker, and animal studies implicate loss of function in bone morphogenetic protein (BMP) signaling and maladaptive transforming growth factor-β (TGFβ) signaling as drivers of pulmonary arterial hypertension (PAH). Although sharing common receptors and effectors with BMP/TGFβ, the function of activin and growth and differentiation factor (GDF) ligands in PAH are less well defined. Increased expression of GDF8, GDF11, and activin A was detected in lung lesions from humans with PAH and experimental rodent models of pulmonary hypertension (PH). ACTRIIA-Fc, a potent GDF8/11 and activin ligand trap, was used to test the roles of these ligands in animal and cellular models of PH. By blocking GDF8/11- and activin-mediated SMAD2/3 activation in vascular cells, ACTRIIA-Fc attenuated proliferation of pulmonary arterial smooth muscle cells and pulmonary microvascular endothelial cells. In several experimental models of PH, prophylactic administration of ACTRIIA-Fc markedly improved hemodynamics, right ventricular (RV) hypertrophy, RV function, and arteriolar remodeling. When administered after the establishment of hemodynamically severe PH in a vasculoproliferative model, ACTRIIA-Fc was more effective than vasodilator in attenuating PH and arteriolar remodeling. Potent antiremodeling effects of ACTRIIA-Fc were associated with inhibition of SMAD2/3 activation and downstream transcriptional activity, inhibition of proliferation, and enhancement of apoptosis in the vascular wall. ACTRIIA-Fc reveals an unexpectedly prominent role of GDF8, GDF11, and activin as drivers of pulmonary vascular disease and represents a therapeutic strategy for restoring the balance between SMAD1/5/9 and SMAD2/3 signaling in PAH.
Topics: Activins; Animals; Cell Differentiation; Endothelial Cells; Hypertension, Pulmonary; Signal Transduction
PubMed: 32404506
DOI: 10.1126/scitranslmed.aaz5660 -
Circulation Jun 2023Activins are novel therapeutic targets in pulmonary arterial hypertension (PAH). We therefore studied whether key members of the activin pathway could be used as PAH...
BACKGROUND
Activins are novel therapeutic targets in pulmonary arterial hypertension (PAH). We therefore studied whether key members of the activin pathway could be used as PAH biomarkers.
METHODS
Serum levels of activin A, activin B, α-subunit of inhibin A and B proteins, and the antagonists follistatin and follistatin-like 3 (FSTL3) were measured in controls and in patients with newly diagnosed idiopathic, heritable, or anorexigen-associated PAH (n=80) at baseline and 3 to 4 months after treatment initiation. The primary outcome was death or lung transplantation. Expression patterns of the inhibin subunits, follistatin, FSTL3, Bambi, Cripto, and the activin receptors type I (ALK), type II (ACTRII), and betaglycan were analyzed in PAH and control lung tissues.
RESULTS
Death or lung transplantation occurred in 26 of 80 patients (32.5%) over a median follow-up of 69 (interquartile range, 50-81) months. Both baseline (hazard ratio, 1.001 [95% CI, 1.000-1.001]; =0.037 and 1.263 [95% CI, 1.049-1.520]; =0.014, respectively) and follow-up (hazard ratio, 1.003 [95% CI, 1.001-1.005]; =0.001 and 1.365 [95% CI, 1.185-1.573]; <0.001, respectively) serum levels of activin A and FSTL3 were associated with transplant-free survival in a model adjusted for age and sex. Thresholds determined by receiver operating characteristic analyses were 393 pg/mL for activin A and 16.6 ng/mL for FSTL3. When adjusted with New York Heart Association functional class, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, the hazard ratios for transplant-free survival for baseline activin A <393 pg/mL and FSTL3 <16.6 ng/mL were, respectively, 0.14 (95% CI, 0.03-0.61; =0.009) and 0.17 (95% CI, 0.06-0.45; <0.001), and for follow-up measures, 0.23 (95% CI, 0.07-0.78; =0.019) and 0.27 (95% CI, 0.09-0.78, =0.015), respectively. Prognostic values of activin A and FSTL3 were confirmed in an independent external validation cohort. Histological analyses showed a nuclear accumulation of the phosphorylated form of Smad2/3, higher immunoreactivities for ACTRIIB, ALK2, ALK4, ALK5, ALK7, Cripto, and FSTL3 in vascular endothelial and smooth muscle layers, and lower immunostaining for inhibin-α and follistatin.
CONCLUSIONS
These findings offer new insights into the activin signaling system in PAH and show that activin A and FSTL3 are prognostic biomarkers for PAH.
Topics: Humans; Follistatin; Pulmonary Arterial Hypertension; Inhibins; Activins; Lung
PubMed: 37096577
DOI: 10.1161/CIRCULATIONAHA.122.061501 -
Immunity Feb 2021Th17 cells are known to exert pathogenic and non-pathogenic functions. Although the cytokine transforming growth factor β1 (TGF-β1) is instrumental for Th17 cell...
Th17 cells are known to exert pathogenic and non-pathogenic functions. Although the cytokine transforming growth factor β1 (TGF-β1) is instrumental for Th17 cell differentiation, it is dispensable for generation of pathogenic Th17 cells. Here, we examined the T cell-intrinsic role of Activin-A, a TGF-β superfamily member closely related to TGF-β1, in pathogenic Th17 cell differentiation. Activin-A expression was increased in individuals with relapsing-remitting multiple sclerosis and in mice with experimental autoimmune encephalomyelitis. Stimulation with interleukin-6 and Activin-A induced a molecular program that mirrored that of pathogenic Th17 cells and was inhibited by blocking Activin-A signaling. Genetic disruption of Activin-A and its receptor ALK4 in T cells impaired pathogenic Th17 cell differentiation in vitro and in vivo. Mechanistically, extracellular-signal-regulated kinase (ERK) phosphorylation, which was essential for pathogenic Th17 cell differentiation, was suppressed by TGF-β1-ALK5 but not Activin-A-ALK4 signaling. Thus, Activin-A drives pathogenic Th17 cell differentiation, implicating the Activin-A-ALK4-ERK axis as a therapeutic target for Th17 cell-related diseases.
Topics: Activin Receptors, Type I; Activins; Animals; Cell Differentiation; Cells, Cultured; Encephalomyelitis, Autoimmune, Experimental; Humans; Mice; Mice, Knockout; Molecular Targeted Therapy; Multiple Sclerosis; Neurogenic Inflammation; Signal Transduction; Th17 Cells; Transforming Growth Factor beta
PubMed: 33421362
DOI: 10.1016/j.immuni.2020.12.010 -
Nature Communications Jan 2023Alveolar macrophages (AMs) are crucial for maintaining normal lung function. They are abundant in lung cancer tissues, but their pathophysiological significance remains...
Alveolar macrophages (AMs) are crucial for maintaining normal lung function. They are abundant in lung cancer tissues, but their pathophysiological significance remains unknown. Here we show, using an orthotopic murine lung cancer model and human carcinoma samples, that AMs support cancer cell proliferation and thus contribute to unfavourable outcome. Inhibin beta A (INHBA) expression is upregulated in AMs under tumor-bearing conditions, leading to the secretion of activin A, a homodimer of INHBA. Accordingly, follistatin, an antagonist of activin A is able to inhibit lung cancer cell proliferation. Single-cell RNA sequence analysis identifies a characteristic subset of AMs specifically induced in the tumor environment that are abundant in INHBA, and distinct from INHBA-expressing AMs in normal lungs. Moreover, postnatal deletion of INHBA/activin A could limit tumor growth in experimental models. Collectively, our findings demonstrate the critical pathological role of activin A-producing AMs in tumorigenesis, and provides means to clearly distinguish them from their healthy counterparts.
Topics: Humans; Animals; Mice; Macrophages, Alveolar; Activins; Follistatin; Lung; Lung Neoplasms; Carcinoma
PubMed: 36650150
DOI: 10.1038/s41467-022-35701-8 -
Physiological Reviews Jan 2019Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be... (Review)
Review
Activins are dimeric glycoproteins belonging to the transforming growth factor beta superfamily and resulting from the assembly of two beta subunits, which may also be combined with alpha subunits to form inhibins. Activins were discovered in 1986 following the isolation of inhibins from porcine follicular fluid, and were characterized as ovarian hormones that stimulate follicle stimulating hormone (FSH) release by the pituitary gland. In particular, activin A was shown to be the isoform of greater physiological importance in humans. The current understanding of activin A surpasses the reproductive system and allows its classification as a hormone, a growth factor, and a cytokine. In more than 30 yr of intense research, activin A was localized in female and male reproductive organs but also in other organs and systems as diverse as the brain, liver, lung, bone, and gut. Moreover, its roles include embryonic differentiation, trophoblast invasion of the uterine wall in early pregnancy, and fetal/neonate brain protection in hypoxic conditions. It is now recognized that activin A overexpression may be either cytostatic or mitogenic, depending on the cell type, with important implications for tumor biology. Activin A also regulates bone formation and regeneration, enhances joint inflammation in rheumatoid arthritis, and triggers pathogenic mechanisms in the respiratory system. In this 30-yr review, we analyze the evidence for physiological roles of activin A and the potential use of activin agonists and antagonists as therapeutic agents.
Topics: Activins; Animals; Follicle Stimulating Hormone; Glycoproteins; Humans; Inhibins; Mammals; Reproduction
PubMed: 30540228
DOI: 10.1152/physrev.00002.2018 -
Methods in Molecular Biology (Clifton,... 2022Different states of pluripotency can be captured in vitro depending on the embryo stage from which they are derived and the culture conditions. Pluripotency is a...
Different states of pluripotency can be captured in vitro depending on the embryo stage from which they are derived and the culture conditions. Pluripotency is a continuum of different states between the two extremes of naïve embryonic stem cells (ESCs) and primed Epiblast Stem Cells (EpiSCs), which resemble the pre/peri- and post- implantation embryo, respectively. The transition from naïve to primed pluripotency can be induced by growing naïve ESCs in EpiSCs medium, containing bFGF and Activin. Here we report the detailed protocol to generate and characterize the epiblast-like cells (EpiLCs), which correspond to a primed intermediate state between naïve ESCs and EpiSCs.
Topics: Activins; Cells, Cultured; Embryonic Stem Cells; Germ Layers; Pluripotent Stem Cells
PubMed: 35486236
DOI: 10.1007/978-1-0716-2281-0_3 -
Placenta May 2023Activin A is a two-subunit protein belonging to the transforming growth factor β superfamily. First discovered almost three decades ago, it has since been implicated in... (Review)
Review
Activin A is a two-subunit protein belonging to the transforming growth factor β superfamily. First discovered almost three decades ago, it has since been implicated in diverse physiological roles, ranging from wound repair to reproduction. After 30 years of research, altered activin A levels are now understood to be associated with the development of various diseases, making activin A a potential therapeutic target. In pregnancy, the placenta and fetal membranes are major producers of activin A, with significantly enhanced serum concentrations now recognised as a contributor to numerous gestational disorders. Evidence now suggests that circulating levels of activin A may be clinically relevant in the early detection of pregnancy complications, including miscarriage and preeclampsia. This review aims to summarise our current understanding of activin A as a potential diagnostic marker in common pregnancy pathologies.
Topics: Pregnancy; Female; Humans; Inhibins; Activins; Reproduction; Pregnancy Complications
PubMed: 37028223
DOI: 10.1016/j.placenta.2023.03.008 -
Endocrinology May 2019Activins and inhibins are closely related protein heterodimers with a similar tissue distribution; however, these two complexes have opposing functions in development... (Review)
Review
Activins and inhibins are closely related protein heterodimers with a similar tissue distribution; however, these two complexes have opposing functions in development and disease. Both are secreted cytokine hormones, with activin the primary inducer of downstream signaling cascades and inhibin acting as a rheostat that exquisitely governs activin function. Adding to the complexity of activin signaling, follistatin, a highly glycosylated monomeric protein, binds activin with high affinity and restrains downstream pathway activation but through a mechanism distinct from that of inhibin. These three proteins were first identified as key ovarian hormones in the pituitary-gonadal axis that direct the synthesis and secretion of FSH from the pituitary, hence controlling folliculogenesis. Research during the past 30 years has expanded the roles of these proteins, first by discovering the ubiquitous expression of the trio and then by implicating them in a wide array of biological functions. In concert, these three hormones govern tissue development, homeostasis, and disease in multiple organ systems through diverse autocrine and paracrine mechanisms. In the present study, we have reviewed the actions of activin and its biological inhibitors, inhibin, and follistatin, in mammary gland morphogenesis and cancer.
Topics: Activins; Animals; Breast Neoplasms; Female; Follistatin; Gene Expression Regulation, Neoplastic; Humans; Inhibins; Mammary Glands, Human; Signal Transduction
PubMed: 30874767
DOI: 10.1210/en.2019-00015 -
Biochemical Pharmacology Aug 2023Activins are a subgroup of the TGFβ superfamily of growth and differentiation factors, dimeric in nature and consisting of two inhibin beta subunits linked via a... (Review)
Review
Activins are a subgroup of the TGFβ superfamily of growth and differentiation factors, dimeric in nature and consisting of two inhibin beta subunits linked via a disulfide bridge. Canonical activin signaling occurs through Smad2/3, with negative feedback initiated by Smad6/7 following signal transduction, which binds activin type I receptor preventing phosphorylation of Smad2/3 and activation of downstream signaling. In addition to Smad6/7, other inhibitors of activin signaling have been identified as well, including inhibins (dimers of an inhibin alpha and beta subunit), BAMBI, Cripto, follistatin, and follistatin-like 3 (fstl3). To date, activins A, B, AB, C, and E have been identified and isolated in mammals, with activin A and B having the most characterization of biological activity. Activin A has been implicated as a regulator of several important functions of liver biology, including hepatocyte proliferation and apoptosis, ECM production, and liver regeneration; the role of other subunits of activin in liver physiology are less understood. There is mounting data to suggest a link between dysregulation of activins contributing to various hepatic diseases such as inflammation, fibrosis, and hepatocellular carcinoma, and emerging studies demonstrating the protective and regenerative effects of inhibiting activins in mouse models of liver disease. Due to their importance in liver biology, activins demonstrate utility as a therapeutic target for the treatment of hepatic diseases such as cirrhosis, NASH, NAFLD, and HCC; further research regarding activins may provide diagnostic or therapeutic opportunity for those suffering from various liver diseases.
Topics: Mice; Animals; Follistatin; Carcinoma, Hepatocellular; Liver Neoplasms; Activins; Activin Receptors; Mammals
PubMed: 37364623
DOI: 10.1016/j.bcp.2023.115668 -
Neuropediatrics Apr 2015Activin A is a multifunctional growth and differentiation factor belonging to the transforming growth factor β (TGF-β) family. Growing evidence indicates its role as a... (Review)
Review
Activin A is a multifunctional growth and differentiation factor belonging to the transforming growth factor β (TGF-β) family. Growing evidence indicates its role as a neurotrophic factor and regulator of synaptic transmission as well as its functional importance in several types of cerebral injury. We recently described age-dependent expression of activin A and its regulation at the mRNA and protein level under different conditions of global hypoxia in the neonatal mouse brain. This review discusses the current knowledge of the function and regulation of activin A from human studies as well as from experimental models of brain injury focusing on acquired lesions of the developing rodent brain during the early stages of brain maturation.
Topics: Activins; Animals; Biomarkers; Brain; Brain Injuries; Female; Humans; Inflammation; Pregnancy; Stroke
PubMed: 25769120
DOI: 10.1055/s-0035-1547345