Transforming growth factor<i>β</i><sub>1</sub> induces differentiation‐specific gene expression in fetal rat brown adipocytes

Teruel, Teresa; Valverde, Ángela M.; Benito, Manuel; Lorenzo, Margarita

doi:10.1016/0014-5793(95)00385-m

Cited by 17 publications

(4 citation statements)

References 37 publications

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“…Furthermore, we showed that TGF- β 1 treatment enhanced the in vitro adipocytic differentiation of hMSCs. This is consistent with several previously reported studies which demonstrate that TGF β 1 has a positive effect on adipogenic differentiation under specific culture conditions [ 18 , 19 ]; an early study considering rat brown adipocytes showed an upregulation of lipogenic enzymes following TGF β 1 treatment [ 19 ].…”

Section: Discussionsupporting

confidence: 93%

TGFβ1-Induced Differentiation of Human Bone Marrow-Derived MSCs Is Mediated by Changes to the Actin Cytoskeleton

Elsafadi

Manikandan

Almalki

et al. 2018

Stem Cells International

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TGFβ is a potent regulator of several biological functions in many cell types, but its role in the differentiation of human bone marrow-derived skeletal stem cells (hMSCs) is currently poorly understood. In the present study, we demonstrate that a single dose of TGFβ1 prior to induction of osteogenic or adipogenic differentiation results in increased mineralized matrix or increased numbers of lipid-filled mature adipocytes, respectively. To identify the mechanisms underlying this TGFβ-mediated enhancement of lineage commitment, we compared the gene expression profiles of TGFβ1-treated hMSC cultures using DNA microarrays. In total, 1932 genes were upregulated, and 1298 genes were downregulated. Bioinformatics analysis revealed that TGFβl treatment was associated with an enrichment of genes in the skeletal and extracellular matrix categories and the regulation of the actin cytoskeleton. To investigate further, we examined the actin cytoskeleton following treatment with TGFβ1 and/or cytochalasin D. Interestingly, cytochalasin D treatment of hMSCs enhanced adipogenic differentiation but inhibited osteogenic differentiation. Global gene expression profiling revealed a significant enrichment of pathways related to osteogenesis and adipogenesis and of genes regulated by both TGFβ1 and cytochalasin D. Our study demonstrates that TGFβ1 enhances hMSC commitment to either the osteogenic or adipogenic lineages by reorganizing the actin cytoskeleton.

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Section: Discussionsupporting

confidence: 93%

TGFβ1-Induced Differentiation of Human Bone Marrow-Derived MSCs Is Mediated by Changes to the Actin Cytoskeleton

Elsafadi

Manikandan

Almalki

et al. 2018

Stem Cells International

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“…Although many studies have reported inhibitory effect of TGF-β1 on adipogenesis, some reports have demonstrated a pro-adipogenic effect of TGF-β1 24 , 25 , which is more consistent with the observed TGF-β1 enhancement of bone marrow adipocyte formation observed in the current study. For example, the treatment of mouse NIH/3T3-L1 fibroblasts with TGF-β1 significantly suppressed mature adipocyte formation, irrespective of whether the treatment constituted a single dose at the initiation of differentiation or a continuous exposure 26 .…”

Section: Discussionsupporting

confidence: 91%

“…Furthermore, it was demonstrated that continuous exposure to TGF-β inhibited adipogenesis due to significant reduction in TGF-β receptor levels, which was mediated through SMAD2 and SMAD3 28 . In contrast, an early study of brown adipocytes in rat showed up-regulation of the expression of lipogenic enzymes upon treatment with 100 pM TGF-β1 25 . TGF-β1-induced inhibition models used either a low single dose (approximately 2 ng/ml) at the time of differentiation induction or a continuous dose (ranging from 0.2–10 ng/ml).…”

Section: Discussionmentioning

confidence: 73%

SERPINB2 is a novel TGFβ-responsive lineage fate determinant of human bone marrow stromal cells

Elsafadi

Manikandan

Atteya

et al. 2017

Sci Rep

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TGF-β1, a multifunctional regulator of cell growth and differentiation, is the most abundant bone matrix growth factor. During differentiation of human bone stromal cells (hBMSCs), which constitute bone marrow osteoblast (OS) and adipocyte (AD) progenitor cells, continuous TGF-β1 (10 ng/ml) treatment enhanced OS differentiation as evidenced by increased mineralised matrix production. Conversely, pulsed TGF-β1 administration during the commitment phase increased mature lipid-filled adipocyte numbers. Global gene expression analysis using DNA microarrays in hBMSCs treated with TGF-β1 identified 1587 up- and 1716 down-regulated genes in OS-induced, TGF-β1-treated compared to OS-induced hBMSCs (2.0 fold change (FC), p < 0.05). Gene ontology (GO) analysis revealed enrichment in ‘osteoblast differentiation’ and ‘skeletal system development-associated’ genes and up-regulation of several genes involved in ‘osteoblastic-differentiation related signalling pathways’. In AD-induced, TGF-β1-treated compared to AD-induced hBMSCs, we identified 323 up- and 369 down-regulated genes (2.0 FC, p < 0.05) associated with ‘fat cell differentiation’, ‘fatty acid derivative biosynthesis process’, ‘fatty acid derivative metabolic process’, and ‘inositol lipid-mediated’. Serpin peptidase inhibitor, clade B (ovalbumin), member 2 (SERPINB2) was down-regulated 3-fold in TGF-β1-treated hBMSCs. siRNA-mediated SERPINB2 inhibition enhanced OS and AD differentiation. Thus, TGF-β signalling is important for hBMSC OS and AD differentiation and SERPINB2 is a TGF-β-responsive gene that plays a negative regulatory role in hBMSC differentiation.

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“…A connection between TGF-β 1 and UCPs was shown in other systems. For instance, TGF-β 1 induces UCP expression in fetal rat brown adipocytes [34]. Recently, UCP2 was shown to be upregulated in an aortic regurgitation model of heart failure, and UCP3 upregulation and mitochondrial uncoupling were demonstrated in viable myocardium of chronically infarcted, failing rat hearts [35], [36].…”

Section: Discussionmentioning

confidence: 99%

Transforming Growth Factor β1 Oppositely Regulates the Hypertrophic and Contractile Response to β-Adrenergic Stimulation in the Heart

et al. 2011

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BackgroundNeuroendocrine activation and local mediators such as transforming growth factor-β1 (TGF-β1) contribute to the pathobiology of cardiac hypertrophy and failure, but the underlying mechanisms are incompletely understood. We aimed to characterize the functional network involving TGF-β1, the renin-angiotensin system, and the β-adrenergic system in the heart.MethodsTransgenic mice overexpressing TGF-β1 (TGF-β1-Tg) were treated with a β-blocker, an AT1-receptor antagonist, or a TGF-β-antagonist (sTGFβR-Fc), were morphologically characterized. Contractile function was assessed by dobutamine stress echocardiography in vivo and isolated myocytes in vitro. Functional alterations were related to regulators of cardiac energy metabolism.ResultsCompared to wild-type controls, TGF-β1-Tg mice displayed an increased heart-to-body-weight ratio involving both fibrosis and myocyte hypertrophy. TGF-β1 overexpression increased the hypertrophic responsiveness to β-adrenergic stimulation. In contrast, the inotropic response to β-adrenergic stimulation was diminished in TGF-β1-Tg mice, albeit unchanged basal contractility. Treatment with sTGF-βR-Fc completely prevented the cardiac phenotype in transgenic mice. Chronic β-blocker treatment also prevented hypertrophy and ANF induction by isoprenaline, and restored the inotropic response to β-adrenergic stimulation without affecting TGF-β1 levels, whereas AT1-receptor blockade had no effect. The impaired contractile reserve in TGF-β1-Tg mice was accompanied by an upregulation of mitochondrial uncoupling proteins (UCPs) which was reversed by β-adrenoceptor blockade. UCP-inhibition restored the contractile response to β-adrenoceptor stimulation in vitro and in vivo. Finally, cardiac TGF-β1 and UCP expression were elevated in heart failure in humans, and UCP – but not TGF-β1 – was downregulated by β-blocker treatment.ConclusionsOur data support the concept that TGF-β1 acts downstream of angiotensin II in cardiomyocytes, and furthermore, highlight the critical role of the β-adrenergic system in TGF-β1-induced cardiac phenotype. Our data indicate for the first time, that TGF-β1 directly influences mitochondrial energy metabolism by regulating UCP3 expression. β-blockers may act beneficially by normalizing regulatory mechanisms of cellular hypertrophy and energy metabolism.

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Transforming growth factorβ₁ induces differentiation‐specific gene expression in fetal rat brown adipocytes

Cited by 17 publications

References 37 publications

TGFβ1-Induced Differentiation of Human Bone Marrow-Derived MSCs Is Mediated by Changes to the Actin Cytoskeleton

TGFβ1-Induced Differentiation of Human Bone Marrow-Derived MSCs Is Mediated by Changes to the Actin Cytoskeleton

SERPINB2 is a novel TGFβ-responsive lineage fate determinant of human bone marrow stromal cells

Transforming Growth Factor β1 Oppositely Regulates the Hypertrophic and Contractile Response to β-Adrenergic Stimulation in the Heart

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Transforming growth factorβ1 induces differentiation‐specific gene expression in fetal rat brown adipocytes

Cited by 17 publications

References 37 publications

TGFβ1-Induced Differentiation of Human Bone Marrow-Derived MSCs Is Mediated by Changes to the Actin Cytoskeleton

TGFβ1-Induced Differentiation of Human Bone Marrow-Derived MSCs Is Mediated by Changes to the Actin Cytoskeleton

SERPINB2 is a novel TGFβ-responsive lineage fate determinant of human bone marrow stromal cells

Transforming Growth Factor β1 Oppositely Regulates the Hypertrophic and Contractile Response to β-Adrenergic Stimulation in the Heart

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Transforming growth factorβ₁ induces differentiation‐specific gene expression in fetal rat brown adipocytes