Angiogenic Capacity of Human Adipose-Derived Stromal Cells During Adipogenic Differentiation: An<i>In Vitro</i>Study

Verseijden, Femke; Jahr, Holger; Sluijs, Sandra J. Posthumus-van; Hagen, Timo L.M. ten; Hovius, Steven E.R.; Seynhaeve, Ann L.B.; Neck, Johan W. van; Osch, Gerjo J.V.M. van; Hofer, Stefan O. P.

doi:10.1089/ten.tea.2007.0429

Cited by 46 publications

(36 citation statements)

References 34 publications

(34 reference statements)

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“…Furthermore, genes in cluster 7 and cluster 12 are of particular interest because preadipocyte markers such as Pref1 (Dlk1), Sox9 and Gata2 are enriched in these clusters (Jing et al, 2009;Tong et al, 2000;Wang and Sul, 2009), as well as genes involved in metabolic homeostasis and WAT mass regulation, such as Igf2, Insig2, Lmna and Angpt1 (Krapivner et al, 2008;Longo et al, 2002;Verseijden et al, 2009;Wojtanik et al, 2009). In addition to previously characterized preadipocyte markers, many of the genes in these clusters also play a role in cell cycle regulation, as shown by gene ontology (GO) term enrichment analysis (Fig.…”

Section: Nrf2/gabpa-binding Sites Are Enriched In the Promoters Of Prmentioning

confidence: 99%

Analysis of gene networks in white adipose tissue development reveals a role for ETS2 in adipogenesis

et al. 2011

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SUMMARYObesity is characterized by an expansion of white adipose tissue mass that results from an increase in the size and the number of adipocytes. However, the mechanisms responsible for the formation of adipocytes during development and the molecular mechanisms regulating their increase and maintenance in adulthood are poorly understood. Here, we report the use of leptinluciferase BAC transgenic mice to track white adipose tissue (WAT) development and guide the isolation and molecular characterization of adipocytes during development using DNA microarrays. These data reveal distinct transcriptional programs that are regulated during murine WAT development in vivo. By using a de novo cis-regulatory motif discovery tool (FIRE), we identify two early gene clusters whose promoters show significant enrichment for NRF2/ETS transcription factor binding sites. We further demonstrate that Ets transcription factors, but not Nrf2, are regulated during early adipogenesis and that Ets2 is essential for the normal progression of the adipocyte differentiation program in vitro. These data identify ETS2 as a functionally important transcription factor in adipogenesis and its possible role in regulating adipose tissue mass in adults can now be tested. Our approach also provides the basis for elucidating the function of other gene networks during WAT development in vivo. Finally these data confirm that although gene expression during adipogenesis in vitro recapitulates many of the patterns of gene expression in vivo, there are additional developmental transitions in pre and post-natal adipose tissue that are not evident in cell culture systems.

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Section: Nrf2/gabpa-binding Sites Are Enriched In the Promoters Of Prmentioning

confidence: 99%

Analysis of gene networks in white adipose tissue development reveals a role for ETS2 in adipogenesis

et al. 2011

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“…14 VEGF also stimulates stem cell self-renewal in normal hemopoietic, 15 endothelial, 14,16 neuronal 17 and adipose tissues. 15,18 Recent data indicate that VEGF drives CSC self-renewal in glioma 19 and skin cancer models, 20 but mechanisms thereof and the spectrum of tumor types affected are not fully characterized. Here, we investigated whether and how VEGF may stimulate CSCs independent of mitogenic or angiogenic effects in breast and lung cancers, two highly prevalent and lethal human malignancies.…”

Section: Introductionmentioning

confidence: 99%

VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2

et al. 2014

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Vascular endothelial growth factor-A (VEGF), a potent angiogenic factor, is also implicated in self-renewal in several normal tissue types. VEGF has been shown to drive malignant stem cells but mechanisms thereof and tumor types affected are not fully characterized. Here, we show VEGF promotes breast and lung cancer stem cell (CSC) self-renewal via VEGF receptor-2 (VEGFR-2)/STAT3-mediated upregulation of Myc and Sox2. VEGF increased tumor spheres and aldehyde dehydrogenase activity, both proxies for stem cell function in vitro, in triple-negative breast cancer (TNBC) lines and dissociated primary cancers, and in lung cancer lines. VEGF exposure before injection increased breast cancer-initiating cell abundance in vivo yielding increased orthotopic tumors, and increased metastasis from orthotopic primaries and following tail vein injection without further VEGF treatment. VEGF rapidly stimulated VEGFR-2/JAK2/STAT3 binding and activated STAT3 to bind MYC and SOX2 promoters and induce their expression. VEGFR-2 knockdown or inhibition abrogated VEGF-mediated STAT3 activation, MYC and SOX2 induction and sphere formation. Notably, knockdown of either STAT3, MYC or SOX2 impaired VEGF-upregulation of pSTAT3, MYC and SOX2 expression and sphere formation. Each transcription factor, once upregulated, appears to promote sustained activation of the others, creating a feed-forward loop to drive self-renewal. Thus, in addition to angiogenic effects, VEGF promotes tumor-initiating cell self-renewal through VEGFR-2/STAT3 signaling. Analysis of primary breast and lung cancers (>1300 each) showed high VEGF expression, was prognostic of poor outcome and strongly associated with STAT3 and MYC expression, supporting the link between VEGF and CSC self-renewal. High-VEGF tumors may be most likely to escape anti-angiogenics by upregulating VEGF, driving CSC self-renewal to re-populate post-treatment. Our work highlights the need to better define VEGF-driven cancer subsets and supports further investigation of combined therapeutic blockade of VEGF or VEGFR-2 and JAK2/STAT3.

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“…Many of the genes expressed by human ADSC were recently reviewed [review]55. In particular, the influence of ASC differentiation per se on gene expression was examined by Verseijden et al 56. Cultured human stromal cells express and secrete a number of angiogenic factors including VEGF, PGF, HGF, ANGPT1, and ANGPT2, FGF-2, PDGFB, and TGFb1 47.…”

Section: Introductionmentioning

confidence: 99%

Stromal Vascular Cells and Adipogenesis: Cells within Adipose Depots Regulate Adipogenesis

Hausman¹,

Dodson²

2013

J. Genomics

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A collection of investigations indicate the importance of adipose tissue stromal/stem cells to vasculogenesis and angiogenesis during adipogenesis. Early in development the stromal-vascular (S-V) elements control and dictate the extent of adipogenesis. For instance, the vasculature and connective tissue collagen matrix develops before overt adipocyte differentiation. Definitive studies of human adipose tissue stem cells (ADSC) provided an understanding of stem cell identity and function. In this regard, a novel vascular stem cell theory proposes that ADSC are a mixed population of vascular stem cells (VSC) with differential potential proportional to the angiogenic potential of the vasculature. The differential potential of VSC can range considerably in a continuous fashion and can include vascular smooth cells, endothelial cells (EC) and adipocytes. These observations are consistent with fetal adipose tissue studies that show location-dependent angiogenic potential ranging from more to less in regards to a predominant presence of EC and developing arterioles before overt adipogenesis.

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Angiogenic Capacity of Human Adipose-Derived Stromal Cells During Adipogenic Differentiation: AnIn VitroStudy

Abstract: In vitro adipogenic differentiation of hASCs improves their ability to support endothelial viable cell numbers and suggests that hASCs differentiated for a short period potentially improve angiogenic responses for in vivo implantation.

Cited by 46 publications

References 34 publications

Analysis of gene networks in white adipose tissue development reveals a role for ETS2 in adipogenesis

Analysis of gene networks in white adipose tissue development reveals a role for ETS2 in adipogenesis

VEGF drives cancer-initiating stem cells through VEGFR-2/Stat3 signaling to upregulate Myc and Sox2

Stromal Vascular Cells and Adipogenesis: Cells within Adipose Depots Regulate Adipogenesis

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