The Experts below are selected from a list of 74487 Experts worldwide ranked by ideXlab platform

Kyungsun Kang - One of the best experts on this subject based on the ideXlab platform.

  • gata4 dependent regulation of the secretory phenotype via mcp 1 underlies lamin a mediated human mesenchymal stem Cell Aging
    Experimental and Molecular Medicine, 2018
    Co-Authors: Jin Young Lee, Byungchul Lee, Insung Kang, Jaejun Kim, Euijung Jung, Hyung Sik Kim, Yoojin Seo, Soon Won Choi, Kyungsun Kang
    Abstract:

    Defects in the nuclear lamina occur during physiological Aging and as. result of premature Aging disorders. Aging is also accompanied by an increase in transcription of genes encoding cytokines and chemokines,. phenomenon known as the senescence-associated secretory phenotype (SASP). Progerin and prelamin. trigger premature senescence and loss of function of human mesenchymal stem Cells (hMSCs), but little is known about how defects in nuclear lamin. regulate SASP. Here, we show that both progerin overexpression and ZMPSTE24 depletion induce paracrine senescence, especially through the expression of monocyte chemoattractant protein-1 (MCP-1), in hMSCs. Importantly, we identified that GATA4 is. mediator regulating MCP-1 expression in response to prelamin. or progerin in hMSCs. Co-immunoprecipitation revealed that GATA4 expression is maintained due to impaired p62-mediated degradation in progerin-expressing hMSCs. Furthermore, depletion of GATA4 abrogated SASP-dependent senescence through suppression of NF-ĸB and MCP-1 in hMSCs with progerin or prelamin A. Thus, our findings indicate that abnormal lamin. proteins trigger paracrine senescence through. GATA4-dependent pathway in hMSCs. This molecular link between defective lamin. and GATA4 can provide insights into physiological Aging and pathological Aging disorders.

  • reactive oxygen species in mesenchymal stem Cell Aging implication to lung diseases
    Oxidative Medicine and Cellular Longevity, 2015
    Co-Authors: Seran Yang, Jeongran Park, Kyungsun Kang
    Abstract:

    MSCs have become an emerging Cell source with their immune modulation, high proliferation rate, and differentiation potential; indeed, they have been challenged in clinical trials. Recently, it has shown that ROS play a dual role as both deleterious and beneficial species depending on their concentration in MSCs. Various environmental stresses-induced excessive production of ROS triggers Cellular senescence and abnormal differentiation on MSCs. Moreover, MSCs have been suggested to participate in the treatment of ALI/ARDS and COPD as a major cause of high morbidity and mortality. Therapeutic mechanisms of MSCs in the treatment of ARDS/COPD were focused on Cell engraftment and paracrine action. However, ROS-mediated therapeutic mechanisms of MSCs still remain largely unknown. Here, we review the key factors associated with Cell cycle and chromatin remodeling to accelerate or delay the MSC Aging process. In addition, the enhanced ROS production and its associated pathophysiological pathways will be discussed along with the MSC senescence process. Furthermore, the present review highlights how the excessive amount of ROS-mediated oxidative stress might interfere with homeostasis of lungs and residual lung Cells in the pathogenesis of ALI/ARDS and COPD.

  • dna methyltransferase controls stem Cell Aging by regulating bmi1 and ezh2 through micrornas
    PLOS ONE, 2011
    Co-Authors: Ahyoung So, Jiwon Jung, Kyungsun Kang
    Abstract:

    Epigenetic regulation of gene expression is well known mechanism that regulates Cellular senescence of cancer Cells. Here we show that inhibition of DNA methyltransferases (DNMTs) with 5-azacytidine (5-AzaC) or with specific small interfering RNA (siRNA) against DNMT1 and 3b induced the Cellular senescence of human umbilical cord blood-derived multipotent stem Cells (hUCB-MSCs) and increased p16INK4A and p21CIP1/WAF1 expression. DNMT inhibition changed histone marks into the active forms and decreased the methylation of CpG islands in the p16INK4A and p21CIP1/WAF1 promoter regions. Enrichment of EZH2, the key factor that methylates histone H3 lysine 9 and 27 residues, was decreased on the p16INK4A and p21CIP1/WAF1 promoter regions. We found that DNMT inhibition decreased expression levels of Polycomb-group (PcG) proteins and increased expression of microRNAs (miRNAs), which target PcG proteins. Decreased CpG island methylation and increased levels of active histone marks at genomic regions encoding miRNAs were observed after 5-AzaC treatment. Taken together, DNMTs have a critical role in regulating the Cellular senescence of hUCB-MSCs through controlling not only the DNA methylation status but also active/inactive histone marks at genomic regions of PcG-targeting miRNAs and p16INK4A and p21CIP1/WAF1 promoter regions.

  • histone deacetylase regulates high mobility group a2 targeting micrornas in human cord blood derived multipotent stem Cell Aging
    Cellular and Molecular Life Sciences, 2011
    Co-Authors: Seunghee Lee, Jiwon Jung, Sangbum Park, Kyounghwan Roh, Su Yeon Lee, Ju Han Kim, Soo Kyung Kang, Kyungsun Kang
    Abstract:

    Cellular senescence involves a reduction in adult stem Cell self-renewal, and epigenetic regulation of gene expression is one of the main underlying mechanisms. Here, we observed that the Cellular senescence of human umbilical cord blood-derived multipotent stem Cells (hUCB-MSCs) caused by inhibition of histone deacetylase (HDAC) activity leads to down-regulation of high mobility group A2 (HMGA2) and, on the contrary, to up-regulation of p16INK4A, p21CIP1/WAF1 and p27KIP1. We found that let-7a1, let-7d, let-7f1, miR-23a, miR-26a and miR-30a were increased during replicative and HDAC inhibitor-mediated senescence of hUCB-MSCs by microRNA microarray and real-time quantitative PCR. Furthermore, the configurations of chromatins beading on these miRNAs were prone to transcriptional activation during HDAC inhibitor-mediated senescence. We confirmed that miR-23a, miR-26a and miR-30a inhibit HMGA2 to accelerate the progress of senescence. These findings suggest that HDACs may play important roles in Cellular senescence by regulating the expression of miRNAs that target HMGA2 through histone modification.

  • histone deacetylase controls adult stem Cell Aging by balancing the expression of polycomb genes and jumonji domain containing 3
    Cellular and Molecular Life Sciences, 2010
    Co-Authors: Jiwon Jung, Sangbum Park, Soo Kyung Kang, Andreas Kurtz, Kyungsun Kang
    Abstract:

    Aging is linked to loss of the self-renewal capacity of adult stem Cells. Here, we observed that human multipotent stem Cells (MSCs) underwent Cellular senescence in vitro. Decreased expression of histone deacetylases (HDACs), followed by downregulation of polycomb group genes (PcGs), such as BMI1, EZH2 and SUZ12, and by upregulation of jumonji domain containing 3 (JMJD3), was observed in senescent MSCs. Similarly, HDAC inhibitors induced Cellular senescence through downregulation of PcGs and upregulation of JMJD3. Regulation of PcGs was associated with HDAC inhibitor-induced hypophosphorylation of RB, which causes RB to bind to and decrease the transcriptional activity of E2F. JMJD3 expression regulation was dependant on histone acetylation status at its promoter regions. A histone acetyltransferase (HAT) inhibitor prevented replicative senescence of MSCs. These results suggest that HDAC activity might be important for MSC self-renewal by balancing PcGs and JMJD3 expression, which govern Cellular senescence by p16INK4A regulation.

Barry R Zirkin - One of the best experts on this subject based on the ideXlab platform.

  • leydig Cell Aging molecular mechanisms and treatments
    Vitamins and Hormones Series, 2021
    Co-Authors: Vassilios Papadopoulos, Barry R Zirkin
    Abstract:

    Late-onset hypogonadism, resulting from deficiency in serum testosterone (T), affects the health and quality of life of millions of Aging men. T is synthesized by Leydig Cells (LCs) in response to luteinizing hormone (LH). LH binds LC plasma membrane receptors, inducing the formation of a supramolecular complex of cytosolic and mitochondrial proteins, the Steroidogenic InteracTomE (SITE). SITE proteins are involved in targeting cholesterol to CYP11A1 in the mitochondria, the first enzyme of the steroidogenic cascade. Cholesterol translocation is the rate-determining step in T formation. With Aging, LC defects occur that include changes in SITE, an increasingly oxidative intraCellular environment, and reduced androgen formation and serum T levels. T replacement therapy (TRT) will restore T levels, but reported side effects make it desirable to develop additional strategies for increasing T. One approach is to target LC protein-protein interactions and thus increase T production by the hypofunctional Leydig Cells themselves.

  • leydig Cell Aging and hypogonadism
    Experimental Gerontology, 2015
    Co-Authors: Matthew C Beattie, Haolin Chen, L Adekola, Vassilios Papadopoulos, Barry R Zirkin
    Abstract:

    Leydig Cell testosterone (T) production is reduced with age, resulting in reduced serum T levels (hypogonadism). A number of Cellular changes have been identified in the steroidogenic pathway of aged Leydig Cells that are associated with reduced T formation, including reductions in luteinizing hormone (LH)-stimulated cAMP production, the cholesterol transport proteins steroidogenic acute regulatory (STAR) protein and translocator protein (TSPO), and downstream steroidogenic enzymes of the mitochondria and smooth endoplasmic reticulum. Many of the changes in steroid formation that characterize aged Leydig Cells can be elicited by the experimental alteration of the redox environment of young Cells, suggesting that changes in the intraCellular redox balance may cause reduced T production. Hypogonadism is estimated to affect about 5 million American men, including both aged and young. This condition has been linked to mood changes, worsening cognition, fatigue, depression, decreased lean body mass, reduced bone mineral density, increased visceral fat, metabolic syndrome, decreased libido, and sexual dysfunction. Exogenous T administration is now used widely to elevate serum T levels in hypogonadal men and thus to treat symptoms of hypogonadism. However, recent evidence suggests that men who take exogenous T may face increased risk of stroke, heart attack, and prostate tumorigenesis. Moreover, it is well established that administered T can have suppressive effects on LH, resulting in lower Leydig Cell T production, reduced intratesticular T concentration, and reduced spermatogenesis. This makes exogenous T administration inappropriate for men who wish to father children. There are promising new approaches to increase serum T by directly stimulating Leydig Cell T production rather than by exogenous T therapy, thus potentially avoiding some of its negative consequences.

  • Leydig Cell Aging and the mechanisms of reduced testosterone synthesis
    Molecular and cellular endocrinology, 2008
    Co-Authors: Andrew Midzak, Haolin Chen, Vassilios Papadopoulos, Barry R Zirkin
    Abstract:

    In males, serum testosterone levels decline with advancing age. Though part of a complex process, this age-related decline in testosterone appears to occur, in part, due to a significant decline in the ability of aged Leydig Cells to produce testosterone maximally in response to luteinizing hormone (LH). The structure of the molecular machinery responsible for the synthesis of testosterone is described, and placed in the context of Leydig Cell biology. Multiple parameters related to the synthesis of testosterone by the Leydig Cell have been observed to change with age. Relationships among these changes are reviewed. A discussion of potential causes of the age-related decline in Leydig Cell steroidogenic capacity presents a model in which the inability of aged Cells to adequately respond to hormonal stimulation results in Cellular regression with concomitant decline in maximal testosterone output.

  • regulation of leydig Cell steroidogenic function during Aging
    Biology of Reproduction, 2000
    Co-Authors: Barry R Zirkin, Haolin Chen
    Abstract:

    This article summarizes a talk on Leydig Cell Aging presented at the 1999 Annual Meeting of the Society for the Study of Reproduction. In the Brown Norway rat, serum testosterone levels decrease with Aging, accompanied by increases in serum FSH. The capacity of Leydig Cells to produce testosterone is higher in young than in old rats. Binding studies with hCG revealed reduced receptor number in old vs. young Leydig Cells. In response to incubation with LH, cAMP production was found to be reduced in old vs. young Leydig Cells, indicating that signal tranduction mechanisms in the old Cells are affected by Aging. Steroidogenic acute regulatory protein and mRNA levels are reduced in old Leydig Cells, suggesting that there may be deficits in the transport of cholesterol to the inner mitochondrial membrane of aged Cells. The activity of P450 side-chain cleavage enzyme is reduced in old vs. young Cells, as are the activities of each of 3b-hydroxysteroid dehydrogenase, 17a-hydroxylase/ C17‐20 lyase, and 17-ketosteroid reductase. Serum LH levels do not differ between young and old rats, and the administration of LH failed to induce old Leydig Cells to produce high (young) testosterone levels, suggesting that the cause of age-related reductions in steroidogenesis is not LH deficits. We hypothesized that reactive oxygen, produced as a by-product of steroidogenesis itself, might be responsible for age-related reductions in testosterone production by the Leydig Cells. Consistent with this, long-term suppression of steroidogenesis was found to prevent or delay the reduced steroidogenesis that accompanies Leydig Cell Aging. A possible explanation of this finding is that longterm suppression of steroidogenesis prevents free radical damage to the Cells by suppressing the production of the reactive oxygen species that are a by-product of steroidogenesis itself. LH, male reproductive tract, testes, testosterone

Thomas A Rando - One of the best experts on this subject based on the ideXlab platform.

  • heterochronic parabiosis historical perspective and methodological considerations for studies of Aging and longevity
    Aging Cell, 2013
    Co-Authors: Michael J. Conboy, Irina M. Conboy, Thomas A Rando
    Abstract:

    Pairing two animals in parabiosis to test for systemic or circulatory factors from one animal affecting the other animal has been used in scientific studies for at least 150 years. These studies have led to advances in fields as diverse as endocrinology, immunology, and oncology. A variation on the technique, heterochronic parabiosis, whereby two animals of different ages are joined to test for systemic regulators of aspects of Aging or age-related diseases also has almost a century-long scientific history. In this review, we focus on the history of heterochronic parabiosis, methodological considerations and caveats, and the major advances that have emerged from those studies, including recent advances in our understanding of stem Cell Aging.

  • manifestations and mechanisms of stem Cell Aging
    Journal of Cell Biology, 2011
    Co-Authors: Ling Liu, Thomas A Rando
    Abstract:

    Adult stem Cells exist in most mammalian organs and tissues and are indispensable for normal tissue homeostasis and repair. In most tissues, there is an age-related decline in stem Cell functionality but not a depletion of stem Cells. Such functional changes reflect deleterious effects of age on the genome, epigenome, and proteome, some of which arise Cell autonomously and others of which are imposed by an age-related change in the local milieu or systemic environment. Notably, some of the changes, particularly epigenomic and proteomic, are potentially reversible, and both environmental and genetic interventions can result in the rejuvenation of aged stem Cells. Such findings have profound implications for the stem Cell–based therapy of age-related diseases.

Weiqi Zhang - One of the best experts on this subject based on the ideXlab platform.

  • sirt7 antagonizes human stem Cell Aging as a heterochromatin stabilizer
    Protein & Cell, 2020
    Co-Authors: Zunpeng Liu, Weiqi Zhang, Moshi Song, Zehua Wang, Xiaoqian Liu, Si Wang, Jie Ren, Yan Yao, Guanghui Liu
    Abstract:

    SIRT7, a sirtuin family member implicated in Aging and disease, is a regulator of metabolism and stress responses. It remains elusive how human somatic stem Cell populations might be impacted by SIRT7. Here, we found that SIRT7 expression declines during human mesenchymal stem Cell (hMSC) Aging and that SIRT7 deficiency accelerates senescence. Mechanistically, SIRT7 forms a complex with nuclear lamina proteins and heterochromatin proteins, thus maintaining the repressive state of heterochromatin at nuclear periphery. Accordingly, deficiency of SIRT7 results in loss of heterochromatin, de-repression of the LINE1 retrotransposon (LINE1), and activation of innate immune signaling via the cGAS-STING pathway. These Aging-associated Cellular defects were reversed by overexpression of heterochromatin proteins or treatment with a LINE1 targeted reverse-transcriptase inhibitor. Together, these findings highlight how SIRT7 safeguards chromatin architecture to control innate immune regulation and ensure geroprotection during stem Cell Aging.

  • differential stem Cell Aging kinetics in hutchinson gilford progeria syndrome and werner syndrome
    Protein & Cell, 2018
    Co-Authors: Weiqi Zhang, Moshi Song, Wei Wang, Gang Wei, Jinghui Lei, Yu Huang, Yanmei Sang, Piu Chan, Chang Chen
    Abstract:

    Hutchinson-Gilford progeria syndrome (HGPS) and Werner syndrome (WS) are two of the best characterized human progeroid syndromes. HGPS is caused by a point mutation in lamin A (LMNA) gene, resulting in the production of a truncated protein product—progerin. WS is caused by mutations in WRN gene, encoding a loss-of-function RecQ DNA helicase. Here, by gene editing we created isogenic human embryonic stem Cells (ESCs) with heterozygous (G608G/+) or homozygous (G608G/G608G) LMNA mutation and biallelic WRN knockout, for modeling HGPS and WS pathogenesis, respectively. While ESCs and endothelial Cells (ECs) did not present any features of premature senescence, HGPS- and WS-mesenchymal stem Cells (MSCs) showed Aging-associated phenotypes with different kinetics. WS-MSCs had early-onset mild premature Aging phenotypes while HGPS-MSCs exhibited late-onset acute premature Aging characterisitcs. Taken together, our study compares and contrasts the distinct pathologies underpinning the two premature Aging disorders, and provides reliable stem-Cell based models to identify new therapeutic strategies for pathological and physiological Aging.

Derrick J Rossi - One of the best experts on this subject based on the ideXlab platform.

  • proliferation dependent alterations of the dna methylation landscape underlie hematopoietic stem Cell Aging
    Cell Stem Cell, 2013
    Co-Authors: Isabel Beerman, Christoph Bock, Brian S Garrison, Zachary D Smith, Alexander Meissner, Derrick J Rossi
    Abstract:

    The functional potential of hematopoietic stem Cells (HSCs) declines during Aging, and in doing so, significantly contributes to hematopoietic pathophysiology in the elderly. To explore the relationship between age-associated HSC decline and the epigenome, we examined global DNA methylation of HSCs during ontogeny in combination with functional analysis. Although the DNA methylome is generally stable during Aging, site-specific alterations of DNA methylation occur at genomic regions associated with hematopoietic lineage potential and selectively target genes expressed in downstream progenitor and effector Cells. We found that age-associated HSC decline, replicative limits, and DNA methylation are largely dependent on the proliferative history of HSCs, yet appear to be telomere-length independent. Physiological Aging and experimentally enforced proliferation of HSCs both led to DNA hypermethylation of genes regulated by Polycomb Repressive Complex 2. Our results provide evidence that epigenomic alterations of the DNA methylation landscape contribute to the functional decline of HSCs during Aging.

  • hematopoietic stem Cells and the Aging hematopoietic system
    Seminars in Hematology, 2008
    Co-Authors: Roi Gazit, Irving L Weissman, Derrick J Rossi
    Abstract:

    The etiology of the age-associated pathophysiological changes of the hematopoietic system including the onset of anemia, diminished adaptive immune competence, and myelogenous disease development are underwritten by the loss of normal homeostatic control. As tissue and organ homeostasis in adults is primarily mediated by the activity of stem and progenitor Cells, it has been suggested that the imbalances accompanying Aging of the hematopoietic system may stem from alterations in the prevalence and/or functional capacity of hematopoietic stem Cells (HSCs) and progenitors. In this review, we examine evidence implicating a role for stem Cells in the Aging of the hematopoietic system, and focus on the mechanisms suggested to contribute to stem Cell Aging.

  • Cell intrinsic alterations underlie hematopoietic stem Cell Aging
    Proceedings of the National Academy of Sciences of the United States of America, 2005
    Co-Authors: Derrick J Rossi, Amy J Wagers, David Bryder, Jacob M Zahn, Henrik Ahlenius, Rebecca Sonu, Irving L Weissman
    Abstract:

    Loss of immune function and an increased incidence of myeloid leukemia are two of the most clinically significant consequences of Aging of the hematopoietic system. To better understand the mechanisms underlying hematopoietic Aging, we evaluated the Cell intrinsic functional and molecular properties of highly purified long-term hematopoietic stem Cells (LT-HSCs) from young and old mice. We found that LT-HSC Aging was accompanied by Cell autonomous changes, including increased stem Cell self-renewal, differential capacity to generate committed myeloid and lymphoid progenitors, and diminished lymphoid potential. Expression profiling revealed that LT-HSC Aging was accompanied by the systemic down-regulation of genes mediating lymphoid specification and function and up-regulation of genes involved in specifying myeloid fate and function. Moreover, LT-HSCs from old mice expressed elevated levels of many genes involved in leukemic transformation. These data support a model in which age-dependent alterations in gene expression at the stem Cell level presage downstream developmental potential and thereby contribute to age-dependent immune decline, and perhaps also to the increased incidence of leukemia in the elderly.