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Biomedicines Apr 2024Fibrodysplasia ossificans progressiva (FOP) is a debilitating genetic disorder characterized by recurrent episodes of heterotopic ossification (HO) formation in muscles,... (Review)
Review
Fibrodysplasia ossificans progressiva (FOP) is a debilitating genetic disorder characterized by recurrent episodes of heterotopic ossification (HO) formation in muscles, tendons, and ligaments. FOP is caused by a missense mutation in the gene (activin A receptor type I), an important signaling receptor involved in endochondral ossification. The mutation induces increased downstream canonical SMAD-signaling and drives tissue-resident progenitor cells with osteogenic potential to participate in endochondral HO formation. In this article, we review aberrant ACVR1 signaling and the cells that give rise to HO in FOP. FOP mouse models and lineage tracing analyses have been used to provide strong evidence for tissue-resident mesenchymal cells as cellular contributors to HO. We assess how the underlying mutation in FOP disrupts muscle-specific dynamics during homeostasis and repair, with a focus on muscle-resident mesenchymal cells known as fibro-adipogenic progenitors (FAPs). Accumulating research points to FAPs as a prominent HO progenitor population, with FAPs not only aberrantly differentiating into chondro-osteogenic lineages but creating a permissive environment for bone formation at the expense of muscle regeneration. We will further discuss the emerging role of FAPs in muscle regeneration and therapeutic targeting of these cells to reduce HO formation in FOP.
PubMed: 38672135
DOI: 10.3390/biomedicines12040779 -
The Journal of Neuroscience : the... Jun 2024l-DOPA-induced dyskinesia (LID) is a debilitating motor side effect arising from chronic dopamine (DA) replacement therapy with l-DOPA for the treatment of Parkinson's...
l-DOPA-induced dyskinesia (LID) is a debilitating motor side effect arising from chronic dopamine (DA) replacement therapy with l-DOPA for the treatment of Parkinson's disease. LID is associated with supersensitivity of striatal dopaminergic signaling and fluctuations in synaptic DA following each l-DOPA dose, shrinking the therapeutic window. The heterogeneous composition of the striatum, including subpopulations of medium spiny output neurons (MSNs), interneurons, and supporting cells, complicates the identification of cell(s) underlying LID. We used single-nucleus RNA sequencing (snRNA-seq) to establish a comprehensive striatal transcriptional profile during LID development. Male hemiparkinsonian mice were treated with vehicle or l-DOPA for 1, 5, or 10 d, and striatal nuclei were processed for snRNA-seq. Analyses indicated a limited population of DA D1 receptor-expressing MSNs (D1-MSNs) formed three subclusters in response to l-DOPA treatment and expressed cellular markers of activation. These activated D1-MSNs display similar transcriptional changes previously associated with LID; however, their prevalence and transcriptional behavior were differentially influenced by l-DOPA experience. Differentially expressed genes indicated acute upregulation of plasticity-related transcription factors and mitogen-activated protein kinase signaling, while repeated l-DOPA-induced synaptic remodeling, learning and memory, and transforming growth factor-β (TGF-β) signaling genes. Notably, repeated l-DOPA sensitized , an activin subunit of the TGF-β superfamily, in activated D1-MSNs, and its pharmacological inhibition impaired LID development, suggesting that activin signaling may play an essential role in LID. These data suggest distinct subsets of D1-MSNs become differentially l-DOPA-responsive due to aberrant induction of molecular mechanisms necessary for neuronal entrainment, similar to processes underlying hippocampal learning and memory.
Topics: Animals; Levodopa; Dyskinesia, Drug-Induced; Male; Mice; Corpus Striatum; Mice, Inbred C57BL; Receptors, Dopamine D1; Antiparkinson Agents; Neurons
PubMed: 38664012
DOI: 10.1523/JNEUROSCI.0050-24.2024 -
American Journal of Hematology Jul 2024A recently approved drug that induces erythroid cell maturation (luspatercept) has been shown to improve anemia and reduce the need for blood transfusion in...
A recently approved drug that induces erythroid cell maturation (luspatercept) has been shown to improve anemia and reduce the need for blood transfusion in non-transfusion-dependent as well as transfusion-dependent β-thalassemia (BT) patients. Although these results were predominantly positive, not all the patients showed the expected increase in hemoglobin (Hb) levels or transfusion burden reduction. Additional studies indicated that administration of luspatercept in transfusion-dependent BT was associated with increased erythropoietic markers, decreased hepcidin levels, and increased liver iron content. Altogether, these studies suggest that luspatercept may necessitate additional drugs for improved erythroid and iron management. As luspatercept does not appear to directly affect iron metabolism, we hypothesized that TMPRSS6-ASO could improve iron parameters and iron overload when co-administered with luspatercept. We used an agent analogous to murine luspatercept (RAP-GRL) and another novel therapeutic, IONIS TMPRSS6-LRx (TMPRSS6-ASO), a hepcidin inducer, to treat non-transfusion-dependent BT-intermedia mice. Our study shows that RAP-GRL alone improved red blood cell (RBC) production, with no or limited effect on splenomegaly and iron parameters. In contrast, TMPRSS6-ASO improved RBC measurements, ameliorated splenomegaly, and improved iron overload most effectively. Our results provide pre-clinical support for combining TMPRSS6-ASO and luspatercept in treating BT, as these drugs together show potential for simultaneously improving both erythroid and iron parameters in BT patients.
Topics: beta-Thalassemia; Mice; Animals; Serine Endopeptidases; Membrane Proteins; Recombinant Fusion Proteins; Immunoglobulin Fc Fragments; Humans; Transforming Growth Factor beta; Iron Overload; Hepcidins; Iron; Female; Male; Drug Therapy, Combination; Activin Receptors, Type II
PubMed: 38659383
DOI: 10.1002/ajh.27332 -
Cell Death & Disease Apr 2024Although bevacizumab (BVZ), a representative drug for anti-angiogenesis therapy (AAT), is used as a first-line treatment for patients with glioblastoma (GBM), its...
Although bevacizumab (BVZ), a representative drug for anti-angiogenesis therapy (AAT), is used as a first-line treatment for patients with glioblastoma (GBM), its efficacy is notably limited. Whereas several mechanisms have been proposed to explain the acquisition of AAT resistance, the specific underlying mechanisms have yet to be sufficiently ascertained. Here, we established that inhibitor of differentiation 1 (ID1)/activin A glioblastoma cell confers resistance to BVZ. The bipotent effect of activin A during its active phase was demonstrated to reduce vasculature dependence in tumorigenesis. In response to a temporary exposure to activin A, this cytokine was found to induce endothelial-to-mesenchymal transition via the Smad3/Slug axis, whereas prolonged exposure led to endothelial apoptosis. ID1 tumors showing resistance to BVZ were established to be characterized by a hypovascular structure, hyperpermeability, and scattered hypoxic regions. Using a GBM mouse model, we demonstrated that AAT resistance can be overcome by administering therapy based on a combination of BVZ and SB431542, a Smad2/3 inhibitor, which contributed to enhancing survival. These findings offer valuable insights that could contribute to the development of new strategies for treating AAT-resistant GBM.
Topics: Glioblastoma; Humans; Animals; Inhibitor of Differentiation Protein 1; Mice; Angiogenesis Inhibitors; Activins; Drug Resistance, Neoplasm; Cell Line, Tumor; Bevacizumab; Neovascularization, Pathologic; Mice, Nude; Apoptosis
PubMed: 38658527
DOI: 10.1038/s41419-024-06678-7 -
Science Translational Medicine Apr 2024The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous...
The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous hypertension and face life-threatening complications of hepatic fibrosis, known as Fontan-associated liver disease (FALD). The fundamental biology and mechanisms of FALD are little understood. Here, we generated a transcriptomic and epigenomic atlas of human FALD at single-cell resolution using multiomic snRNA-ATAC-seq. We found profound cell type-specific transcriptomic and epigenomic changes in FC livers. Central hepatocytes (cHep) exhibited the most substantial changes, featuring profound metabolic reprogramming. These cHep changes preceded substantial activation of hepatic stellate cells and liver fibrosis, suggesting cHep as a potential first "responder" in the pathogenesis of FALD. We also identified a network of ligand-receptor pairs that transmit signals from cHep to hepatic stellate cells, which may promote their activation and liver fibrosis. We further experimentally demonstrated that activins A and B promote fibrotic activation in vitro and identified mechanisms of activin A's transcriptional activation in FALD. Together, our single-cell transcriptomic and epigenomic atlas revealed mechanistic insights into the pathogenesis of FALD and may aid identification of potential therapeutic targets.
Topics: Humans; Epigenomics; Fontan Procedure; Hepatic Stellate Cells; Hepatocytes; Liver; Liver Cirrhosis; Liver Diseases; Multiomics; Single-Cell Analysis; Transcriptome
PubMed: 38657025
DOI: 10.1126/scitranslmed.adk6213 -
Scientific Reports Apr 2024Acute Pancreatitis (AP) is associated with high mortality and current treatment options are limited to supportive care. We found that blockade of activin A (activin) in...
Acute Pancreatitis (AP) is associated with high mortality and current treatment options are limited to supportive care. We found that blockade of activin A (activin) in mice improves outcomes in two murine models of AP. To test the hypothesis that activin is produced early in response to pancreatitis and is maintained throughout disease progression to stimulate immune cells, we first performed digital spatial profiling (DSP) of human chronic pancreatitis (CP) patient tissue. Then, transwell migration assays using RAW264.7 mouse macrophages and qPCR analysis of "neutrophil-like" HL-60 cells were used for functional correlation. Immunofluorescence and western blots on cerulein-induced pancreatitis samples from pancreatic acinar cell-specific Kras knock-in (Ptf1aCre™; LSL-Kras) and functional WT Ptf1aCre™ mouse lines mimicking AP and CP to allow for in vivo confirmation. Our data suggest activin promotes neutrophil and macrophage activation both in situ and in vitro, while pancreatic activin production is increased as early as 1 h in response to pancreatitis and is maintained throughout CP in vivo. Taken together, activin is produced early in response to pancreatitis and is maintained throughout disease progression to promote neutrophil and macrophage activation.
Topics: Animals; Activins; Mice; Humans; Macrophages; Pancreatitis; Signal Transduction; Cell Movement; Neutrophil Activation; Neutrophils; Disease Models, Animal; RAW 264.7 Cells; Macrophage Activation; HL-60 Cells; Pancreatitis, Chronic; Male
PubMed: 38654064
DOI: 10.1038/s41598-024-60065-y -
British Journal of Haematology Jun 2024
Topics: Humans; Female; beta-Thalassemia; Pregnancy; Adult; Recombinant Fusion Proteins; Pregnancy, Unplanned; Immunoglobulin Fc Fragments; Activin Receptors, Type II; Pregnancy Complications, Hematologic
PubMed: 38652468
DOI: 10.1111/bjh.19480 -
Frontiers in Aging Neuroscience 2024Activin A, a member of the transforming growth factor β (TGF-β) family, is widely recognized for its neurotrophic and neuroprotective function in the developing and...
Activin A, a member of the transforming growth factor β (TGF-β) family, is widely recognized for its neurotrophic and neuroprotective function in the developing and injured brain, respectively. Moreover, in the healthy adult brain, activin A has been shown to tune signal processing at excitatory synapses in a fashion that improves cognitive performance. Because its level in human cerebrospinal fluid rises with age, we wondered whether activin A has a role in mitigating the gradual cognitive decline that healthy individuals experience in late-life. To interrogate the role of activin A in synaptic plasticity in the aging brain, we used an established transgenic mouse line, in which expression of a dominant-negative mutant of activin receptor IB (dnActRIB) serves to disrupt activin receptor signaling in a forebrain-specific fashion. In brain slices of young adult dnActRIB mice (2-4 months old), the NMDA receptor-dependent and -independent forms of long-term potentiation (LTP) at the Schaffer collateral-CA1 pyramidal cell synapse of the hippocampus were equally impaired relative to the extent of LTP measured in the wild-type preparation. Unexpectedly, the difference between the genotypes disappeared when the two forms of LTP were re-examined in slices from middle-aged mice (13-16 months old). Since the level of activin A and endogenous ActRIB both displayed a significant elevation in middle-aged hippocampus, we reasoned that with such a rise, the dominant-negative effect of the mutant receptors could be overcome. Substantiating this idea, we found that administration of recombinant activin A was indeed capable of restoring full-blown LTP in slices from young dnActRIB mice. Our data suggest that, beginning in the middle-aged brain, endogenous activin receptor signaling appears to become strengthened in an attempt to stave off cognitive decline. If further corroborated, this concept would also hold promise for new therapeutic venues to preserve cognitive functions in the aged brain.
PubMed: 38646448
DOI: 10.3389/fnagi.2024.1382492 -
Science Translational Medicine Apr 2024Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought...
Peripartum cardiomyopathy (PPCM) is an idiopathic form of pregnancy-induced heart failure associated with preeclampsia. Circulating factors in late pregnancy are thought to contribute to both diseases, suggesting a common underlying pathophysiological process. However, what drives this process remains unclear. Using serum proteomics, we identified the senescence-associated secretory phenotype (SASP), a marker of cellular senescence associated with biological aging, as the most highly up-regulated pathway in young women with PPCM or preeclampsia. Placentas from women with preeclampsia displayed multiple markers of amplified senescence and tissue aging, as well as overall increased gene expression of 28 circulating proteins that contributed to SASP pathway enrichment in serum samples from patients with preeclampsia or PPCM. The most highly expressed placental SASP factor, activin A, was associated with cardiac dysfunction or heart failure severity in women with preeclampsia or PPCM. In a murine model of PPCM induced by cardiomyocyte-specific deletion of the gene encoding peroxisome proliferator-activated receptor γ coactivator-1α, inhibiting activin A signaling in the early postpartum period with a monoclonal antibody to the activin type II receptor improved heart function. In addition, attenuating placental senescence with the senolytic compound fisetin in late pregnancy improved cardiac function in these animals. These findings link senescence biology to cardiac dysfunction in pregnancy and help to elucidate the pathogenesis underlying cardiovascular diseases of pregnancy.
Topics: Humans; Pregnancy; Female; Mice; Animals; Pre-Eclampsia; Peripartum Period; Placenta; Cardiomyopathies; Heart Failure; Transcription Factors; Heart Diseases
PubMed: 38630848
DOI: 10.1126/scitranslmed.adi0077 -
American Journal of Hematology Jul 2024β-thalassemia is a disorder characterized by anemia, ineffective erythropoiesis (IE), and iron overload, whose treatment still requires improvement. The activin...
β-thalassemia is a disorder characterized by anemia, ineffective erythropoiesis (IE), and iron overload, whose treatment still requires improvement. The activin receptor-ligand trap Luspatercept, a novel therapeutic option for β-thalassemia, stimulates erythroid differentiation inhibiting the transforming growth factor β pathway. However, its exact mechanism of action and the possible connection with erythropoietin (Epo), the erythropoiesis governing cytokine, remain to be clarified. Moreover, Luspatercept does not correct all the features of the disease, calling for the identification of strategies that enhance its efficacy. Transferrin receptor 2 (TFR2) regulates systemic iron homeostasis in the liver and modulates the response to Epo of erythroid cells, thus balancing red blood cells production with iron availability. Stimulating Epo signaling, hematopoietic Tfr2 deletion ameliorates anemia and IE in Hbb thalassemic mice. To investigate whether hematopoietic Tfr2 inactivation improves the efficacy of Luspatercept, we treated Hbb mice with or without hematopoietic Tfr2 (Tfr2/Hbb) with RAP-536, the murine analog of Luspatercept. As expected, both hematopoietic Tfr2 deletion and RAP-536 significantly ameliorate IE and anemia, and the combined approach has an additive effect. Since RAP-536 has comparable efficacy in both Hbb and Tfr2/Hbb animals, we propose that the drug promotes erythroid differentiation independently of TFR2 and EPO stimulation. Notably, the lack of Tfr2, but not RAP-536, can also attenuate iron-overload and related complications. Overall, our results shed further light on the mechanism of action of Luspatercept and suggest that strategies aimed at inhibiting hematopoietic TFR2 might improve the therapeutic efficacy of activin receptor-ligand traps.
Topics: Animals; beta-Thalassemia; Mice; Receptors, Transferrin; Recombinant Fusion Proteins; Erythropoiesis; Immunoglobulin Fc Fragments; Mice, Knockout; Bone Marrow; Erythropoietin; Gene Deletion; Activin Receptors, Type II
PubMed: 38629683
DOI: 10.1002/ajh.27336