Tumor Necrosis Factor Receptor Superfamily Member 19 (TNFRSF19) Regulates Differentiation Fate of Human Mesenchymal (Stromal) Stem Cells through Canonical Wnt Signaling and C/EBP

Qiu, Weimin; Hu, Yuhui; Andersen, T.; Jafari, Abbas; Li, Na; Chen, Wei; Kassem, Moustapha

doi:10.1074/jbc.m109.052001

Cited by 68 publications

(65 citation statements)

References 55 publications

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“…For early osteogenic differentiation, alkaline phosphatase activity was measured and normalized to cell viability as described [17]. Alizarin Red staining was used to assess in vitro formation of mineralized matrix at day 15 after osteogenic induction as described [16].…”

Section: Methodsmentioning

confidence: 99%

Evidence of two distinct functionally specialized fibroblast lineages in breast stroma

et al. 2016

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BackgroundThe terminal duct lobular unit (TDLU) is the most dynamic structure in the human breast and the putative site of origin of human breast cancer. Although stromal cells contribute to a specialized microenvironment in many organs, this component remains largely understudied in the human breast. We here demonstrate the impact on epithelium of two lineages of breast stromal fibroblasts, one of which accumulates in the TDLU while the other resides outside the TDLU in the interlobular stroma.MethodsThe two lineages are prospectively isolated by fluorescence activated cell sorting (FACS) based on different expression levels of CD105 and CD26. The characteristics of the two fibroblast lineages are assessed by immunocytochemical staining and gene expression analysis. The differentiation capacity of the two fibroblast populations is determined by exposure to specific differentiating conditions followed by analysis of adipogenic and osteogenic differentiation. To test whether the two fibroblast lineages are functionally imprinted by their site of origin, single cell sorted CD271low/MUC1high normal breast luminal epithelial cells are plated on fibroblast feeders for the observation of morphological development. Epithelial structure formation and polarization is shown by immunofluorescence and digitalized quantification of immunoperoxidase-stained cultures.ResultsLobular fibroblasts are CD105high/CD26low while interlobular fibroblasts are CD105low/CD26high. Once isolated the two lineages remain phenotypically stable and functionally distinct in culture. Lobular fibroblasts have properties in common with bone marrow derived mesenchymal stem cells and they specifically convey growth and branching morphogenesis of epithelial progenitors.ConclusionsTwo distinct functionally specialized fibroblast lineages exist in the normal human breast, of which the lobular fibroblasts have properties in common with mesenchymal stem cells and support epithelial growth and morphogenesis. We propose that lobular fibroblasts constitute a specialized microenvironment for human breast luminal epithelial progenitors, i.e. the putative precursors of breast cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0769-2) contains supplementary material, which is available to authorized users.

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Section: Methodsmentioning

confidence: 99%

Evidence of two distinct functionally specialized fibroblast lineages in breast stroma

et al. 2016

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“…Mouse preosteoblastic MC3T3-E1 calvarial cells were maintained and differentiated as described (14). The osteoblast phenotype was evaluated by determining ALP activity as previously described (34). Alizarin Red staining was performed to detect matrix mineralization with 40 mM alizarin red S (AR-S; Sigma-Aldrich), pH 4.2, for 10 min at room temperature.…”

Section: Methodsmentioning

confidence: 99%

MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo

Eskildsen

Taipaleenmäki

Stenvang

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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Elucidating the molecular mechanisms that regulate human stromal (mesenchymal) stem cell (hMSC) differentiation into osteogenic lineage is important for the development of anabolic therapies for treatment of osteoporosis. MicroRNAs (miRNAs) are short, noncoding RNAs that act as key regulators of diverse biological processes by mediating translational repression or mRNA degradation of their target genes. Here, we show that miRNA-138 (miR-138) modulates osteogenic differentiation of hMSCs. miRNA array profiling and further validation by quantitative RT-PCR (qRT-PCR) revealed that miR-138 was down-regulated during osteoblast differentiation of hMSCs. Overexpression of miR-138 inhibited osteoblast differentiation of hMSCs in vitro, whereas inhibition of miR-138 function by antimiR-138 promoted expression of osteoblast-specific genes, alkaline phosphatase (ALP) activity, and matrix mineralization. Furthermore, overexpression of miR-138 reduced ectopic bone formation in vivo by 85%, and conversely, in vivo bone formation was enhanced by 60% when miR-138 was antagonized. Target prediction analysis and experimental validation by luciferase 3′ UTR reporter assay confirmed focal adhesion kinase, a kinase playing a central role in promoting osteoblast differentiation, as a bona fide target of miR-138. We show that miR-138 attenuates bone formation in vivo, at least in part by inhibiting the focal adhesion kinase signaling pathway. Our findings suggest that pharmacological inhibition of miR-138 by antimiR-138 could represent a therapeutic strategy for enhancing bone formation in vivo.regulatory RNA | bone biology | osteoblastic differentiation

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“…Alkaline phosphatase activity was measured using p-nitrophenyl phosphate (Fluka Chemie) as substrate (28). Cells were stained with 40 mmol/L Alizarin Red S (Sigma-Aldrich), pH 4.2, for 10 min at room temperature as previously described (13 …”

Section: Alkaline Phosphatase and Alizarin Red Stainingmentioning

confidence: 99%

DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

et al. 2015

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The endocrine role of the skeleton in regulating energy metabolism is supported by a feed-forward loop between circulating osteoblast (OB)-derived undercarboxylated osteocalcin (Glu-OCN) and pancreatic b-cell insulin; in turn, insulin favors osteocalcin (OCN) bioactivity. These data suggest the existence of a negative regulation of this cross talk between OCN and insulin. Recently, we identified delta like-1 (DLK1) as an endocrine regulator of bone turnover. Because DLK1 is colocalized with insulin in pancreatic b-cells, we examined the role of DLK1 in insulin signaling in OBs and energy metabolism. We show that Glu-OCN specifically stimulates Dlk1 expression by the pancreas. Conversely, Dlk1-deficient (Dlk1 2/2 ) mice exhibited increased circulating Glu-OCN levels and increased insulin sensitivity, whereas mice overexpressing Dlk1 in OB displayed reduced insulin secretion and sensitivity due to impaired insulin signaling in OB and lowered Glu-OCN serum levels. Furthermore, Dlk1 2/2 mice treated with Glu-OC experienced significantly lower blood glucose levels than Glu-OCN-treated wild-type mice. The data suggest that Glu-OCN-controlled production of DLK1 by pancreatic b-cells acts as a negative feedback mechanism to counteract the stimulatory effects of insulin on OB production of Glu-OCN, a potential mechanism preventing OCN-induced hypoglycemia.A growing body of work indicates that bone is an endocrine organ that regulates glucose metabolism through, in part, the hormone osteocalcin (OCN). OCN signals in b-cells through its bona fide receptor Gprotein-coupled receptor (Gprc6a) to increase b-cell proliferation and insulin secretion and acts on peripheral tissues to increase energy expenditure (1-3). In turn, insulin signaling in osteoblasts (OBs) stimulates the activation of OCN by promoting its decarboxylation (Glu-OCN) through the bone resorption arm of bone remodeling (1,4). The physiological relevance of these findings have been supported through studies demonstrating skeleton as a site of insulin resistance in mice fed a high-fat diet (5). Moreover, patients with a dominant negative mutation in Gprc6a show evidence of glucose intolerance (3). In all likelihood, the Glu-OCN-insulin feed-forward loop must be under a negative regulation to protect from hypoglycemia. Soluble factors responsible for this regulation have not yet been identified despite the demonstrated ability of transcription factors activating transcription factor 4 (ATF4) and forkhead box protein O1 (FoxO1) to regulate glucose metabolism through a negative regulation of OCN bioavailability (6,7). Delta like-1 (DLK1), also known as preadipocyte factor-1 (Pref-1), is a transmembrane protein belonging to the Notch/serrate/delta family (8,9). The full ectodomain of DLK1 is proteolytically cleaved to generate a soluble active protein named fetal antigen-1 (FA1), which is secreted by endocrine cells of pancreas, ovary, Leydig cells of the testis, adrenal glands, and pituitary gland (10). DLK1 has

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Tumor Necrosis Factor Receptor Superfamily Member 19 (TNFRSF19) Regulates Differentiation Fate of Human Mesenchymal (Stromal) Stem Cells through Canonical Wnt Signaling and C/EBP

Cited by 68 publications

References 55 publications

Evidence of two distinct functionally specialized fibroblast lineages in breast stroma

Evidence of two distinct functionally specialized fibroblast lineages in breast stroma

MicroRNA-138 regulates osteogenic differentiation of human stromal (mesenchymal) stem cells in vivo

DLK1 Regulates Whole-Body Glucose Metabolism: A Negative Feedback Regulation of the Osteocalcin-Insulin Loop

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