Doses Of Fibroblast Growth Factor Research Articles

FGF4 alleviates hyperglycemia in diabetes and obesity conditions

Increasing evidence suggests that the brain plays a key role in glucose homeostasis, making it a potential target for the treatment of type 2 diabetes (T2D). Sun et al. recently reported that intracerebroventricular (ICV) administration of a single dose of fibroblast growth factor 4 (FGF4) can induce sustained T2D remission in mouse models in the absence of any risk of hypoglycemia.

WNT Inhibition and Increased FGF Signaling Promotes Derivation of Less Heterogeneous Primed Human Embryonic Stem Cells, Compatible with Differentiation.

Human embryonic stem cells (hESCs) hold great value for future clinical applications. However, standard culture conditions maintain hESCs in a primed state, which bears heterogeneity in pluripotency and a tendency for spontaneous differentiation. To counter these drawbacks, primed hESCs have been converted to a naive state, but this has restricted the efficiency of existing directed differentiation protocols. In mouse, WNT inhibition by inhibitor of WNT production-2, together with a higher dose of fibroblast growth factor 2 (12 ng/mL) in DMEM/F12 basal medium (DhiFI), markedly improved derivation and maintenance of primed mouse epiblast stem cells. In this study, we show that DhiFI conditions similarly improved primed hESC traits, such as conferring a primed transcriptional signature with high levels of pluripotency markers and reduced levels of differentiation markers. When triggered to differentiate to neuronal and cardiac lineages, DhiFI hESCs and isogenic primed hESCs progressed similarly. Moreover, DhiFI conditions supported the derivation of hESC lines from a post-inner cell mass intermediate (PICMI). DhiFI-derived hESCs showed less spontaneous differentiation and expressed significantly lower levels of lineage-specific markers, compared to primed-derived lines from the same PICMI. Overall, DhiFI hESCs retained advantages of both primed and naive pluripotency and may ultimately represent a more favorable starting point for differentiation toward clinically desired cell types.

Mechanisms by which fibroblast growth factor 20 improves motor performance in a mouse model of Parkinson's disease.

Genome-wide studies have reported that Parkinson's disease is associated with abnormal expression of various growth factors. In this study, male C57BL/6 mice aged 10 weeks were used to establish Parkinson's disease models using an intraperitoneal injection of 60 mg/kg 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine. 28 days later, 10 or 100 ng fibroblast growth factor 20 was injected intracerebroventricularly. The electrophysiological changes in the mouse hippocampus were recorded using a full-cell patch clamp. Expression of Kv4.2 in the substantia nigra was analyzed using a western blot assay. Serum malondialdehyde levels were analyzed by enzyme-linked immunosorbent assay. The motor coordination of mice was evaluated using the rotarod test. The results showed that fibroblast growth factor 20 decreased A-type potassium current in neurons of the substantia nigra, increased long-term potentiation amplitude in the hippocampus, and downregulated Kv4.2 expression. A high dose of fibroblast growth factor 20 reduced serum malondialdehyde levels and enhanced the motor coordination of mice. These findings confirm that fibroblast growth factor 20 has a therapeutic effect on the toxicity induced by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine, and its mechanism of action is associated with the inhibition of A-type K+ currents and Kv4.2 expression. All animal procedures were approved by the Animal Care and Use Committee of Qilu Hospital of Shandong University, China in 2017 (approval No. KYLL-2017-0012).

Chronic Over-expression of Fibroblast Growth Factor 21 Increases Bile Acid Biosynthesis by Opposing FGF15/19 Action

Pharmacological doses of fibroblast growth factor (FGF) 21 effectively normalize glucose, lipid and energy homeostasis in multiple animal models with many benefits translating to obese humans with type 2 diabetes. However, a role for FGF21 in the regulation of bile acid metabolism has not been reported. Herein, we demonstrate AAV-mediated FGF21 overexpression in mice increases liver expression of the key bile acid producing enzyme, Cyp7a1, resulting in an increased bile acid pool. Furthermore, in cholecystectomized mice, FGF21-mediated bile acid pool increase led to increased transit of bile acids into colon. We elucidate that the mechanism of FGF21 induced bile acid changes is mainly through antagonizing FGF15/19 function on liver βKlotho/FGFR4 receptor complex; thus inhibiting FGF15/19-mediated suppression of Cyp7a1 expression. In conclusion, these data reveal a previously unidentified role for FGF21 on bile acid metabolism and may be relevant to understand the effects of FGF21 analogs in clinical studies.

Targeting the brain as a cure for type 2 diabetes.

A recent study has shown that a single dose of fibroblast growth factor (FGF) 1 into the central nervous system (CNS) of various mouse and rat models of type 2 diabetes results in profound and exceptionally long-lasting reductions in blood glucose. This work raises the possibility of truly revolutionary therapies for individuals with type 2 diabetes that target the brain FGF system.

A Randomized Clinical Trial Evaluating rh-FGF-2/β-TCP in Periodontal Defects

Biological mediators have been used to enhance periodontal regeneration. The aim of this prospective randomized controlled study was to evaluate the safety and effectiveness of 3 doses of fibroblast growth factor 2 (FGF-2) when combined with a β-tricalcium phosphate (β-TCP) scaffold carrier placed in vertical infrabony periodontal defects in adult patients. In this double-blinded, dose-verification, externally monitored clinical study, 88 patients who required surgical intervention to treat a qualifying infrabony periodontal defect were randomized to 1 of 4 treatment groups—β-TCP alone (control) and 0.1% recombinant human FGF-2 (rh-FGF-2), 0.3% rh-FGF-2, and 0.4% rh-FGF-2 with β-TCP—following scaling and root planing of the tooth prior to a surgical appointment. Flap surgery was performed with EDTA conditioning of the root prior to device implantation. There were no statistically significant differences in patient demographics and baseline characteristics among the 4 treatment groups. When a composite outcome of gain in clinical attachment of 1.5 mm was used with a linear bone growth of 2.5 mm, a dose response pattern detected a plateau in the 0.3% and 0.4% rh-FGF-2/β-TCP groups with significant improvements over control and 0.1% rh-FGF-2/β-TCP groups. The success rate at 6 mo was 71% in the 2 higher-concentration groups, as compared with 45% in the control and lowest treatment groups. Percentage bone fill in the 2 higher-concentration groups was 75% and 71%, compared with 63% and 61% in the control and lowest treatment group. No increases in specific antibody to rh-FGF-2 were detected, and no serious adverse events related to the products were reported. The results from this multicenter trial demonstrated that the treatment of infrabony vertical periodontal defects can be enhanced with the addition of rh-FGF-2/β-TCP (ClinicalTrials.gov NCT01728844).

Effects of low dose FGF-2 and BMP-2 on healing of calvarial defects in old mice

There is an age-associated reduction in the bone healing activity of bone morphogenetic protein-2 (BMP-2) that is currently addressed by administering higher doses of BMP-2 in elderly patients. The unwanted medical complications from high dose BMP-2 motivated this investigation to determine whether the addition of a low dose of fibroblast growth factor 2 (FGF-2) could enhance the ability of a lower dose of BMP-2 to heal calvarial bone defects in old mice (18–20months old). FGF-2 (5ng) and BMP-2 (2μg) were administered by a controlled release two-phase biomaterial scaffold placed into the bone defect. FGF-2 released more rapidly and completely in vitro than BMP-2 (40% vs 2%). In vivo, both BMP-2 and FGF-2+BMP-2 groups formed more new bone in calvarial defects than scaffold alone (p<0.001) or FGF-2 only groups (p<0.01). The overall total volume of new bone was not statistically increased by the addition of FGF-2 to BMP-2 as measured by microCT, but the pattern of bone deposition was different. In old mice, but not young, there was enhanced bony fill in the central bone defect area when the BMP-2 was supplemented with FGF-2. Histological analysis of the center of the defect revealed an increased bone volume (%BV/TV (p=0.004)) from the addition of FGF-2. These studies suggest that combining a low dose of FGF-2 with a low dose of BMP-2 has the potential to increase bone healing in old mice relative to BMP-2 alone.

High efficacy of fibroblast and hepatocyte growth factors on the in vitro blastocyst production of post- thaw mouse two-cell embryo: The cryotop method

There is great need to improve our understanding of what increases an embryo’s development potential, after vitrification-thawing processes. For this subject, 358 two-cell stage embryos were collected from oviduct of pregnant two-day old mice and vitrified. After thawing, embryos were cultured in Tyrode's (T6) medium supplemented with different doses of fibroblast growth factor (FGF; 0, 10, 20, 50 and 100 ng/ml) and hepatocyte growth factor (HGF; 0, 10, 20, 50 and 100 ng/ml) until the blastocyst stage. To determine quality of blastocysts, blastocysts were stained with hoechst and propidium iodide. After culture for 24 h, 92.65% of treated embryos with 20 ng/ml of FGF had higher (P 64 cells had a significantly higher inner cell mass (ICM) in comparison to the control group (P< 0.01). In conclusion, in this experiment, addition of growth factors in the culture had favorable effects on post-thawed cleavage of vitrified 2-cell embryos and blastocyst quality. Key words: Blastocyst quality, growth factors, preimplantation development, vitrification.

High efficacy of fibroblast and hepatocyte growth factors on the in vitro blastocyst production of post-thaw mouse two-cell embryo: The cryotop method

There is great need to improve our understanding of what increases an embryo’s development potential, after vitrification-thawing processes. For this subject, 358 two-cell stage embryos were collected from oviduct of pregnant two-day old mice and vitrified. After thawing, embryos were cultured in Tyrode's (T6) medium supplemented with different doses of fibroblast growth factor (FGF; 0, 10, 20, 50 and 100 ng/ml) and hepatocyte growth factor (HGF; 0, 10, 20, 50 and 100 ng/ml) until the blastocyst stage. To determine quality of blastocysts, blastocysts were stained with hoechst and propidium iodide. After culture for 24 h, 92.65% of treated embryos with 20 ng/ml of FGF had higher (P 64 cells had a significantly higher inner cell mass (ICM) in comparison to the control group (P< 0.01). In conclusion, in this experiment, addition of growth factors in the culture had favorable effects on post-thawed cleavage of vitrified 2-cell embryos and blastocyst quality. Key words: Blastocyst quality, growth factors, preimplantation development, vitrification.

Duration of ERK1/2 phosphorylation induced by FGF or ocular media determines lens cell fate

The ocular environment is important for the establishment and maintenance of lens growth patterns and polarity. In the anterior chamber of the eye, the aqueous humour regulates lens epithelial cell proliferation whereas in the posterior, the vitreous humour regulates the differentiation of the lens cells into fiber cells. Members of the fibroblast growth factor (FGF) growth factor family have been shown to induce lens epithelial cells to undergo cell division and differentiate into fibers, with a low dose of FGF able to induce cell proliferation (but not fiber differentiation), and higher doses required to induce fiber differentiation. Both these cellular events have been shown to be regulated by the MAPK/ERK1/2 signalling pathway. In the present study, to better understand the contribution of ERK1/2 signalling in regulating lens cell proliferation and differentiation, we characterized the ERK1/2 signalling profiles induced by different doses of FGF, and compared these to those induced by the different ocular media. Here, we show that FGF induced a dose-dependent sustained activation of ERK1/2, with both a high (fiber differentiating) dose of FGF and vitreous, stimulating and maintaining a prolonged (up to 18 hr) ERK1/2 phosphorylation profile. In contrast, a lower (proliferating) dose of FGF, and aqueous, stimulated ERK1/2 phosphorylation for only up to 6 hr. If we selectively reduce the 18 hr ERK1/2 phosphorylation profile induced by vitreous to 6 hr, by specifically blocking FGF receptor signalling, the vitreous now fails to induce lens fiber differentiation but retains the ability to induce lens cell proliferation. These findings not only provide insights into the important role that FGF plays in the different ocular media that bathe the lens, but enlighten us on some of the putative molecular mechanisms by which one specific growth factor, in this case FGF, can elicit a different cellular response in the same cell type.

Long-term effects of surgical angiogenic therapy with fibroblast growth factor 2 protein

Objective: The long-term effects of surgical fibroblast growth factor 2 therapy are examined. Methods: In a randomized, double-blind study, fibroblast growth factor 2 (10 μg or 100 μg) or placebo (n = 8 each) was delivered in the ungraftable myocardial territory of patients concomitantly undergoing coronary artery bypass grafting. Patients were followed up to 32.2 ± 6.8 months postoperatively with clinical assessment and nuclear perfusion imaging. Results: Baseline patient characteristics were similar between the 3 groups. There were 2 late deaths, one of pancreatic cancer and one of undetermined cause (both in the 100-μg fibroblast growth factor 2 group). Two patients (both in the control group) underwent a total of 6 repeat cardiac catheterizations for recurrent coronary events. Mean Canadian Cardiovawcular Society angina class improved at late follow-up from baseline in all groups (P ≤.02); however, patients treated with either dose of fibroblast growth factor 2 had significantly more freedom from angina recurrence than those treated with placebo (P =.03). Late nuclear perfusion scans revealed a persistent reversible or a new, fixed perfusion defect in the ungraftable territory of 4 of 5 patients who received placebo versus only 1 of 9 patients treated with fibroblast growth factor 2 (P =.02). The overall sum of left ventricular stress perfusion defect scores was also lower in fibroblast growth factor 2-treated patients than in control subjects (1.3 ± 1.4 vs 3.9 ± 2.1, respectively; P =.04). A trend toward a higher late left ventricular ejection fraction was noted in fibroblast growth factor 2-treated patients (55.1% ± 14.6% vs 44.3% ± 6.5%, fibroblast growth factor 2-treated patients versus control subjects; P =.12). Conclusions: These data suggest that surgical angiogenic therapy with sustained-release fibroblast growth factor 2 may result in a prolonged myocardial revascularization effect that could translate into clinical benefit.J Thorac Cardiovasc Surg 2002;124:28-34

Effect of various growth factors in a defined culture medium on in vitro development of bovine embryos matured and fertilized in vitro

Bovine embryos matured and fertilized in vitro were cultured in a simple, protein-free, chemically defined medium consisting of synthetic oviduct fluid medium (SOFM) modified by substituting polyvinyl alcohol (PVA) for BSA and supplementing with Basal Medium Eagle (BME) amino acids, and glutamine, to investigate the effects of standard fibroblast growth factor (FGF), epidermal growth factor (EGF), insulin-like growth factor-I (IGF-I) and transforming growth factor β1 (TGFβ1) on bovine embryonic development. In Experiment Ia, when the 2-cell, 8-cell, morula and early blastocyst stage embryos obtained from the culture in human serum (HS)-supplemented SOFM were cultured singly in growth factor-supplemented medium (SOFM + PVA) for 48 h and further cultured in SOFM+PVA without growth factor, FGF and EGF significantly (p < 0.05) increased development to blastocysts of morula (73.3%) and early blastocyst embryos (84.4%) compared to control (51.1% and 60.0% for morula and early blastocyst, respectively), and SOF + HS (positive control) showed significantly higher developmental rates than control in all stages of embryos (p < 0.05). However, supplementation with IGF-I or TGFβ1 did not improve embryo development in all stages of embryos compared to controls. In Experiments Ib, II and III, 2-cell embryos were selected after 30 h of IVF and then cultured in a defined medium to investigate the effects of single or group culture, different doses of FGF and the synergistic effect of EGF and FGF on embryo development. There was no significant difference in developmental rate to blastocysts with the number (single or group) of embryos cultured per well and the doses (0, 0.05, 1 and 10 ng/ml) of FGF. The medium supplemented with both FGF and EGF showed significantly (p < 0.05) higher developmental rate to blastocysts (31.4%) of 2-cell embryos cultured in a group than control medium (22.0%), and FGF and/or EGF increased the cell number of blastocysts(93.6 ± 7.0, 90.5 ± 4.7 and 87.3 ± 3.8 for EGF, FGF, and EGF and FGF, respectively) compared to controis (73.5 ± 3.1). The results indicate that the supplementation of FGF, EGF or both in a defined culture medium can improve the in vitro development of bovine embryos to morula and blastocyst stages; FGF and EGF may act synergistically on bovine embryo development in vitro.

Adrenocorticotropin is a specific mitogen for mammalian myogenic cells

Peptides derived from proopiomelanocortin (POMC) have been found to stimulate the proliferation of murine myogenic cells. Among these peptides, adrenocorticotropin (ACTH) and alpha-, beta-, and gamma-melanocyte-stimulating hormones (MSH) were found to be active, whereas the opioid peptides were not. At clonal density, both ACTH and MSH caused a three- to fourfold increase in the average number of cells per clone in myogenic but not in fibroblast colonies. At high cell density, ACTH and MSH caused a three- to fourfold increase in proliferation of myogenic cells, reflected by an increased accumulation of skeletal myosin. On the other hand mouse embryo skin or muscle fibroblasts or vertebral chondroblasts did not increase proliferation in response to POMC-derived peptides. The half-maximal dose at which ACTH stimulated myoblast proliferation was around 5 nM, and the mitogenic effect was doubled by suboptimal doses of fibroblast growth factor. The possible physiological significance of the mitogenic effect of ACTH on myogenic cells is discussed.