scholarly journals Transcriptomic analysis links diverse hypothalamic cell types to fibroblast growth factor 1-induced sustained diabetes remission

2020 ◽  
Vol 11 (1) ◽  
Author(s):  
Marie A. Bentsen ◽  
Dylan M. Rausch ◽  
Zaman Mirzadeh ◽  
Kenjiro Muta ◽  
Jarrad M. Scarlett ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Cell Types ◽  
Diabetes Remission ◽  
Ependymal Cells ◽  
Sustained Remission ◽  
Fibroblast Growth ◽  
Transcriptional Responses ◽  
Wide Range ◽  
Melanocortin Signaling

Abstract In rodent models of type 2 diabetes (T2D), sustained remission of hyperglycemia can be induced by a single intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1), and the mediobasal hypothalamus (MBH) was recently implicated as the brain area responsible for this effect. To better understand the cellular response to FGF1 in the MBH, we sequenced >79,000 single-cell transcriptomes from the hypothalamus of diabetic Lepob/ob mice obtained on Days 1 and 5 after icv injection of either FGF1 or vehicle. A wide range of transcriptional responses to FGF1 was observed across diverse hypothalamic cell types, with glial cell types responding much more robustly than neurons at both time points. Tanycytes and ependymal cells were the most FGF1-responsive cell type at Day 1, but astrocytes and oligodendrocyte lineage cells subsequently became more responsive. Based on histochemical and ultrastructural evidence of enhanced cell-cell interactions between astrocytes and Agrp neurons (key components of the melanocortin system), we performed a series of studies showing that intact melanocortin signaling is required for the sustained antidiabetic action of FGF1. These data collectively suggest that hypothalamic glial cells are leading targets for the effects of FGF1 and that sustained diabetes remission is dependent on intact melanocortin signaling.

scholarly journals Role of hypothalamic MAPK/ERK signaling in diabetes remission induced by the central action of fibroblast growth factor 1

2020 ◽  
Author(s):  
Jenny M. Brown ◽  
Marie A. Bentsen ◽  
Dylan M. Rausch ◽  
Bao Anh Phan ◽  
Danielle Wieck ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Diabetes Remission ◽  
Mitogen Activated Protein Kinase ◽  
Erk Signaling ◽  
Sustained Remission ◽  
Fibroblast Growth ◽  
Extracellular Signal ◽  
Mitogen Activated Protein

SummaryThe capacity of the brain to elicit sustained remission of hyperglycemia in rodent models of type 2 diabetes following intracerebroventricular (icv) injection of fibroblast growth factor 1 (FGF1) is well established. Here, we show that following icv FGF1 injection, hypothalamic signaling by extracellular signal-regulated kinases 1 and 2 (ERK1/2), members of the mitogen-activated protein kinase (MAPK) family is induced for at least 24h. Further, we show that in diabetic Lepob/ob mice, this prolonged response is required for the sustained antidiabetic action of FGF1, since it is abolished by sustained (but not acute) pharmacologic blockade of hypothalamic MAPK/ERK signaling. We also demonstrate that FGF1 R50E, a FGF1 mutant that activates FGF receptors but induces only transient hypothalamic MAPK/ERK signaling, fails to mimic the sustained glucose lowering induced by FGF1. These data identify sustained activation of hypothalamic MAPK/ERK signaling as playing an essential role in the mechanism underlying diabetes remission induced by icv FGF1 administration.

A Single-Cell Transcriptomics Roadmap to Investigate Diabetes Remission Induced by the Central Action of Fibroblast Growth Factor-1 (FGF-1)

Diabetes ◽  
2018 ◽  
Vol 67 (Supplement 1) ◽  
pp. 375-OR
Author(s):  
MARIE A. BENTSEN ◽  
DYLAN RAUSCH ◽  
JARRAD SCARLETT ◽  
KIMBERLY M. ALONGE ◽  
PASCAL N. TIMSHEL ◽  
...  
Keyword(s):  
Growth Factor ◽  
Single Cell ◽  
Fibroblast Growth Factor ◽  
Diabetes Remission ◽  
Central Action ◽  
Fibroblast Growth

1800-P: Transcriptomic Evidence of a Role for Neuron-Glia Interactions in Diabetes Remission Induced by the Central Action of Fibroblast Growth Factor 1 (FGF-1)

Diabetes ◽  
2019 ◽  
Vol 68 (Supplement 1) ◽  
pp. 1800-P
Author(s):  
MARIE A. BENTSEN ◽  
DYLAN RAUSCH ◽  
ZAMAN MIRZADEH ◽  
JARRAD SCARLETT ◽  
JENNY M. BROWN ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Diabetes Remission ◽  
Central Action ◽  
Fibroblast Growth

scholarly journals Half-life modeling of basic fibroblast growth factor released from growth factor-eluting polyelectrolyte multilayers

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Ivan Ding ◽  
Amy M. Peterson
Keyword(s):  
Cell Culture ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Basic Fibroblast Growth Factor ◽  
Half Life ◽  
Cell Types ◽  
Polyelectrolyte Multilayers ◽  
Enzyme Linked Immunosorbent Assay ◽  
Fibroblast Growth ◽  
Cell Culture Study

AbstractGrowth factor-eluting polymer systems have been widely reported to improve cell and tissue outcomes; however, measurements of actual growth factor concentration in cell culture conditions are limited. The problem is compounded by a lack of knowledge of growth factor half-lives, which impedes efforts to determine real-time growth factor concentrations. In this work, the half-life of basic fibroblast growth factor (FGF2) was determined using enzyme linked immunosorbent assay (ELISA). FGF2 release from polyelectrolyte multilayers (PEMs) was measured and the data was fit to a simple degradation model, allowing for the determination of FGF2 concentrations between 2 and 4 days of culture time. After the first hour, the FGF2 concentration for PEMs assembled at pH = 4 ranged from 2.67 ng/mL to 5.76 ng/mL, while for PEMs assembled at pH = 5, the concentration ranged from 0.62 ng/mL to 2.12 ng/mL. CRL-2352 fibroblasts were cultured on PEMs assembled at pH = 4 and pH = 5. After 2 days, the FGF2-eluting PEM conditions showed improved cell count and spreading. After 4 days, only the pH = 4 assembly condition had higher cells counts, while the PEM assembled at pH = 5 and PEM with no FGF2 showed increased spreading. Overall, the half-life model and cell culture study provide optimal concentration ranges for fibroblast proliferation and a framework for understanding how temporal FGF2 concentration may affect other cell types.

scholarly journals MicroRNA-Regulated Rickettsial Invasion into Host Endothelium via Fibroblast Growth Factor 2 and Its Receptor FGFR1

Cells ◽  
2018 ◽  
Vol 7 (12) ◽  
pp. 240 ◽  
Author(s):  
Abha Sahni ◽  
Hema Narra ◽  
Jignesh Patel ◽  
Sanjeev Sahni
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Host Cells ◽  
Microvascular Endothelial Cells ◽  
Target Cells ◽  
Fibroblast Growth ◽  
Wide Range ◽  
Microvascular Endothelial

Microvascular endothelial cells (ECs) represent the primary target cells during human rickettsioses and respond to infection via the activation of immediate–early signaling cascades and the resultant induction of gene expression. As small noncoding RNAs dispersed throughout the genome, microRNAs (miRNAs) regulate gene expression post-transcriptionally to govern a wide range of biological processes. Based on our recent findings demonstrating the involvement of fibroblast growth factor receptor 1 (FGFR1) in facilitating rickettsial invasion into host cells and published reports suggesting miR-424 and miR-503 as regulators of FGF2/FGFR1, we measured the expression of miR-424 and miR-503 during R. conorii infection of human dermal microvascular endothelial cells (HMECs). Our results revealed a significant decrease in miR-424 and miR-503 expression in apparent correlation with increased expression of FGF2 and FGFR1. Considering the established phenomenon of endothelial heterogeneity and pulmonary and cerebral edema as the prominent pathogenic features of rickettsial infections, and significant pathogen burden in the lungs and brain in established mouse models of disease, we next quantified miR-424 and miR-503 expression in pulmonary and cerebral microvascular ECs. Again, R. conorii infection dramatically downregulated both miRNAs in these tissue-specific ECs as early as 30 min post-infection in correlation with higher FGF2/FGFR1 expression. Changes in the expression of both miRNAs and FGF2/FGFR1 were next confirmed in a mouse model of R. conorii infection. Furthermore, miR-424 overexpression via transfection of a mimic into host ECs reduced the expression of FGF2/FGFR1 and gave a corresponding decrease in R. conorii invasion, while an inhibitor of miR-424 had the expected opposite effect. Together, these findings implicate the rickettsial manipulation of host gene expression via regulatory miRNAs to ensure efficient cellular entry as the critical requirement to establish intracellular infection.

scholarly journals Latent transforming growth factor-β complex in Chinese hamster ovary cells contains the multifunctional cysteine-rich fibroblast growth factor receptor, also termed E-selectin-ligand or MG-160

1997 ◽  
Vol 324 (2) ◽  
pp. 427-434 ◽  
Author(s):  
Anders OLOFSSON ◽  
Ulf HELLMAN ◽  
Peter TEN DIJKE ◽  
Susanne GRIMSBY ◽  
Hidenori ICHIJO ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Major Part ◽  
Transforming Growth Factor ◽  
Chinese Hamster ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Fibroblast Growth ◽  
Selectin Ligand ◽  
Tgf Β1

Transforming growth factor-β (TGF-β) is secreted as latent high molecular mass complexes from producer cells. The N-terminal precursor remnant, also called latency-associated peptide (LAP), forms a non-covalently linked complex with TGF-β and confers the latency to TGF-β. In human platelets and certain other cell types, latent TGF-β binding protein-1 (LTBP-1) is disulphide-linked to LAP, and forms complexes of more than 230 kDa. In addition, LTBP-2 and -3, which are structurally similar to LTBP-1, can be part of latent TGF-β complexes. In Chinese hamster ovary (CHO) cells transfected with the TGF-β1 cDNA, a major part of the latent TGF-β secreted into the medium is a 100-kDa small latent complex containing TGF-β and LAP. In addition, we found two other forms of latent TGF-β complexes, i.e. a 220-kDa complex containing LTBP-1, and a 220-kDa complex containing a 140-kDa protein. Purification of the 140-kDa component, termed latent TGF-β complexed protein-1 (LTCP-1), followed by amino acid sequencing and cDNA cloning from a CHO cell cDNA library, revealed that it is a hamster counterpart of a previously identified, multifunctional protein known as chicken cysteine-rich fibroblast growth factor (FGF) receptor, mouse E-selectin-ligand and rat MG-160 (a 160-kDa membrane sialoglycoprotein of the Golgi apparatus). Immunoprecipitation of LTCP-1 and TGF-β1 from CHO cells stably transfected with TGF-β1 precursor cDNA revealed that the expressed protein forms a complex with LAP, and that a major part of the complex is secreted. Northern blot analysis showed that mRNA for LTCP-1 was expressed in large amounts in testis, ovary and placenta, but less abundantly in other tissues. These results suggest that TGF-β, produced in certain cell types, may form a complex with LTCP-1, which may have different properties compared with other latent TGF-β complexes. It remains to be investigated whether the complex formation between LTCP-1 and TGF-β1 also occurs in other cells, whether the association between them occurs in the Golgi complex, and whether it affects the interaction of LTCP-1 with FGF or E-selectin.

scholarly journals Role of Hypothalamic MAPK/ERK Signaling in Diabetes Remission Induced by the Central Action of Fibroblast Growth Factor 1

2021 ◽  
Author(s):  
Jenny M. Brown ◽  
Marie A. Bentsen ◽  
Dylan M. Rausch ◽  
Bao Anh Phan ◽  
Danielle Wieck ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Diabetes Remission ◽  
Erk Signaling ◽  
Central Action ◽  
Fibroblast Growth

scholarly journals Subcellular localization of fibroblast growth factor receptor type 2 and correlation with CTNNB1 genotype in adrenocortical carcinoma

2020 ◽  
Author(s):  
Matthias Haase ◽  
Anne Thiel ◽  
Ute I. Scholl ◽  
Hany Ashmawy ◽  
Matthias Schott ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Adrenocortical Carcinoma ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Beta Catenin ◽  
Fibroblast Growth ◽  
Mutational Status ◽  
Cancer Types

Abstract Objective: Fibroblast growth factor receptor (FGFR) 2 regulates the development of the adrenal gland in mice. In addition, FGFR2-mediated signalling has been shown to prevent apoptosis and to enhance proliferation in adrenocortical precursor cells. The activation of the Wingless/Int-1 (WNT) / beta catenin pathway as a key mechanism of adrenocortical tumourigenesis has been linked to FGFR2 signalling in other cell types. Therefore we hypothesised that FGFR2 expression may also play a role in adrenocortical carcinoma (ACC). We conducted a pilot study and analysed protein expression of FGFR2 in 26 ACCs using immunohistochemistry technique. Data on the CTNNB1 mutation status and clinical data were correlated to the expression of FGFR2. Results: We observed a high variability in FGFR2 expression between the different tumour samples. There was a subset of ACC with comparatively high nuclear expression of FGFR2. We did not find a clear association between the CTNNB1 mutational status or clinical features and the FGFR2 expression. We conclude that FGFR signalling plays a role in adrenocortical carcinoma. Our data encourages further investigations of FGFR signalling in ACC, especially since new inhibitors of FGFR signalling are already entering clinical trials for the treatment of other cancer types.

scholarly journals Subcellular localization of fibroblast growth factor receptor type 2 and correlation with CTNNB1 genotype in adrenocortical carcinoma

2020 ◽  
Author(s):  
Matthias Haase ◽  
Anne Thiel ◽  
Ute I. Scholl ◽  
Hany Ashmawy ◽  
Matthias Schott ◽  
...  
Keyword(s):  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Adrenocortical Carcinoma ◽  
Fibroblast Growth Factor Receptor ◽  
Growth Factor Receptor ◽  
Cell Types ◽  
Beta Catenin ◽  
Fibroblast Growth ◽  
Mutational Status ◽  
Cancer Types

Abstract Objective: Fibroblast growth factor receptor (FGFR)2 regulates the development of the adrenal gland in mice. In addition, FGFR2-mediated signalling has been shown to prevent apoptosis and to enhance proliferation in adrenocortical precursor cells. The activation of the Wingless/Int-1 (WNT) / beta catenin pathway as a key mechanism of adrenocortical tumourigenesis has been linked to FGFR2 signalling in other cell types. Therefore we hypothesised that FGFR2 expression may also play a role in adrenocortical carcinoma (ACC). We conducted a pilot study and analysed protein expression of FGFR2 in 26 ACCs using immunohistochemistry technique. Data on the CTNNB1 mutation status and clinical data were correlated to the expression of FGFR2. Results: We observed a high variability in FGFR2 expression between the different tumour samples. There was a subset of ACC with comparatively high nuclear expression of FGFR2. We did not find a clear association between the CTNNB1 mutational status or clinical features and the FGFR2 expression. We conclude that FGFR signalling plays a role in adrenocortical carcinoma. Our data encourages further investigations of FGFR signalling in ACC, especially since new inhibitors of FGFR signalling are already entering clinical trials for the treatment of other cancer types.

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