scholarly journals A growth factor–expressing macrophage subpopulation orchestrates regenerative inflammation via GDF-15

2021 ◽  
Vol 219 (1) ◽  
Author(s):  
Andreas Patsalos ◽  
Laszlo Halasz ◽  
Miguel A. Medina-Serpas ◽  
Wilhelm K. Berger ◽  
Bence Daniel ◽  
...  
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Muscle Regeneration ◽  
Tissue Repair ◽  
Cell Types ◽  
Transcriptional Level ◽  
Loss Of Function ◽  
Repair Gene ◽  
Multiple Cell ◽  
Inflammatory Macrophages

Muscle regeneration is the result of the concerted action of multiple cell types driven by the temporarily controlled phenotype switches of infiltrating monocyte–derived macrophages. Pro-inflammatory macrophages transition into a phenotype that drives tissue repair through the production of effectors such as growth factors. This orchestrated sequence of regenerative inflammatory events, which we termed regeneration-promoting program (RPP), is essential for proper repair. However, it is not well understood how specialized repair-macrophage identity develops in the RPP at the transcriptional level and how induced macrophage–derived factors coordinate tissue repair. Gene expression kinetics–based clustering of blood circulating Ly6Chigh, infiltrating inflammatory Ly6Chigh, and reparative Ly6Clow macrophages, isolated from injured muscle, identified the TGF-β superfamily member, GDF-15, as a component of the RPP. Myeloid GDF-15 is required for proper muscle regeneration following acute sterile injury, as revealed by gain- and loss-of-function studies. Mechanistically, GDF-15 acts both on proliferating myoblasts and on muscle-infiltrating myeloid cells. Epigenomic analyses of upstream regulators of Gdf15 expression identified that it is under the control of nuclear receptors RXR/PPARγ. Finally, immune single-cell RNA-seq profiling revealed that Gdf15 is coexpressed with other known muscle regeneration–associated growth factors, and their expression is limited to a unique subpopulation of repair-type macrophages (growth factor–expressing macrophages [GFEMs]).

scholarly journals Hormonal control of programmed cell death/apoptosis

1998 ◽  
pp. 482-491 ◽  
Author(s):  
W Kiess ◽  
B Gallaher
Keyword(s):  
Cell Death ◽  
Mammary Gland ◽  
Growth Factors ◽  
Growth Factor ◽  
Programmed Cell Death ◽  
Cell Types ◽  
Hormonal Control ◽  
Endocrine Glands ◽  
Survival Factors ◽  
Endocrine Tissues

Apoptosis or programmed cell death is a physiological form of cell death that occurs in embryonic development and during involution of organs. It is characterized by distinct biochemical and morphological changes such as DNA fragmentation, plasma membrane blebbing and cell volume shrinkage. Many hormones, cytokines and growth factors are known to act as general and/or tissue-specific survival factors preventing the onset of apoptosis. In addition, many hormones and growth factors are also capable of inducing or facilitating programmed cell death under physiological or pathological conditions, or both. Steroid hormones are potent regulators of apoptosis in steroid-dependent cell types and tissues such as the mammary gland, the prostate, the ovary and the testis. Growth factors such as epidermal growth factor, nerve growth factor, platelet-derived growth factor (PDGF) and insulin-like growth factor-I act as survival factors and inhibit apoptosis in a number of cell types such as haematopoietic cells, preovulatory follicles, the mammary gland, phaeochromocytoma cells and neurones. Conversely, apoptosis modulates the functioning and the functional integrity of many endocrine glands and of many cells that are capable of synthesizing and secreting hormones. In addition, exaggeration of the primarily natural process of apoptosis has a key role in the pathogenesis of diseases involving endocrine tissues. Most importantly, in autoimmune diseases such as autoimmune thyroid disease and type 1 diabetes mellitus, new data suggest that the immune system itself may not carry the final act of organ injury: rather, the target cells (i.e. thyrocytes and beta cells of the islets) commit suicide through apoptosis. The understanding of how hormones influence programmed cell death and, conversely, of how apoptosis affects endocrine glands, is central to further design strategies to prevent and treat diseases that affect endocrine tissues. This short review summarizes the available evidence showing where and how hormones control apoptosis and where and how programmed cell death exerts modulating effects upon hormonally active tissues.

TMOD-21. A NOVEL IN-VITRO METHOD TO MODEL MACROPHAGES IN GLIOBLASTOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi220-vi220
Author(s):  
Hasan Alrefai ◽  
Andee Beierle ◽  
Lauren Nassour ◽  
Nicholas Eustace ◽  
Zeel Patel ◽  
...  
Keyword(s):  
Cell Types ◽  
In Vitro Models ◽  
Tumor Initiating Cells ◽  
Serum Free ◽  
Brain Tumor Initiating Cells ◽  
Multiple Cell ◽  
Anti Inflammatory ◽  
Free Media ◽  
Inflammatory Macrophages

Abstract BACKGROUND The GBM tumor microenvironment (TME) is comprised of a plethora of cancerous and non-cancerous cells that contribute to GBM growth, invasion, and chemoresistance. In-vitro models of GBM typically fail to incorporate multiple cell types. Others have addressed this problem by employing 3D bioprinting to incorporate astrocytes and macrophages in an extracellular matrix; however, they used serum-containing media and classically polarized anti-inflammatory macrophages. Serum has been shown to cause GBM brain-tumor initiating cells to lose their stem-like properties, highlighting the importance of excluding it from these models. Additionally, tumor-associated macrophages (TAMs) do not adhere to the traditional M2 phenotype. METHODS THP-1 monocytes and normal human astrocytes (NHAs) were transitioned into serum-free HL-1 and neurobasal-based media, respectively. Monocytes were stimulated towards a macrophage-like state with PMA and polarized by co-culturing them with GBM patient-derived xenograft(PDX) lines, using a transwell insert. CD206 expression was used to validate polarization and a cytokine array was used to characterize the cells. RESULTS There was no difference in proliferation rates at 72 hours for THP-1 monocytes grown in serum-free HL-1 media compared to serum-containing RPMI 1640 (p > 0.95). Macrophages polarized via transwell inserts expressed the lymphocyte chemoattractant protein, CCL2, whereas resting(M0), pro-inflammatory(M1), and anti-inflammatory(M2) macrophages did not. Additionally, these macrophages expressed more CXCL1 and IL-1ß relative to M1 macrophages. We have also demonstrated a method to maintain a tri-culture model of GBM PDX cells, NHAs, and TAMs in a serum-free media that supports the growth/maintenance of all cell types. CONCLUSIONS We have demonstrated a novel method by which we can polarize macrophages towards a tumor-supportive phenotype that differs in cytokine expression from traditionally polarized macrophages. This higher-fidelity method of modeling TAMs in GBM can aid in the development of targeted therapeutics that may one day enter the clinic in hopes of improving outcomes in GBM.

scholarly journals Abcg2 labels multiple cell types in skeletal muscle and participates in muscle regeneration

2011 ◽  
Vol 195 (1) ◽  
pp. 147-163 ◽  
Author(s):  
Michelle J. Doyle ◽  
Sheng Zhou ◽  
Kathleen Kelly Tanaka ◽  
Addolorata Pisconti ◽  
Nicholas H. Farina ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Side Population ◽  
Cell Types ◽  
Lineage Tracing ◽  
Skeletal Muscle Regeneration ◽  
Genetic Lineage ◽  
Multiple Cell ◽  
A Minor

Skeletal muscle contains progenitor cells (satellite cells) that maintain and repair muscle. It also contains muscle side population (SP) cells, which express Abcg2 and may participate in muscle regeneration or may represent a source of satellite cell replenishment. In Abcg2-null mice, the SP fraction is lost in skeletal muscle, although the significance of this loss was previously unknown. We show that cells expressing Abcg2 increased upon injury and that muscle regeneration was impaired in Abcg2-null mice, resulting in fewer centrally nucleated myofibers, reduced myofiber size, and fewer satellite cells. Additionally, using genetic lineage tracing, we demonstrate that the progeny of Abcg2-expressing cells contributed to multiple cell types within the muscle interstitium, primarily endothelial cells. After injury, Abcg2 progeny made a minor contribution to regenerated myofibers. Furthermore, Abcg2-labeled cells increased significantly upon injury and appeared to traffic to muscle from peripheral blood. Together, these data suggest an important role for Abcg2 in positively regulating skeletal muscle regeneration.

Nerve growth factor regulates gene expression by several distinct mechanisms

1989 ◽  
Vol 9 (1) ◽  
pp. 135-143
Author(s):  
K O Cho ◽  
W C Skarnes ◽  
B Minsk ◽  
S Palmieri ◽  
L Jackson-Grusby ◽  
...  
Keyword(s):  
Gene Expression ◽  
Growth Factors ◽  
Nerve Growth Factor ◽  
Growth Factor ◽  
Cholera Toxin ◽  
Phorbol Myristate Acetate ◽  
Kinase Inhibitor ◽  
Transcriptional Level ◽  
Myristate Acetate ◽  
Nerve Growth

To help elucidate the mechanisms by which nerve growth factor (NGF) regulates gene expression, we have identified and studied four genes (a-2, d-2, d-4, and d-5) that are positively regulated by NGF in PC12 cells, including one (d-2) which has previously been identified as a putative transcription factor (NGF I-A). Three of these genes, including d-2, were induced very rapidly at the transcriptional level, but the relative time courses of transcription and mRNA accumulation of each of these three genes were distinct. The fourth gene (d-4) displayed no apparent increase in transcription that corresponded to the increase in its mRNA, suggesting that NGF may regulate its expression at a posttranscriptional level. Thus, NGF positively regulates gene expression by more than one mechanism. These genes could also be distinguished on the basis of their response to cyclic AMP. The expression of d-2 and a-2 was increased by cholera toxin and further augmented by NGF; however, cholera toxin not only failed to increase the levels of d-5 and d-4 mRNA but also actually inhibited the NGF-dependent increase. The expression of each of these genes, including d-2 (NGF I-A), was also increased by fibroblast growth factor, epidermal growth factor (EGF), phorbol myristate acetate, and in some cases insulin, showing that the regulation of these genes is not unique to NGF. Because each of these genes was expressed in response to phorbol myristate acetate and EGF, their expression may be necessary but is certainly not sufficient for neurite formation. The protein kinase inhibitor K-252a prevented the NGF-associated, but not the acidic FGF-associated, induction of d-2 and d-5 gene expression, suggesting that these two growth factors may regulate gene expression via different cellular pathways. The study of the regulation of the expression of these and other NGF-inducible genes should valuable new information concerning how NGF and other growth factors cause neural differentiation.

scholarly journals Keratinocyte Function in Normal and Diabetic Wounds and Modulation by FOXO1

2020 ◽  
Vol 2020 ◽  
pp. 1-9
Author(s):  
Yulan Wang ◽  
Dana T. Graves
Keyword(s):  
Growth Factor ◽  
Connective Tissue ◽  
Transforming Growth Factor ◽  
Negative Impact ◽  
Healing Process ◽  
Transforming Growth Factor Β ◽  
Cell Types ◽  
Tissue Growth ◽  
Complex Interactions ◽  
Multiple Cell

Diabetes has a significant and negative impact on wound healing, which involves complex interactions between multiple cell types. Keratinocytes play a crucial role in the healing process by rapidly covering dermal and mucosal wound surfaces to reestablish an epithelial barrier with the outside environment. Keratinocytes produce multiple factors to promote reepithelialization and produce factors that enhance connective tissue repair through the elaboration of mediators that stimulate angiogenesis and production of connective tissue matrix. Among the factors that keratinocytes produce to aid healing are transforming growth factor-β (TGF-β), vascular endothelial growth factor-A (VEGF-A), connective tissue growth factor (CTGF), and antioxidants. In a diabetic environment, this program is disrupted, and keratinocytes fail to produce growth factors and instead switch to a program that is detrimental to healing. Changes in keratinocyte behavior have been linked to high glucose and advanced glycation end products that alter the activities of the transcription factor, FOXO1. This review examines reepithelialization and factors produced by keratinocytes that upregulate connective tissue healing and angiogenesis and how they are altered by diabetes.

scholarly journals Vascular Endothelial Growth Factor Induces Abnormal Microvasculature in the Endoglin Heterozygous Mouse Brain

2004 ◽  
Vol 24 (2) ◽  
pp. 237-244 ◽  
Author(s):  
Bin Xu ◽  
Yong Qin Wu ◽  
Madeleine Huey ◽  
Helen M. Arthur ◽  
Douglas A. Marchuk ◽  
...  
Keyword(s):  
Vascular Endothelial Growth Factor ◽  
Growth Factor ◽  
Mouse Brain ◽  
Disease Model ◽  
Cell Types ◽  
Saline Group ◽  
Vegf Receptor ◽  
Vascular Endothelial ◽  
Loss Of Function ◽  
Endothelial Growth Factor

Hereditary hemorrhagic telangiectasia (HHT), associated with brain arteriovenous malformations, is caused by a loss of function mutation in either the endoglin (HHT1) or activin receptor-like kinase 1 gene (ALK-1, HHT2). Endoglin heterozygous ( Eng+/−)mice have been proposed as a disease model. To better understand the role of endoglin in vascular malformation development, we examined the effect of vascular endothelial growth factor (VEGF) hyperstimulation on microvessels in adult endoglin heterozygous ( Eng+/−) mice using an adenoviral vector to deliver recombinant human VEGF165 cDNA (Ad hVEGF) into basal ganglia. VEGF expression was increased in Ad hVEGF mice compared with the Ad lacZ and saline group ( P < 0.05) and localized to multiple cell types (neurons, astrocytes, endothelial cells, and smooth muscle cells) by double-labeled immunostaining. VEGF overexpression increased microvessel count for up to 4 weeks in both the Eng+/+ and Eng+/+ groups ( Eng+/+ 185 ± 14 vs. Eng+/− 201 ± 10 microvessels/mm2). Confocal microscopic examination revealed grossly abnormal microvessels in eight of nine Eng+/− mouse brains compared with zero of nine in Eng+/+ mice ( P < 0.05). Abnormal microvessels featured enlargement, clustering, twist, or spirals. VEGF receptor Flk-1 and TGF-β receptor 1 (TβR1) expression were reduced in the Eng+/− mouse brain compared with control. Excessive VEGF stimulation may play a pivotal role in the initiation and development of brain vessel malformations in states of relative endoglin insufficiency in adulthood. These observations are relevant to our general understanding of the maintenance of vascular integrity.

scholarly journals Phosphatase and Tensin Homologue: Novel Regulation by Developmental Signaling

2015 ◽  
Vol 2015 ◽  
pp. 1-13 ◽  
Author(s):  
Travis J. Jerde
Keyword(s):  
Growth Factor ◽  
Mammalian Cells ◽  
Hedgehog Signaling ◽  
Transforming Growth Factor ◽  
Signal Transduction Pathway ◽  
Cell Types ◽  
Loss Of Function ◽  
Pten Loss ◽  
Developmental Signaling ◽  
Phosphatase And Tensin Homologue

Phosphatase and tensin homologue (PTEN) is a critical cell endogenous inhibitor of phosphoinositide signaling in mammalian cells. PTEN dephosphorylates phosphoinositide trisphosphate (PIP3), and by so doing PTEN has the function of negative regulation of Akt, thereby inhibiting this key intracellular signal transduction pathway. In numerous cell types, PTEN loss-of-function mutations result in unopposed Akt signaling, producing numerous effects on cells. Numerous reports exist regarding mutations in PTEN leading to unregulated Akt and human disease, most notably cancer. However, less is commonly known about nonmutational regulation of PTEN. This review focuses on an emerging literature on the regulation of PTEN at the transcriptional, posttranscriptional, translational, and posttranslational levels. Specifically, a focus is placed on the role developmental signaling pathways play in PTEN regulation; this includes insulin-like growth factor, NOTCH, transforming growth factor, bone morphogenetic protein, wnt, and hedgehog signaling. The regulation of PTEN by developmental mediators affects critical biological processes including neuronal and organ development, stem cell maintenance, cell cycle regulation, inflammation, response to hypoxia, repair and recovery, and cell death and survival. Perturbations of PTEN regulation consequently lead to human diseases such as cancer, chronic inflammatory syndromes, developmental abnormalities, diabetes, and neurodegeneration.

Fibroblast Growth Factor 21 Exerts its Anti-inflammatory Effects on Multiple Cell Types of Adipose Tissue in Obesity

Obesity ◽  
2019 ◽  
Vol 27 (3) ◽  
pp. 399-408 ◽  
Author(s):  
Nan Wang ◽  
Ting-ting Zhao ◽  
Si-ming Li ◽  
Xu Sun ◽  
Zi-cheng Li ◽  
...  
Keyword(s):  
Adipose Tissue ◽  
Growth Factor ◽  
Fibroblast Growth Factor ◽  
Cell Types ◽  
Fibroblast Growth Factor 21 ◽  
Fibroblast Growth ◽  
Multiple Cell ◽  
Anti Inflammatory

scholarly journals Activation of an enhancer on the syndecan-1 gene is restricted to fibroblast growth factor family members in mesenchymal cells.

1997 ◽  
Vol 17 (6) ◽  
pp. 3210-3219 ◽  
Author(s):  
P Jaakkola ◽  
T Vihinen ◽  
A Määttä ◽  
M Jalkanen
Keyword(s):  
Growth Factors ◽  
Growth Factor ◽  
Tyrosine Kinase ◽  
Mutational Analysis ◽  
Biological Effects ◽  
Protein A ◽  
Cell Types ◽  
Regulatory Elements ◽  
Tyrosine Kinase Receptor ◽  
Fibroblast Growth

Fibroblast growth factors (FGFs) induce a variety of biological effects on different cell types. They activate a number of genes, including immediate-early genes, such as the transcription factors Fos and Jun, which are also common targets for other tyrosine kinase receptor-activating growth factors. Here we describe a secondary far-upstream enhancer on the syndecan-1 gene that is activated only by members of the FGF family in NIH 3T3 cells, not by other receptor tyrosine kinase-activating growth factors (e.g., epidermal growth factor, platelet-derived growth factor, insulin-like growth factor, or serum). This FGF-inducible response element (FiRE) consists of a 170-bp array of five DNA motifs which bind two FGF-inducible Fos-Jun heterodimers, one inducible AP-2-related protein, a constitutively expressed upstream stimulatory factor, and one constitutive 46-kDa transcription factor. Mutational analysis showed that both AP-1 binding motifs are required, but not sufficient, for FiRE activation. Moreover, agents such as 12-O-tetradecanoylphorbol-13-acetate, okadaic acid, or forskolin, which are known to activate AP-1 complexes and AP-1-driven promoters, fail to activate FiRE. However, FiRE can be activated by the tyrosine kinase phosphatase inhibitor orthovanadate. Taken together, this data implies a differential activation of growth factor-initiated signaling on AP-1-driven regulatory elements.

scholarly journals Growth Factors VEGF-A165 and FGF-2 as Multifunctional Biomolecules Governing Cell Adhesion and Proliferation

2021 ◽  
Vol 22 (4) ◽  
pp. 1843
Author(s):  
Antonín Sedlář ◽  
Martina Trávníčková ◽  
Roman Matějka ◽  
Šimon Pražák ◽  
Zuzana Mészáros ◽  
...  
Keyword(s):  
Tissue Engineering ◽  
Cell Adhesion ◽  
Growth Factors ◽  
Growth Factor ◽  
Umbilical Vein ◽  
Expression System ◽  
Cell Types ◽  
Simple Method ◽  
Yeast Expression System ◽  
Negative Effect

Vascular endothelial growth factor-A165 (VEGF-A165) and fibroblast growth factor-2 (FGF-2) are currently used for the functionalization of biomaterials designed for tissue engineering. We have developed a new simple method for heterologous expression and purification of VEGF-A165 and FGF-2 in the yeast expression system of Pichia pastoris. The biological activity of the growth factors was assessed in cultures of human and porcine adipose tissue-derived stem cells (ADSCs) and human umbilical vein endothelial cells (HUVECs). When added into the culture medium, VEGF-A165 stimulated proliferation only in HUVECs, while FGF-2 stimulated the proliferation of both cell types. A similar effect was achieved when the growth factors were pre-adsorbed to polystyrene wells. The effect of our recombinant growth factors was slightly lower than that of commercially available factors, which was attributed to the presence of some impurities. The stimulatory effect of the VEGF-A165 on cell adhesion was rather weak, especially in ADSCs. FGF-2 was a potent stimulator of the adhesion of ADSCs but had no to negative effect on the adhesion of HUVECs. In sum, FGF-2 and VEGF-A165 have diverse effects on the behavior of different cell types, which maybe utilized in tissue engineering.

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