FGF10 and Lipofibroblasts in Lung Homeostasis and Disease: Insights Gained From the Adipocytes

Adipocytes not only function as energy depots but also secrete numerous adipokines that regulate multiple metabolic processes, including lipid homeostasis. Dysregulation of lipid homeostasis, which often leads to adipocyte hypertrophy and/or ectopic lipid deposition in non-adipocyte cells such as muscle and liver, is linked to the development of insulin resistance. Similarly, an altered secretion profile of adipokines or imbalance between calorie intake and energy expenditure is associated with obesity, among other related metabolic disorders. In lungs, lipid-laden adipocyte-like cells known as lipofibroblasts share numerous developmental and functional similarities with adipocytes, and similarly influence alveolar lipid homeostasis by facilitating pulmonary surfactant production. Unsurprisingly, disruption in alveolar lipid homeostasis may propagate several chronic inflammatory disorders of the lung. Given the numerous similarities between the two cell types, dissecting the molecular mechanisms underlying adipocyte development and function will offer valuable insights that may be applied to, at least, some aspects of lipofibroblast biology in normal and diseased lungs. FGF10, a major ligand for FGFR2b, is a multifunctional growth factor that is indispensable for several biological processes, including development of various organs and tissues such as the lung and WAT. Moreover, accumulating evidence strongly implicates FGF10 in several key aspects of adipogenesis as well as lipofibroblast formation and maintenance, and as a potential player in adipocyte metabolism. This review summarizes our current understanding of the role of FGF10 in adipocytes, while attempting to derive insights on the existing literature and extrapolate the knowledge to pulmonary lipofibroblasts.

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Epigenetic Regulation of the Hippocampus, with Special Reference to Radiation Exposure

International Journal of Molecular Sciences ◽

10.3390/ijms21249514 ◽

2020 ◽

Vol 21 (24) ◽

pp. 9514

Author(s):

Genevieve Saw ◽

Feng Ru Tang

Keyword(s):

Epigenetic Regulation ◽

Molecular Mechanisms ◽

Cell Types ◽

Epigenetic Changes ◽

Epigenetic Factors ◽

Hippocampal Function ◽

Neuropsychological Disorders ◽

Radiation Induced ◽

Non Coding Rnas ◽

And Function

The hippocampus is crucial in learning, memory and emotion processing, and is involved in the development of different neurological and neuropsychological disorders. Several epigenetic factors, including DNA methylation, histone modifications and non-coding RNAs, have been shown to regulate the development and function of the hippocampus, and the alteration of epigenetic regulation may play important roles in the development of neurocognitive and neurodegenerative diseases. This review summarizes the epigenetic modifications of various cell types and processes within the hippocampus and their resulting effects on cognition, memory and overall hippocampal function. In addition, the effects of exposure to radiation that may induce a myriad of epigenetic changes in the hippocampus are reviewed. By assessing and evaluating the current literature, we hope to prompt a more thorough understanding of the molecular mechanisms that underlie radiation-induced epigenetic changes, an area which can be further explored.

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Essential Roles of C/EBPβ in Survival of Ly6C– monocytes

Blood ◽

10.1182/blood.v124.21.224.224 ◽

2014 ◽

Vol 124 (21) ◽

pp. 224-224

Author(s):

Akihiro Tamura ◽

Hideyo Hirai ◽

Asumi Yokota ◽

Atsushi Sato ◽

Hisayuki Yao ◽

...

Keyword(s):

Peripheral Blood ◽

Leucine Zipper ◽

Molecular Mechanisms ◽

Conflicts Of Interest ◽

Cell Types ◽

Hematopoietic Stem ◽

Retroviral Transduction ◽

Inflammatory Monocytes ◽

And Function ◽

Myeloid Progenitors

Abstract Accumulating evidences have shown that mouse monocytes can be divided into two subsets, based on the expression of a surface marker Ly6C. Although distinct functions of Ly6C+ monocytes (also called classical or inflammatory monocytes) and Ly6C– monocytes (also known as patrolling monocytes) have been gradually uncovered, molecular mechanisms which govern development of these monocytes remain largely unknown. We have previously reported the requirement of CCAAT Enhancer Binding Protein β (C/EBPβ), a leucine zipper transcription factor, for ‘emergency’ granulopoiesis (Nat Immunol, 2006, J Immunol, 2012, Leukemia 2013). C/EBPβ is also known to play roles in the differentiation and function of macrophages. However, involvement of C/EBPβ in monocyte development has not been fully investigated. The aim of this study is to elucidate the roles of C/EBPβ in monopoiesis. First, we measured C/EBPβ mRNA expression in purified hematopoietic stem cells, myeloid progenitors and monocyte subsets, and found that monocytes, especially Ly6C– monocytes, expressed C/EBPβ mRNA at extremely higher level than any of other cell types examined. When we analyzed peripheral blood, the frequencies of total monocytes (CD11b+ CD115+ cells) in C/EBPβ–/– mice was significantly lower than those in wild type (WT) mice (4.24±2.71% in WT mice vs. 0.72±0.50% in C/EBPβ–/– mice, p<0.001). Of note, Ly6C– monocytes were almost absent in peripheral blood of C/EBPβ–/– mice (0.67±0.57% in WT mice vs. 0.017±0.021% in C/EBPβ–/– mice). In order to clarify whether the defects in C/EBPβ–/– monopoiesis were cell-intrinsic or cell-extrinsic, we generated mixed bone marrow (BM) chimeras by reconstituting lethally irradiated mice (CD45.1+) with BM cells from WT (CD45.1+) mice together with the equal number of BM cells from either WT or C/EBPβ–/– (CD45.2+) mice. Six weeks after reconstitution, we confirmed that C/EBPβ–/– BM-derived Ly6C– monocytes were absent in peripheral blood of the recipient mice, suggesting that monopoiesis in C/EBPβ–/– mice is impaired in a cell-intrinsic manner. A recent report revealed that MX1-Cre transgenic system can be used for monocyte specific deletion of genes of interest, as MX1 is highly expressed by monocytes (Hashimoto D et al. Immunity 2013). In MX1-Cre+ C/EBPβfloxed/floxed mice, the number of monocytes were decreased to the level similar to C/EBPβ–/– mice, suggesting that C/EBPβ is specifically required in monocytes rather than other progenitors during monopoiesis. As cell cycle status of myeloid progenitors and monocytes did not differ between WT mice and C/EBPβ–/– mice, we evaluated apoptosis by flow cytometry. The frequencies of late apoptotic/dead cells within Ly6C– monocytes in peripheral blood of C/EBPβ–/– mice were significantly higher than those in peripheral blood of WT mice (5.84±2.90% in WT mice vs. 50.4±22.4% in C/EBPβ–/– mice, p<0.001). These enhanced apoptosis of C/EBPβ–/– Ly6C– monocyte was partially reversed by retroviral transduction of Bcl2 gene. Previous reports have shown that Nr4a1, CX3CR1 and S1PR5 are required for survival or BM egress of Ly6C– monocytes. We found that mRNA expressions of these factors are severely reduced in C/EBPβ–/– Ly6C– monocytes. These results suggested that C/EBPβ maintains survival of Ly6C– monocytes through direct or indirect association of these molecules. Collectively, our data strongly indicate that C/EBPβ is essential for survival of Ly6C– monocytes. We are currently investigating the molecular mechanisms involved in the enhanced apoptosis of of Ly6C– monocytes in C/EBPβ–/– mice. Disclosures No relevant conflicts of interest to declare.

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Molecular mechanisms of the glucocorticoid receptor in steroid therapy – lessons from transgenic mice

BioMolecular Concepts ◽

10.1515/bmc-2011-0033 ◽

2012 ◽

Vol 3 (3) ◽

pp. 241-253 ◽

Cited By ~ 4

Author(s):

Sabine Hübner ◽

Jan Tuckermann

Keyword(s):

Side Effects ◽

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Pathological Condition ◽

Cell Types ◽

Therapeutic Effects ◽

Gene Promoters ◽

Inflammatory Conditions ◽

Anti Inflammatory ◽

And Function

AbstractGlucocorticoids (GCs) are potent anti-inflammatory agents that are used to treat chronic inflammatory diseases, allergic conditions, and some cancers. However, their therapeutic effects are hampered by severe side effects, such as muscle weakness, insulin resistance, fat redistribution, and osteoporosis. GCs act on many cell types that express the GC receptor (GR) via several modes of action. One of them includes GR homodimers recognizing binding sequences in the DNA of gene promoters. Another mode involves the modulation of other DNA-bound transcription factors via dimer-independent mechanisms. To what extent these mechanisms contribute to GC-mediated effects is currently being elucidated from analyses of mice with conditional and function-selective mutations of the GR and is summarized in this review. Whether GR homodimerization or its monomer activity is decisive in the therapeutic effectiveness and associated side effects of GCs for the treatment of inflammatory conditions depends on the type of the pathological condition. Thus, the classic criterion for selective GR modulators, discrimination between GR dimer- and GR monomer-dependent protein-protein interaction, will not help in any condition to avoid side effects and maintain anti-inflammatory activity. Rather, novel criteria for selective GR modulators have to be defined that take into consideration the tissue-specific mechanisms of the GR to achieve optimized anti-inflammatory therapies with reduced side effects. In the case of avoiding osteoporosis as a side effect, a first example of such optimized compounds can be provided.

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IL-10-Producing ILCs: Molecular Mechanisms and Disease Relevance

Frontiers in Immunology ◽

10.3389/fimmu.2021.650200 ◽

2021 ◽

Vol 12 ◽

Author(s):

Hui Sun ◽

Yuzhang Wu ◽

Yi Zhang ◽

Bing Ni

Keyword(s):

Nk Cells ◽

Molecular Mechanisms ◽

Inflammatory Diseases ◽

Cell Types ◽

Interleukin 10 ◽

Vital Role ◽

Lymphoid Cells ◽

Stable Production ◽

Disease Relevance ◽

And Function

Innate lymphoid cells (ILCs) are mainly composed of natural killer (NK) cells and helper-like lymphoid cells, which play a vital role in maintaining tissue homeostasis, enhancing adaptive immunity and regulating tissue inflammation. Alteration of the distribution and function of ILCs subgroups are closely related to the pathogenesis of inflammatory diseases and cancers. Interleukin-10 (IL-10) is a highly pleiotropic cytokine, and can be secreted by several cell types, among of which ILCs are recently verified to be a key source of IL-10. So far, the stable production of IL-10 can only be observed in certain NK subsets and ILC2s. Though the regulatory mechanisms for ILCs to produce IL-10 are pivotal for understanding ILCs and potential intervenes of diseases, which however is largely unknown yet. The published studies show that ILCs do not share exactly the same mechanisms for IL-10 production with helper T cells. In this review, the molecular mechanisms regulating IL-10 production in NK cells and ILC2s are discussed in details for the first time, and the role of IL-10-producing ILCs in diseases such as infections, allergies, and cancers are summarized.

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Building and Regenerating the Lung Cell by Cell

Physiological Reviews ◽

10.1152/physrev.00001.2018 ◽

2019 ◽

Vol 99 (1) ◽

pp. 513-554 ◽

Cited By ~ 31

Author(s):

Jeffrey A. Whitsett ◽

Tanya V. Kalin ◽

Yan Xu ◽

Vladimir V. Kalinichenko

Keyword(s):

Molecular Mechanisms ◽

Cell Types ◽

Early Embryo ◽

Sequencing Data ◽

Chronic Lung Diseases ◽

Lung Morphogenesis ◽

Pulmonary Cells ◽

Mammalian Lung ◽

Resolution Imaging ◽

And Function

The unique architecture of the mammalian lung is required for adaptation to air breathing at birth and thereafter. Understanding the cellular and molecular mechanisms controlling its morphogenesis provides the framework for understanding the pathogenesis of acute and chronic lung diseases. Recent single-cell RNA sequencing data and high-resolution imaging identify the remarkable heterogeneity of pulmonary cell types and provides cell selective gene expression underlying lung development. We will address fundamental issues related to the diversity of pulmonary cells, to the formation and function of the mammalian lung, and will review recent advances regarding the cellular and molecular pathways involved in lung organogenesis. What cells form the lung in the early embryo? How are cell proliferation, migration, and differentiation regulated during lung morphogenesis? How do cells interact during lung formation and repair? How do signaling and transcriptional programs determine cell-cell interactions necessary for lung morphogenesis and function?

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The Enigmatic HOX Genes: Can We Crack Their Code?

Cancers ◽

10.3390/cancers11030323 ◽

2019 ◽

Vol 11 (3) ◽

pp. 323 ◽

Cited By ~ 14

Author(s):

Zhifei Luo ◽

Suhn Rhie ◽

Peggy Farnham

Keyword(s):

Transcription Factors ◽

Embryonic Development ◽

Molecular Mechanisms ◽

Hox Genes ◽

Homeobox Genes ◽

Large Family ◽

Cell Types ◽

Interacting Protein ◽

Developmental Problems ◽

And Function

Homeobox genes (HOX) are a large family of transcription factors that direct the formation of many body structures during early embryonic development. There are 39 genes in the subgroup of homeobox genes that constitute the human HOX gene family. Correct embryonic development of flies and vertebrates is, in part, mediated by the unique and highly regulated expression pattern of the HOX genes. Disruptions in these fine-tuned regulatory mechanisms can lead to developmental problems and to human diseases such as cancer. Unfortunately, the molecular mechanisms of action of the HOX family of transcription factors are severely under-studied, likely due to idiosyncratic details of their structure, expression, and function. We suggest that a concerted and collaborative effort to identify interacting protein partners, produce genome-wide binding profiles, and develop HOX network inhibitors in a variety of human cell types will lead to a deeper understanding of human development and disease. Within, we review the technological challenges and possible approaches needed to achieve this goal.

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Organoids as tools to investigate the molecular mechanisms of male infertility and its treatments

Reproduction ◽

10.1530/rep-20-0499 ◽

2021 ◽

Vol 161 (5) ◽

pp. R103-R112

Author(s):

Marc Kanbar ◽

Maxime Vermeulen ◽

Christine Wyns

Keyword(s):

Self Assembly ◽

Molecular Mechanisms ◽

Cell Types ◽

Testicular Tissue ◽

Innovative Methods ◽

Potential Applications ◽

Cell Niche ◽

And Function ◽

Conventional Systems

Organoids are 3D structures characterized by cellular spatial organizations and functions close to the native tissue they mimic. Attempts to create organoids originating from several tissues have now been reported, including the testis. Testicular organoids have the potential to improve our knowledge of the mechanisms that regulate testicular morphogenesis, physiology, and pathophysiology. They could especially prove as useful tools to understand the complex mechanisms involved in the regulation of the germ cell niche in infertility cases as they offer the possibility to control and modify the nature of cell types before self-assembly and thereby opening the perspective for developing innovative methods to restore fertility. To date, there are only few studies targeted at testicular organoids’ formation and even less describing the generation of organoids with both testis-specific structure and function. While researchers described interesting applications with regards to testicular tissue morphogenesis and drug toxicity, further research is needed before testicular organoids would eventually lead to the generation of fertilizing spermatozoa. This review will present the conventional systems used to induce in vitro maturation of testicular cells, describe the different approaches that have been used for the development of testicular organoids and discuss the potential applications they could have in the field of male reproductive biology.

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Alteration of STIM1/Orai1-Mediated SOCE in Skeletal Muscle: Impact in Genetic Muscle Diseases and Beyond

Cells ◽

10.3390/cells10102722 ◽

2021 ◽

Vol 10 (10) ◽

pp. 2722

Author(s):

Elena Conte ◽

Paola Imbrici ◽

Paola Mantuano ◽

Maria Coppola ◽

Giulia Maria Camerino ◽

...

Keyword(s):

Skeletal Muscle ◽

Muscle Function ◽

Molecular Mechanisms ◽

Therapeutic Potential ◽

Critical Role ◽

Protein A ◽

Cell Types ◽

Muscle Diseases ◽

Cellular Processes ◽

And Function

Intracellular Ca2+ ions represent a signaling mediator that plays a critical role in regulating different muscular cellular processes. Ca2+ homeostasis preservation is essential for maintaining skeletal muscle structure and function. Store-operated Ca2+ entry (SOCE), a Ca2+-entry process activated by depletion of intracellular stores contributing to the regulation of various function in many cell types, is pivotal to ensure a proper Ca2+ homeostasis in muscle fibers. It is coordinated by STIM1, the main Ca2+ sensor located in the sarcoplasmic reticulum, and ORAI1 protein, a Ca2+-permeable channel located on transverse tubules. It is commonly accepted that Ca2+ entry via SOCE has the crucial role in short- and long-term muscle function, regulating and adapting many cellular processes including muscle contractility, postnatal development, myofiber phenotype and plasticity. Lack or mutations of STIM1 and/or Orai1 and the consequent SOCE alteration have been associated with serious consequences for muscle function. Importantly, evidence suggests that SOCE alteration can trigger a change of intracellular Ca2+ signaling in skeletal muscle, participating in the pathogenesis of different progressive muscle diseases such as tubular aggregate myopathy, muscular dystrophy, cachexia, and sarcopenia. This review provides a brief overview of the molecular mechanisms underlying STIM1/Orai1-dependent SOCE in skeletal muscle, focusing on how SOCE alteration could contribute to skeletal muscle wasting disorders and on how SOCE components could represent pharmacological targets with high therapeutic potential.

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Kinesin motors and primary cilia

Biochemical Society Transactions ◽

10.1042/bst0391120 ◽

2011 ◽

Vol 39 (5) ◽

pp. 1120-1125 ◽

Cited By ~ 49

Author(s):

Kristen J. Verhey ◽

John Dishinger ◽

Hooi Lynn Kee

Keyword(s):

Primary Cilia ◽

Molecular Mechanisms ◽

Intraflagellar Transport ◽

Cell Types ◽

Cellular Motility ◽

Form And Function ◽

Cilia And Flagella ◽

Protein Components ◽

And Function ◽

Kidney Liver

Cilia and flagella play important roles in human health by contributing to cellular motility as well as sensing and responding to environmental cues. Defects in ciliary assembly and/or function can lead to a range of human diseases, collectively known as the ciliopathies, including polycystic kidney, liver and pancreatic diseases, sterility, obesity, situs inversus, hydrocephalus and retinal degeneration. A basic understanding of how cilia form and function is essential for deciphering ciliopathies and generating therapeutic treatments. The cilium is a unique compartment that contains a distinct complement of protein and lipid. However, the molecular mechanisms by which soluble and membrane protein components are targeted to and trafficked into the cilium are not well understood. Cilia are generated and maintained by IFT (intraflagellar transport) in which IFT cargoes are transported along axonemal microtubules by kinesin and dynein motors. A variety of genetic, biochemical and cell biological approaches has established the heterotrimeric kinesin-2 motor as the ‘core’ IFT motor, whereas other members of the kinesin-2, kinesin-3 and kinesin-4 families function as ‘accessory’ motors for the transport of specific cargoes in diverse cell types. Motors of the kinesin-9 and kinesin-13 families play a non-IFT role in regulating ciliary beating or axonemal length, respectively. Entry of kinesin motors and their cargoes into the ciliary compartment requires components of the nuclear import machinery, specifically importin-β2 (transportin-1) and Ran-GTP (Ran bound to GTP), suggesting that similar mechanisms may regulate entry into the nuclear and ciliary compartments.

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Role of the 807 C/T Polymorphism of the α2 Gene in Platelet GP Ia Collagen Receptor Expression and Function

Thrombosis and Haemostasis ◽

10.1055/s-0037-1614605 ◽

1999 ◽

Vol 81 (06) ◽

pp. 951-956 ◽

Cited By ~ 59

Author(s):

J. Corral ◽

R. González-Conejero ◽

J. Rivera ◽

F. Ortuño ◽

P. Aparicio ◽

...

Keyword(s):

Venous Thrombosis ◽

Cell Types ◽

Receptor Expression ◽

Case Control Studies ◽

Platelet Surface ◽

Vitro Analysis ◽

And Function ◽

In Vitro Analysis

SummaryThe variability of the platelet GP Ia/IIa density has been associated with the 807 C/T polymorphism (Phe 224) of the GP Ia gene in American Caucasian population. We have investigated the genotype and allelic frequencies of this polymorphism in Spanish Caucasians. The T allele was found in 35% of the 284 blood donors analyzed. We confirmed in 159 healthy subjects a significant association between the 807 C/T polymorphism and the platelet GP Ia density. The T allele correlated with high number of GP Ia molecules on platelet surface. In addition, we observed a similar association of this polymorphism with the expression of this protein in other blood cell types. The platelet responsiveness to collagen was determined by “in vitro” analysis of the platelet activation and aggregation response. We found no significant differences in these functional platelet parameters according to the 807 C/T genotype. Finally, results from 3 case/control studies involving 302 consecutive patients (101 with coronary heart disease, 104 with cerebrovascular disease and 97 with deep venous thrombosis) determined that the 807 C/T polymorphism of the GP Ia gene does not represent a risk factor for arterial or venous thrombosis.

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