Similar Datasets
Project description:Fibroblasts residing in the connective tissue of all organs constitute the stem cell niche particularly in connective tissue rich organs like skin. Though the impact of the connective tissue resident fibroblasts on stem cell niches and organ aging is an emerging concept, the underlying mechanisms are largely unresolved. Here, we report a novel mechanism of redox-dependent activation of the transcription factor JunB, which through concomitant upregulation of cyclin dependent kinase inhibitor p16INK4A and repression of IGF-1 dependent cell growth and protein translation initiates the installment of irreversible fibroblast senescence. Fibroblast senescence in turn profoundly disrupts the metabolic and structural niche and its essential interactions with different stem cells thus enforcing depletion of stem cells pools and skin tissue decline. In fact, silencing of JunB in a fibroblast niche-specific knock out mouse - by the reinstatement of IGF-1 and p16 levels - fully restored skin stem cell pools and overall tissue integrity of the skin. We here uncovered a previously unreported role of JunB in the control of the endogenous connective tissue niche and identified promising targets to combat skin aging and associated pathologies.
2021-07-16 | GSE180008 | GEO
Project description:ATAC-seq was performed in control murine dermal fibroblasts (MDF) in the absence and presence of rotenone at a concentration of 250µM for 3 hrs), and in freshly isolated control (Co) and Sod2 cKO MDF.
2021-07-16 | GSE180007 | GEO
Project description:Persistent JunB Activation in Fibroblasts Disrupts Stem Cell Niche Interactions Enforcing Skin Aging
| PRJNA746260 | ENA
Project description:Persistent JunB Activation in Fibroblasts Disrupts Stem Cell Niche Interactions Enforcing Skin Aging [ATAC-seq]
| PRJNA746264 | ENA
Project description:Persistent JunB Activation in Fibroblasts Disrupts Stem Cell Niche Interactions Enforcing Skin Aging [RNA-seq]
| PRJNA746263 | ENA
Project description:Skin aging is driven by intrinsic and extrinsic factors impacting on skin functionality with progressive age. One factor of this multifaceted process is cellular senescence, as it has recently been identified to contribute to a declining tissue functionality in old age. In the skin, senescent cells have been found to markedly accumulate with age, and thus might impact directly on skin characteristics. Especially the switch from young, extracellular matrix-building fibroblasts to a senescence-associated secretory phenotype (SASP) could alter the microenvironment in the skin drastically and therefore promote skin aging. In order to study the influence of senescence in human skin, 3D organotypic cultures are a well-suited model system. However, only few "aged" skin- equivalent (SE) models are available, requiring complex and long-term experimental setups. Here, we adapted a previously published full-thickness SE model by seeding increasing ratios of stress-induced premature senescent versus normal fibroblasts into the collagen matrix, terming these SE "senoskin". Immunohistochemistry stainings revealed a shift in the balance between proliferation (Ki67) and differentiation (Keratin 10 and Filaggrin) of keratinocytes within our senoskin equivalents, as well as partial impairment of skin barrier function and changed surface properties. Monitoring of cytokine levels of known SASP factors confirmedly showed an upregulation in 2D cultures of senescent cells and at the time of seeding into the skin equivalent. Surprisingly, we find a blunted response of cytokines in the senoskin equivalent over time during 3D differentiation.
| S-EPMC7060247 | biostudies-literature
Project description:Reactive oxygen species (ROS) play a major role in both chronological aging and photoaging. ROS induce skin aging through their damaging effect on cellular constituents. However, the origins of ROS have not been fully elucidated. We investigated that ROS generation of replicative senescent fibroblasts is generated by the modulation of phosphatidylinositol 3,4,5-triphosphate (PIP3) metabolism. Reduction of the PTEN protein, which dephosphorylates PIP3, was responsible for maintaining a high level of PIP3 in replicative cells and consequently mediated the activation of the phosphatidylinositol-3-OH kinase (PI3K)/Akt pathway. Increased ROS production was blocked by inhibition of PI3K or protein kinase C (PKC) or by NADPH oxidase activating in replicative senescent cells. These data indicate that the signal pathway to ROS generation in replicative aged skin cells can be stimulated by reduced PTEN level. Our results provide new insights into skin aging-associated modification of the PI3K/NADPH oxidase signaling pathway and its relationship with a skin aging-dependent increase of ROS in human dermal fibroblasts.
| S-EPMC5149682 | biostudies-literature
Project description:There is evidence to suggest that the primary tumor induces the formation of a pre-metastatic niche in distal organs by stimulating the production of pro-metastatic factors. Given the fundamental role of the pre-metastatic niche in the development of metastases, interruption of its formation would be a promising strategy to take early action against tumor metastasis. Here we report an enzyme-activated assembled peptide FR17 that can serve as a "flame-retarding blanket" in the pre-metastatic niche specifically to extinguish the "fire" of tumor-supportive microenvironment adaption. We show that the in-situ assembled peptide nano-blanket inhibits fibroblasts activation, suppressing the remodeling of the metastasis-supportive host stromal tissue, and reversing vascular destabilization and angiogenesis. Furthermore, we demonstrate that the nano-blanket prevents the recruitment of myeloid cells to the pre-metastatic niche, regulating the immune-suppressive microenvironment. We show that FR17 administration effectively inhibits the formation of the pulmonary pre-metastatic niche and postoperative metastasis, offering a therapeutic strategy against pre-metastatic niche formation.
| S-EPMC9132894 | biostudies-literature
Project description:Tissues contain distinct stem cell niches, but whether cell turnover is coordinated between niches during growth is unknown. Here, we report that in mouse skin, hair growth is accompanied by sebaceous gland and interfollicular epidermis expansion. During hair growth, cells in the bulge and outer root sheath temporarily upregulate the glutamate transporter SLC1A3, and the number of SLC1A3+ basal cells in interfollicular epidermis and sebaceous gland increases. Fate mapping of SLC1A3+ cells in mice revealed transient expression in proliferating stem/progenitor cells in all three niches. Deletion of slc1a3 delays hair follicle anagen entry, uncouples interfollicular epidermis and sebaceous gland expansion from the hair cycle, and leads to reduced fur density in aged mice, indicating a role of SLC1A3 in stem/progenitor cell activation. Modulation of metabotropic glutamate receptor 5 activity mimics the effects of SLC1A3 deletion or inhibition. These data reveal that stem/progenitor cell activation is synchronized over distinct niches during growth and identify SLC1A3 as a general marker and effector of activated epithelial stem/progenitor cells throughout the skin.
| S-EPMC5920238 | biostudies-literature
Project description:Collagen type I production decreases with aging, leading to wrinkles and impaired skin function. Prostaglandin E2 (PGE2), a lipid-derived signaling molecule produced from arachidonic acid by cyclo-oxygenase, inhibits collagen production, and induces matrix metallopeptidase 1 (MMP1) expression by fibroblasts in vitro. PGE2-induced collagen expression inhibition and MMP1 promotion are aging mechanisms. This study investigated the role of E-prostanoid 1 (EP1) in PGE2 signaling in normal human dermal fibroblasts (NHDFs). When EP1 expression was inhibited by EP1 small interfering RNA (siRNA), there were no significant changes in messenger RNA (mRNA) levels of collagen, type I, alpha 1 (COL1A1)/MMP1 between siRNA-transfected NHDFs and siRNA-transfected NHDFs with PGE2. This result showed that EP1 is a PGE2 receptor. Extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation after PGE2 treatment significantly increased by ~2.5 times. In addition, PGE2 treatment increased the intracellular Ca2+ concentration in NHDFs. These results indicated that PGE2 is directly associated with EP1 pathway-regulated ERK1/2 and inositol trisphosphate (IP3) signaling in NHDFs.
| S-EPMC6887779 | biostudies-literature