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1.
Cell Rep ; 41(3): 111509, 2022 10 18.
Article in English | MEDLINE | ID: mdl-36261014

ABSTRACT

Noradrenergic afferents to hypothalamic corticotropin releasing hormone (CRH) neurons provide a major excitatory drive to the hypothalamic-pituitary-adrenal (HPA) axis via α1 adrenoreceptor activation. Noradrenergic afferents are recruited preferentially by somatic, rather than psychological, stress stimuli. Stress-induced glucocorticoids feed back onto the hypothalamus to negatively regulate the HPA axis, providing a critical autoregulatory constraint that prevents glucocorticoid overexposure and neuropathology. Whether negative feedback mechanisms target stress modality-specific HPA activation is not known. Here, we describe a desensitization of the α1 adrenoreceptor activation of the HPA axis following acute stress in male mice that is mediated by rapid glucocorticoid regulation of adrenoreceptor trafficking in CRH neurons. Glucocorticoid-induced α1 receptor trafficking desensitizes the HPA axis to a somatic but not a psychological stressor. Our findings demonstrate a rapid glucocorticoid suppression of adrenergic signaling in CRH neurons that is specific to somatic stress activation, and they reveal a rapid, stress modality-selective glucocorticoid negative feedback mechanism.


Subject(s)
Hypothalamo-Hypophyseal System , Pituitary-Adrenal System , Animals , Mice , Male , Pituitary-Adrenal System/metabolism , Hypothalamo-Hypophyseal System/metabolism , Corticotropin-Releasing Hormone/metabolism , Glucocorticoids , Receptors, Glucocorticoid/metabolism , Stress, Psychological , Adrenergic Agents
2.
Int J Mol Sci ; 21(21)2020 Nov 07.
Article in English | MEDLINE | ID: mdl-33171717

ABSTRACT

The growth and differentiation of adipose tissue-derived stem cells (ASCs) is stimulated and regulated by the adipose tissue (AT) microenvironment. In lipedema, both inflammation and hypoxia influence the expansion and differentiation of ASCs, resulting in hypertrophic adipocytes and deposition of collagen, a primary component of the extracellular matrix (ECM). The goal of this study was to characterize the adipogenic differentiation potential and assess the levels of expression of ECM-remodeling markers in 3D spheroids derived from ASCs isolated from both lipedema and healthy individuals. The data showed an increase in the expression of the adipogenic genes (ADIPOQ, LPL, PPAR-γ and Glut4), a decrease in matrix metalloproteinases (MMP2, 9 and 11), with no significant changes in the expression of ECM markers (collagen and fibronectin), or integrin A5 in 3D differentiated lipedema spheroids as compared to healthy spheroids. In addition, no statistically significant changes in the levels of expression of inflammatory genes were detected in any of the samples. However, immunofluorescence staining showed a decrease in fibronectin and increase in laminin and Collagen VI expression in the 3D differentiated spheroids in both groups. The use of 3D ASC spheroids provide a functional model to study the cellular and molecular characteristics of lipedema AT.


Subject(s)
Extracellular Matrix/metabolism , Lipedema/metabolism , Mesenchymal Stem Cells/metabolism , Adipocytes/metabolism , Adipogenesis , Adipose Tissue/cytology , Adipose Tissue/metabolism , Cell Culture Techniques/methods , Cell Differentiation , Cell Proliferation , Cells, Cultured , Extracellular Matrix/physiology , Humans , Organoids/metabolism , Stem Cells/metabolism , Tissue Engineering/methods
3.
Cells ; 9(10)2020 09 30.
Article in English | MEDLINE | ID: mdl-33008073

ABSTRACT

Human adipose-derived stem cells (ASCs) show immense promise for treating inflammatory diseases, attributed primarily to their potent paracrine signaling. Previous investigations demonstrated that short-term Rapamycin preconditioning of bone marrow-derived stem cells (BMSCs) elevated secretion of prostaglandin E2, a pleiotropic molecule with therapeutic effects in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), and enhanced immunosuppressive capacity in vitro. However, this has yet to be examined in ASCs. The present study examined the therapeutic potential of short-term Rapamycin-preconditioned ASCs in the EAE model. Animals were treated at peak disease with control ASCs (EAE-ASCs), Rapa-preconditioned ASCs (EAE-Rapa-ASCs), or vehicle control (EAE). Results show that EAE-ASCs improved clinical disease scores and elevated intact myelin compared to both EAE and EAE-Rapa-ASC animals. These results correlated with augmented CD4+ T helper (Th) and T regulatory (Treg) cell populations in the spinal cord, and increased gene expression of interleukin-10 (IL-10), an anti-inflammatory cytokine. Conversely, EAE-Rapa-ASC mice showed no improvement in clinical disease scores, reduced myelin levels, and significantly less Th and Treg cells in the spinal cord. These findings suggest that short-term Rapamycin preconditioning reduces the therapeutic efficacy of ASCs when applied to late-stage EAE.


Subject(s)
Anti-Bacterial Agents/therapeutic use , Mesenchymal Stem Cell Transplantation/methods , Mesenchymal Stem Cells/metabolism , Multiple Sclerosis/drug therapy , Sirolimus/adverse effects , Animals , Anti-Bacterial Agents/pharmacology , Disease Models, Animal , Humans , Mice , Sirolimus/pharmacology
4.
Biochem Biophys Res Commun ; 529(4): 1180-1185, 2020 09 03.
Article in English | MEDLINE | ID: mdl-32819583

ABSTRACT

Volumetric muscle loss and muscle degeneration are conditions for which there are currently no effective treatment options. Human adipose stem cells (hASCs) offer promise in cell-based regenerative therapies to treat muscle damage due to their ability to self-renew and differentiate. However, in the absence of universal culture conditions that yield greater than 15% myogenic differentiation, the clinical potential of these cells is limited. Here we report on the evaluation of two different media recipes, three extracellular matrix (ECM) proteins, and a poly (ethylene glycol) (PEGDMA) hydrogel with a physiologically relevant elasticity to determine how the extracellular chemical and physical environment work together to enhance myogenic differentiation of hASCs. Our results identify a combination of unique biochemical and physical factors that promote myogenesis, laying the groundwork for creating a scaffold and culture medium that will effectively and efficiently direct myogenic differentiation of adult stem cells for clinical applications in the future.


Subject(s)
Adipose Tissue/cytology , Biocompatible Materials/pharmacology , Muscle Development , Stem Cells/cytology , Tissue Scaffolds/chemistry , Azacitidine/pharmacology , Cell Differentiation/drug effects , Cells, Cultured , Culture Media/pharmacology , Extracellular Matrix Proteins/metabolism , Gene Expression Regulation/drug effects , Humans , Hydrogels/pharmacology , Methacrylates/pharmacology , Muscle Development/drug effects , Muscle Development/genetics , Myoblasts/cytology , Myoblasts/drug effects , Polyethylene Glycols/pharmacology , Solubility , Stem Cells/drug effects , Stem Cells/metabolism , Stromal Cells/cytology , Stromal Cells/drug effects , Stromal Cells/metabolism
5.
J Biomater Sci Polym Ed ; 30(11): 895-918, 2019 08.
Article in English | MEDLINE | ID: mdl-31039085

ABSTRACT

Three-dimensional (3 D) hydrogel scaffolds are an attractive option for tissue regeneration applications because they allow for cell migration, fluid exchange, and can be synthesized to closely mimic the physical properties of the extracellular matrix environment. The material properties of hydrogels play a vital role in cellular migration and differentiation. In light of this, in-depth understanding of material properties is required before such scaffolds can be used to study their influence on cells. Herein, various blends and thicknesses of poly (ethylene glycol) dimethacrylate (PEGDMA) hydrogels were synthesized, flash frozen, and dried by lyophilization to create scaffolds with multiscale porosity. Environmental scanning electron microscopy (ESEM) images demonstrated that lyophilization induced microporous voids in the PEGDMA hydrogels while swelling studies show the hydrogels retain their innate swelling properties. Change in pore size was observed between drying methods, polymer blend, and thickness when imaged in the hydrated state. Human adipose-derived stem cells (hASCs) were seeded on lyophilized and non-lyophilized hydrogels to determine if the scaffolds would support cell attachment and proliferation of a clinically relevant cell type. Cell attachment and morphology of the hASCs were evaluated using fluorescence imaging. Qualitative observations in cell attachment and morphology of hASCs on the surface of the different hydrogel spatial configurations indicate these multiscale porosity hydrogels create a suitable scaffold for hASC culture. These findings offer another factor of tunability in creating biomimetic hydrogels for various tissue engineering applications including tissue repair, regeneration, wound healing, and controlled release of growth factors.


Subject(s)
Biocompatible Materials/chemistry , Hydrogels/chemistry , Methacrylates/chemistry , Polyethylene Glycols/chemistry , Tissue Scaffolds/chemistry , Adipocytes/metabolism , Biocompatible Materials/metabolism , Cell Adhesion , Cell Differentiation , Cell Survival , Cross-Linking Reagents/chemistry , Humans , Hydrogels/metabolism , Mesenchymal Stem Cells/metabolism , Methacrylates/metabolism , Molecular Conformation , Polyethylene Glycols/metabolism , Porosity , Rheology , Surface Properties , Tissue Engineering
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