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Wnt6 maintains anterior escort cells as an integral component of the germline stem cell niche.
Wang X, Page-McCaw A
(2018) Development 145:
MeSH Terms: Animals, Animals, Genetically Modified, Bone Morphogenetic Proteins, Cadherins, Cell Count, Cell Differentiation, Cell Lineage, Cell Survival, Drosophila Proteins, Drosophila melanogaster, Female, Germ Cells, Ligands, Models, Biological, Ovary, Signal Transduction, Stem Cell Niche, Wnt Proteins
Show Abstract · Added March 20, 2018
Stem cells reside in a niche, a local environment whose cellular and molecular complexity is still being elucidated. In ovaries, germline stem cells depend on cap cells for self-renewing signals and physical attachment. Germline stem cells also contact the anterior escort cells, and here we report that anterior escort cells are absolutely required for germline stem cell maintenance. When escort cells die from impaired Wnt signaling or expression, the loss of anterior escort cells causes loss of germline stem cells. Anterior escort cells function as an integral niche component by promoting DE-cadherin anchorage and by transiently expressing the Dpp ligand to promote full-strength BMP signaling in germline stem cells. Anterior escort cells are maintained by Wnt6 ligands produced by cap cells; without Wnt6 signaling, anterior escort cells die leaving vacancies in the niche, leading to loss of germline stem cells. Our data identify anterior escort cells as constituents of the germline stem cell niche, maintained by a cap cell-produced Wnt6 survival signal.
© 2018. Published by The Company of Biologists Ltd.
0 Communities
1 Members
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18 MeSH Terms
Coordinated Proliferation and Differentiation of Human-Induced Pluripotent Stem Cell-Derived Cardiac Progenitor Cells Depend on Bone Morphogenetic Protein Signaling Regulation by GREMLIN 2.
Bylund JB, Trinh LT, Awgulewitsch CP, Paik DT, Jetter C, Jha R, Zhang J, Nolan K, Xu C, Thompson TB, Kamp TJ, Hatzopoulos AK
(2017) Stem Cells Dev 26: 678-693
MeSH Terms: Bone Morphogenetic Proteins, Cell Differentiation, Cell Line, Cell Proliferation, Cells, Cultured, Gene Expression Profiling, Gene Expression Regulation, Developmental, Humans, Induced Pluripotent Stem Cells, Intercellular Signaling Peptides and Proteins, Myocardium, Myocytes, Cardiac, Organogenesis, Signal Transduction, Stem Cells
Show Abstract · Added September 6, 2017
Heart development depends on coordinated proliferation and differentiation of cardiac progenitor cells (CPCs), but how the two processes are synchronized is not well understood. Here, we show that the secreted Bone Morphogenetic Protein (BMP) antagonist GREMLIN 2 (GREM2) is induced in CPCs shortly after cardiac mesoderm specification during differentiation of human pluripotent stem cells. GREM2 expression follows cardiac lineage differentiation independently of the differentiation method used, or the origin of the pluripotent stem cells, suggesting that GREM2 is linked to cardiogenesis. Addition of GREM2 protein strongly increases cardiomyocyte output compared to established procardiogenic differentiation methods. Our data show that inhibition of canonical BMP signaling by GREM2 is necessary to promote proliferation of CPCs. However, canonical BMP signaling inhibition alone is not sufficient to induce cardiac differentiation, which depends on subsequent JNK pathway activation specifically by GREM2. These findings may have broader implications in the design of approaches to orchestrate growth and differentiation of pluripotent stem cell-derived lineages that depend on precise regulation of BMP signaling.
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15 MeSH Terms
Emerging roles of the bone morphogenetic protein pathway in cancer: potential therapeutic target for kinase inhibition.
Jiramongkolchai P, Owens P, Hong CC
(2016) Biochem Soc Trans 44: 1117-34
MeSH Terms: Animals, Bone Morphogenetic Protein Receptors, Bone Morphogenetic Proteins, Disease Progression, Humans, Models, Biological, Neoplasms, Signal Transduction, Tumor Microenvironment
Show Abstract · Added September 6, 2016
Bone morphogenetic proteins (BMPs) belong to the transforming growth factor-β (TGF-β) family signalling pathway. Similar to TGF-β, the complex roles of BMPs in development and disease are demonstrated by their dichotomous roles in various cancers and cancer stages. Although early studies implicated BMP signalling in tumour suppressive phenotypes, the results of more recent experiments recognize BMPs as potent tumour promoters. Many of these complexities are becoming illuminated by understanding the role of BMPs in their contextual role in unique cell types of cancer and the impact of their surrounding tumour microenvironment. Here we review the emerging roles of BMP signalling in cancer, with a focus on the molecular underpinnings of BMP signalling in individual cancers as a valid therapeutic target for cancer prevention and treatment.
© 2016 The Author(s). published by Portland Press Limited on behalf of the Biochemical Society.
1 Communities
1 Members
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9 MeSH Terms
BMP signaling and cellular dynamics during regeneration of airway epithelium from basal progenitors.
Tadokoro T, Gao X, Hong CC, Hotten D, Hogan BL
(2016) Development 143: 764-73
MeSH Terms: Animals, Apoptosis, Basement Membrane, Bone Morphogenetic Proteins, Cell Differentiation, Cell Proliferation, Epithelial Cells, Green Fluorescent Proteins, Ligands, Lung, Male, Mice, Mice, Inbred C57BL, Pyrazoles, Pyrimidines, Regeneration, Respiratory Mucosa, Signal Transduction, Stem Cells, Trachea
Show Abstract · Added February 22, 2016
The pseudostratified epithelium of the lung contains ciliated and secretory luminal cells and basal stem/progenitor cells. To identify signals controlling basal cell behavior we screened factors that alter their self-renewal and differentiation in a clonal organoid (tracheosphere) assay. This revealed that inhibitors of the canonical BMP signaling pathway promote proliferation but do not affect lineage choice, whereas exogenous Bmp4 inhibits proliferation and differentiation. We therefore followed changes in BMP pathway components in vivo in the mouse trachea during epithelial regeneration from basal cells after injury. The findings suggest that BMP signaling normally constrains proliferation at steady state and this brake is released transiently during repair by the upregulation of endogenous BMP antagonists. Early in repair, the packing of epithelial cells along the basal lamina increases, but density is later restored by active extrusion of apoptotic cells. Systemic administration of the BMP antagonist LDN-193189 during repair initially increases epithelial cell number but, following the shedding phase, normal density is restored. Taken together, these results reveal crucial roles for both BMP signaling and cell shedding in homeostasis of the respiratory epithelium.
© 2016. Published by The Company of Biologists Ltd.
1 Communities
1 Members
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20 MeSH Terms
Bone morphogenetic protein signaling promotes tumorigenesis in a murine model of high-grade glioma.
Hover LD, Owens P, Munden AL, Wang J, Chambless LB, Hopkins CR, Hong CC, Moses HL, Abel TW
(2016) Neuro Oncol 18: 928-38
MeSH Terms: Animals, Astrocytes, Bone Morphogenetic Protein Receptors, Type I, Bone Morphogenetic Proteins, Carcinogenesis, Cell Proliferation, Cell Transformation, Neoplastic, Gene Expression Regulation, Glioma, Mice, Transgenic, Signal Transduction
Show Abstract · Added December 20, 2015
BACKGROUND - Improved therapies for high-grade glioma (HGG) are urgently needed as the median survival for grade IV gliomas is only 15 months. Bone morphogenetic protein (BMP) signaling plays critical and complex roles in many types of cancer, including glioma, with most of the recently published work focusing on BMP-mediated regulation of glioma stem cells (GSCs). We hypothesized that BMP signaling may be an important modulator of tumorigenic properties in glioma cells outside of the GSC compartment.
METHODS - We used a human HGG tissue microarray and performed immunohistochemistry for phospho-Smads1,5,8. To examine the role of BMP signaling in tumorigenic astrocytes, transgenic mice were used to delete the BMP type IA receptor (Bmpr1a) and generate astrocytes transformed with oncogenic Ras and homozygous deletion of p53. The cells were transplanted orthotopically into immunocompetent adult host mice.
RESULTS - First we established that BMP signaling is active within the vast majority of HGG tumor cells. Mice implanted with BMPR1a-knockout transformed astrocytes showed an increase in median survival compared with mice that received BMPR1a-intact transformed astrocytes (52.5 vs 16 days). In vitro analysis showed that deletion of BMPR1a in oncogenic astrocytes resulted in decreased proliferation, decreased invasion, decreased migration, and increased expression of stemness markers. In addition, inhibition of BMP signaling in murine cells and astrocytoma cells with a small molecule BMP receptor kinase inhibitor resulted in similar tumor suppressive effects in vitro.
CONCLUSION - BMP inhibition may represent a viable therapeutic approach in adult HGG.
© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
2 Communities
5 Members
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11 MeSH Terms
Small molecule inhibitor of the bone morphogenetic protein pathway DMH1 reduces ovarian cancer cell growth.
Hover LD, Young CD, Bhola NE, Wilson AJ, Khabele D, Hong CC, Moses HL, Owens P
(2015) Cancer Lett 368: 79-87
MeSH Terms: Antineoplastic Agents, Bone Morphogenetic Protein Receptors, Bone Morphogenetic Proteins, Cell Proliferation, Cisplatin, Disease-Free Survival, Drug Resistance, Neoplasm, Female, Gene Expression Regulation, Neoplastic, Humans, Ovarian Neoplasms, Pyrazoles, Quinolines, Signal Transduction, Spheroids, Cellular, Tumor Cells, Cultured
Show Abstract · Added August 4, 2015
The bone morphogenetic protein (BMP) pathway belonging to the Transforming Growth Factor beta (TGFβ) family of secreted cytokines/growth factors is an important regulator of cancer. BMP ligands have been shown to play both tumor suppressive and promoting roles in human cancers. We have found that BMP ligands are amplified in human ovarian cancers and that BMP receptor expression correlates with poor progression-free-survival (PFS). Furthermore, active BMP signaling has been observed in human ovarian cancer tissue. We also determined that ovarian cancer cell lines have active BMP signaling in a cell autonomous fashion. Inhibition of BMP signaling with a small molecule receptor kinase antagonist is effective at reducing ovarian tumor sphere growth. Furthermore, BMP inhibition can enhance sensitivity to Cisplatin treatment and regulates gene expression involved in platinum resistance in ovarian cancer. Overall, these studies suggest targeting the BMP pathway as a novel source to enhance chemo-sensitivity in ovarian cancer.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
2 Communities
4 Members
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16 MeSH Terms
Association of circulating sclerostin with vascular calcification in Afro-Caribbean men.
Kuipers AL, Miljkovic I, Carr JJ, Terry JG, Nestlerode CS, Ge Y, Bunker CH, Patrick AL, Zmuda JM
(2015) Atherosclerosis 239: 218-23
MeSH Terms: African Continental Ancestry Group, Aged, Aorta, Blood Glucose, Bone Morphogenetic Proteins, Caribbean Region, Genetic Markers, Humans, Male, Middle Aged, Multivariate Analysis, Risk Factors, Tomography, X-Ray Computed, Trinidad and Tobago, Vascular Calcification, Vascular Diseases, Wnt Signaling Pathway
Show Abstract · Added January 28, 2015
OBJECTIVE - Sclerostin, a Wingless (Wnt) pathway antagonist, is an established regulator of bone mineralization in humans but its potential importance in the regulation of vascular calcification is less clear. Therefore, our objective was to assess the relationship of serum sclerostin levels with coronary and aortic artery calcification (CAC and AAC, respectively) in Afro-Caribbean men on the island of Tobago.
METHODS - Serum sclerostin levels and computed tomography of CAC and AAC were measured in 191 men (age mean(SD): 62.9(8.0)years) recruited without regard to health status. Multivariable logistic regression models were used to assess the cross-sectional association of sclerostin with prevalent arterial calcification.
RESULTS - Mean(SD) sclerostin was 45.2 pmol/L (15.6 pmol/L). After adjusting for risk factors including age, physical and lifestyle characteristics, comorbidities, lipoproteins and kidney function, 1 SD greater sclerostin level was associated with a 1.61-times (95%CI 1.02-2.53) greater odds of having CAC. Sclerostin was not associated with AAC in any model.
CONCLUSIONS - This is the first study to show that, among Afro-Caribbean men, greater serum sclerostin concentrations were associated with prevalence and extent of CAC. Further studies are needed to better define the role of the Wnt signaling pathway in arterial calcification in humans.
Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.
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2 Members
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17 MeSH Terms
Inhibition of BMP signaling suppresses metastasis in mammary cancer.
Owens P, Pickup MW, Novitskiy SV, Giltnane JM, Gorska AE, Hopkins CR, Hong CC, Moses HL
(2015) Oncogene 34: 2437-49
MeSH Terms: Animals, Bone Morphogenetic Proteins, Female, Fibroblasts, Humans, Lung Neoplasms, Lymphatic Vessels, Macrophages, Mammary Neoplasms, Animal, Mice, Mice, Inbred C57BL, Mice, Transgenic, Pyrazoles, Quinolines, Signal Transduction, Tumor Microenvironment
Show Abstract · Added July 8, 2014
Bone morphogenetic proteins (BMPs) are secreted cytokines/growth factors that have differing roles in cancer. BMPs are overexpressed in human breast cancers, but loss of BMP signaling in mammary carcinomas can accelerate metastasis. We show that human breast cancers display active BMP signaling, which is rarely downregulated or homozygously deleted. We hypothesized that systemic inhibition of BMP signaling in both the tumor and the surrounding microenvironment could prevent tumor progression and metastasis. To test this hypothesis, we used DMH1, a BMP antagonist, in MMTV.PyVmT expressing mice. Treatment with DMH1 reduced lung metastasis and the tumors were less proliferative and more apoptotic. In the surrounding tumor microenvironment, treatment with DMH1 altered fibroblasts, lymphatic vessels and macrophages to be less tumor promoting. These results indicate that inhibition of BMP signaling may successfully target both the tumor and the surrounding microenvironment to reduce tumor burden and metastasis.
2 Communities
4 Members
0 Resources
16 MeSH Terms
Jagged1 is essential for osteoblast development during maxillary ossification.
Hill CR, Yuasa M, Schoenecker J, Goudy SL
(2014) Bone 62: 10-21
MeSH Terms: Animals, Bone Density, Bone Morphogenetic Proteins, Calcification, Physiologic, Calcium, Calcium-Binding Proteins, Cell Differentiation, Embryo, Mammalian, Intercellular Signaling Peptides and Proteins, Jagged-1 Protein, Maxilla, Membrane Proteins, Mesoderm, Mice, Knockout, Organ Size, Osteoblasts, Osteogenesis, Palate, Receptors, Fc, Receptors, Notch, Serrate-Jagged Proteins, Signal Transduction, X-Ray Microtomography
Show Abstract · Added May 28, 2014
Maxillary hypoplasia occurs due to insufficient maxillary intramembranous ossification, leading to poor dental occlusion, respiratory obstruction and cosmetic deformities. Conditional deletion of Jagged1 (Jag1) in cranial neural crest (CNC) cells using Wnt1-cre; Jagged1(f/f) (Jag1CKO) led to maxillary hypoplasia characterized by intrinsic differences in bone morphology and density using μCT evaluation. Jag1CKO maxillas revealed altered collagen deposition, delayed ossification, and reduced expression of early and late determinants of osteoblast development during maxillary ossification. In vitro bone cultures on Jag1CKO mouse embryonic maxillary mesenchymal (MEMM) cells demonstrated decreased mineralization that was also associated with diminished induction of osteoblast determinants. BMP receptor expression was dysregulated in the Jag1CKO MEMM cells suggesting that these cells were unable to respond to BMP-induced differentiation. JAG1-Fc rescued in vitro mineralization and osteoblast gene expression changes. These data suggest that JAG1 signaling in CNC-derived MEMM cells is required for osteoblast development and differentiation during maxillary ossification.
Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
0 Communities
2 Members
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23 MeSH Terms
Sclerostin is positively associated with bone mineral density in men and women and negatively associated with carotid calcified atherosclerotic plaque in men from the African American-Diabetes Heart Study.
Register TC, Hruska KA, Divers J, Bowden DW, Palmer ND, Carr JJ, Wagenknecht LE, Hightower RC, Xu J, Smith SC, Dietzen DJ, Langefeld CD, Freedman BI
(2014) J Clin Endocrinol Metab 99: 315-21
MeSH Terms: Adult, African Americans, Aged, Biomarkers, Bone Density, Bone Morphogenetic Proteins, Carotid Artery Diseases, Cross-Sectional Studies, Diabetes Complications, Female, Genetic Markers, Humans, Male, Middle Aged, Plaque, Atherosclerotic, Sex Factors, Vascular Calcification
Show Abstract · Added February 15, 2014
CONTEXT - Bone mineral density (BMD) and calcified atherosclerotic plaque (CP) demonstrate inverse relationships. Sclerostin, an endogenous regulator of the Wnt pathway and bone formation, has been associated with impaired osteoblast activation and may play a role in vascular calcification.
OBJECTIVE - Our objective was to assess the relationships between sclerostin, BMD, and CP.
DESIGN - Generalized linear models were fitted to test for associations between sclerostin, volumetric BMD (vBMD), and CP.
PARTICIPANTS - A targeted population of 450 unrelated African Americans (AAs) with type 2 diabetes (T2D) was 56% female with mean/SD/median age of 55.4/9.5/55.0 years and a diabetes duration of 10.3/8.2/8.0 years.
MAIN OUTCOME MEASURES - Plasma sclerostin, computed tomography-derived thoracic and lumbar vertebrae trabecular vBMD, coronary artery, carotid artery, and aortoiliac CP were measured.
RESULTS - Plasma sclerostin was 1119/401/1040 pg/mL, thoracic vBMD was 206.3/52.4/204.8 mg/cm3, lumbar vBMD was 180.7/47.0/179.0 mg/cm3, coronary artery CP score was 284/648/13, carotid artery CP score was 46/132/0, and aortoiliac CP score was 1613/2910/282. Sclerostin levels were higher in men than women (P<.0001). Before and after adjusting for age, sex, body mass index, blood pressure, smoking, hemoglobin A1c, and low-density lipoprotein-cholesterol, plasma sclerostin levels were positively associated with thoracic and lumbar vertebrae vBMD (P<.0001). Sex-stratified analyses verified significant relationships in both men and women (both P<.001). Sclerostin was not associated with CP except for an inverse relationship with carotid CP in men (fully adjusted model, P=.03).
CONCLUSIONS - In this cross-sectional study of AA men and women with T2D, circulating sclerostin was positively associated with vBMD in the spine in both sexes and inversely associated with carotid artery CP in men. Sclerostin may play a role in skeletal mineral metabolism in AA but fails to explain inverse relationships between BMD and CP.
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17 MeSH Terms