scholarly journals Nuclear envelope defects cause stem cell dysfunction in premature-aging mice

2008 ◽  
Vol 181 (1) ◽  
pp. 27-35 ◽  
Author(s):  
Jesús Espada ◽  
Ignacio Varela ◽  
Ignacio Flores ◽  
Alejandro P. Ugalde ◽  
Juan Cadiñanos ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Nuclear Envelope ◽  
Nuclear Architecture ◽  
Nuclear Lamina ◽  
Premature Aging ◽  
Molecular Signaling ◽  
Cell Dysfunction ◽  
Age Related ◽  
Microphthalmia Transcription Factor

Nuclear lamina alterations occur in physiological aging and in premature aging syndromes. Because aging is also associated with abnormal stem cell homeostasis, we hypothesize that nuclear envelope alterations could have an important impact on stem cell compartments. To evaluate this hypothesis, we examined the number and functional competence of stem cells in Zmpste24-null progeroid mice, which exhibit nuclear lamina defects. We show that Zmpste24 deficiency causes an alteration in the number and proliferative capacity of epidermal stem cells. These changes are associated with an aberrant nuclear architecture of bulge cells and an increase in apoptosis of their supporting cells in the hair bulb region. These alterations are rescued in Zmpste24−/−Lmna+/− mutant mice, which do not manifest progeroid symptoms. We also report that molecular signaling pathways implicated in the regulation of stem cell behavior, such as Wnt and microphthalmia transcription factor, are altered in Zmpste24−/− mice. These findings establish a link between age-related nuclear envelope defects and stem cell dysfunction.

scholarly journals Hematopoietic stem cell dysfunction underlies the progressive lymphocytopenia in XLF/Cernunnos deficiency

Blood ◽  
2014 ◽  
Vol 124 (10) ◽  
pp. 1622-1625 ◽  
Author(s):  
Serine Avagyan ◽  
Michael Churchill ◽  
Kenta Yamamoto ◽  
Jennifer L. Crowe ◽  
Chen Li ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Hematopoietic Stem Cells ◽  
Hematopoietic Stem Cell ◽  
Premature Aging ◽  
Hematopoietic Stem ◽  
Cell Dysfunction ◽  
Key Points ◽  
Deficient Mice

Key Points XLF-deficient mice recapitulate the lymphocytopenia of XLF-deficient patients. Premature aging of hematopoietic stem cells underlies the severe and progressive lymphocytopenia in XLF-deficient mice.

scholarly journals Nuclear envelope defects cause stem cell dysfunction in premature-aging mice

2008 ◽  
Vol 205 (4) ◽  
pp. i10-i10
Author(s):  
Jesús Espada ◽  
Ignacio Varela ◽  
Ignacio Flores ◽  
Alejandro P. Ugalde ◽  
Juan Cadiñanos ◽  
...  
Keyword(s):  
Stem Cell ◽  
Nuclear Envelope ◽  
Premature Aging ◽  
Cell Dysfunction

scholarly journals Nuclear Architecture Disruption During Aging Causes Misexpression of Genes Lacking CpG Islands

2021 ◽  
Vol 5 (Supplement_1) ◽  
pp. 676-677
Author(s):  
Jun-Yeong Lee ◽  
Ian Davis ◽  
Samuel Beck
Keyword(s):  
Large Scale ◽  
Structural Changes ◽  
Meta Analysis ◽  
Cpg Islands ◽  
Nuclear Architecture ◽  
Nuclear Lamina ◽  
Premature Aging ◽  
Degenerative Changes ◽  
Age Related ◽  
Direct Outcome

Abstract Global disorganization of chromatin architecture, characterized by disrupted nuclear lamina and associated heterochromatin, is commonly observed in various aging contexts, including premature aging diseases, cellular senescence, and normative aging. Although these conserved structural changes have been reported for over two decades, their impact on transcription and contribution to age-related degenerative changes remain unclear. Here we show that genes not associated with CpG islands (CGI- genes), which form heterochromatin when transcriptionally silent, are globally misexpressed in aged nuclei with disrupted chromatin architectures. Our data also show that CGI- gene misexpression is a direct outcome of nuclear architecture disruption. Notably, CGI- gene misexpression explains the molecular basis of various defects observed during aging, including loss of cellular identity and increased noises in transcription. We also show that uncontrolled secretory phenotypes commonly observed during aging are largely attributable to CGI- gene misexpression, which drives disruption of intercellular communication and fuel chronic inflammation in aged tissues. Our large-scale meta-analysis further demonstrates that CGI- gene misexpression is a common feature of mammalian aging and age-associated diseases. Interestingly, CGI- gene misexpression can be suppressed by anti-aging interventions. Our study suggests that age-associated CGI- gene misexpression is a novel biomarker of physiological aging which offers an effective therapeutic target for delaying or ameliorating degenerative changes associated with aging.

Abstract 15352: Age-associated Nuclear Remodeling May Contribute to Cardiac Dysfunction

Circulation ◽  
2020 ◽  
Vol 142 (Suppl_3) ◽  
Author(s):  
Natalie J Kirkland ◽  
James D Hocker ◽  
Sebastian Preissl ◽  
Bing Ren ◽  
Rolf Bodmer ◽  
...  
Keyword(s):  
Cardiac Dysfunction ◽  
Nuclear Architecture ◽  
Nuclear Lamina ◽  
Tissue Level ◽  
Chromatin Accessibility ◽  
Premature Aging ◽  
Proper Function ◽  
Nuclear Lamins ◽  
Age Related ◽  
Level Function

Introduction: Cardiac performance depends on proper function of the extracellular matrix, cytoskeleton and nucleus to regulate systolic contraction and diastolic relaxation. As we age, the mechanical properties of these structures change, but their influence on tissue-level function is unclear. Nuclear Lamins (Lam), intermediate filaments that underly the nuclear envelope, change in expression and localization with age, leading to irregularly shaped nuclei. Mutations in LamA/C can cause premature aging and cardiomyopathy but whether Lamin changes with age contribute to cardiac dysfunction is unknown. Hence, we hypothesize that age-associated LamA/C reduction remodels nuclear shape, force propagation, and gene accessibility to reduce cardiac function. Methods: We profiled nuclear morphology and protein expression in hearts from two wildtype Drosophila melanogaster strains for up to 5 weeks, when median survival is less than 50%. We performed live imaging to assess heart performance in wildtype flies and flies with Lamin knock-down using the Gal4-UAS system. To profile chromatin accessibility changes we use an ATAC-seq protocol that we optimized for frozen heart nuclei. Results: Cardiomyocyte nuclei become smaller and more circular with age in contrast to skeletal nuclei across w 1118 and yw wildtype fly strains. Expression of both LamB and LamC ( Drosophila LamA/C) decrease with age and differentially regulate nucleus size and circularity. LamC knockdown, but not LamB, induces contractile dysfunction, measured by fractional shortening, at 1-week, and shortens lifespan. LamB and LamC knockdown also mimicked DNA decondensation observed in aged wildtype flies, suggesting that reduced DNA packaging could result from fewer contacts with the nuclear lamina. Thus, we developed a novel ATAC-seq pipeline that will identify how age-related nuclear architecture may influence the epigenome and contribute to pathogenic heart remodeling. Conclusions: Cardiomyocyte nuclei decrease in size and increase in circularity upon aging as a result of diminished Lamin expression. Loss of Lamin expression induces cardiac dysfunction. Our future work aims to elucidate the mechanism by which nuclear aging contributes to age-related cardiac dysfunction.

Alterations of nuclear envelope and chromatin organization in mandibuloacral dysplasia, a rare form of laminopathy

2005 ◽  
Vol 23 (2) ◽  
pp. 150-158 ◽  
Author(s):  
Ilaria Filesi ◽  
Francesca Gullotta ◽  
Giovanna Lattanzi ◽  
Maria Rosaria D'Apice ◽  
Cristina Capanni ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Protein A ◽  
Nuclear Architecture ◽  
Mendelian Inheritance ◽  
Premature Aging ◽  
Lamin A ◽  
Lamin B ◽  
Lamin B Receptor ◽  
Epigenetic Events ◽  
Mandibuloacral Dysplasia

Autosomal recessive mandibuloacral dysplasia [mandibuloacral dysplasia type A (MADA); Online Mendelian Inheritance in Man (OMIM) no. 248370 ] is caused by a mutation in LMNA encoding lamin A/C. Here we show that this mutation causes accumulation of the lamin A precursor protein, a marked alteration of the nuclear architecture and, hence, chromatin disorganization. Heterochromatin domains are altered or completely lost in MADA nuclei, consistent with the finding that heterochromatin-associated protein HP1β and histone H3 methylated at lysine 9 and their nuclear envelope partner protein lamin B receptor (LBR) are delocalized and solubilized. Both accumulation of lamin A precursor and chromatin defects become more severe in older patients. These results strongly suggest that altered chromatin remodeling is a key event in the cascade of epigenetic events causing MADA and could be related to the premature-aging phenotype.

scholarly journals Lineage specification of early embryos and embryonic stem cells at the dawn of enabling technologies

2017 ◽  
Vol 4 (4) ◽  
pp. 533-542 ◽  
Author(s):  
Guangdun Peng ◽  
Patrick P. L. Tam ◽  
Naihe Jing
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Cell Biology ◽  
Developmental Process ◽  
Embryonic Stem ◽  
Molecular Signaling ◽  
Lineage Specification ◽  
Genomic Technologies ◽  
Enabling Technologies ◽  
Stem Cell Pluripotency

Abstract Establishment of progenitor cell populations and lineage diversity during embryogenesis and the differentiation of pluripotent stem cells is a fascinating and intricate biological process. Conceptually, an understanding of this developmental process provides a framework to integrate stem-cell pluripotency, cell competence and differentiating potential with the activity of extrinsic and intrinsic molecular determinants. The recent advent of enabling technologies of high-resolution transcriptome analysis at the cellular, population and spatial levels proffers the capability of gaining deeper insights into the attributes of the gene regulatory network and molecular signaling in lineage specification and differentiation. In this review, we provide a snapshot of the emerging enabling genomic technologies that contribute to the study of development and stem-cell biology.

scholarly journals Antioxidant Effects of Caffeic Acid Lead to Protection of Drosophila Intestinal Stem Cell Aging

2021 ◽  
Vol 9 ◽  
Author(s):  
Xiao Sheng ◽  
Yuedan Zhu ◽  
Juanyu Zhou ◽  
La Yan ◽  
Gang Du ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Caffeic Acid ◽  
Stress Responses ◽  
Adult Stem Cells ◽  
Cell Function ◽  
Cell Aging ◽  
Positive Effects ◽  
Age Related ◽  
Tissue Aging

The dysfunction or exhaustion of adult stem cells during aging is closely linked to tissue aging and age-related diseases. Circumventing this aging-related exhaustion of adult stem cells could significantly alleviate the functional decline of organs. Therefore, identifying small molecular compounds that could prevent the age-related decline of stem cell function is a primary goal in anti-aging research. Caffeic acid (CA), a phenolic compound synthesized in plants, offers substantial health benefits for multiple age-related diseases and aging. However, the effects of CA on adult stem cells remain largely unknown. Using the Drosophila midgut as a model, this study showed that oral administration with CA significantly delayed age-associated Drosophila gut dysplasia caused by the dysregulation of intestinal stem cells (ISCs) upon aging. Moreover, administering CA retarded the decline of intestinal functions in aged Drosophila and prevented hyperproliferation of age-associated ISC by suppressing oxidative stress-associated JNK signaling. On the other hand, CA supplementation significantly ameliorated the gut hyperplasia defect and reduced environmentally induced mortality, revealing the positive effects of CA on tolerance to stress responses. Taken together, our findings report a crucial role of CA in delaying age-related changes in ISCs of Drosophila.

scholarly journals A Balance Between Intermediate Filaments and Microtubules Maintains Nuclear Architecture in the Cardiomyocyte

2020 ◽  
Vol 126 (3) ◽  
Author(s):  
Julie Heffler ◽  
Parisha P. Shah ◽  
Patrick Robison ◽  
Sai Phyo ◽  
Kimberly Veliz ◽  
...  
Keyword(s):  
Nuclear Envelope ◽  
Intermediate Filaments ◽  
Genome Organization ◽  
Contractile Function ◽  
Nuclear Architecture ◽  
Super Resolution ◽  
Nuclear Lamina ◽  
Linc Complex ◽  
Spectrin Repeat ◽  
Balance Of Forces

Rationale: Mechanical forces are transduced to nuclear responses via the linkers of the nucleoskeleton and cytoskeleton (LINC) complex, which couples the cytoskeleton to the nuclear lamina and associated chromatin. While disruption of the LINC complex can cause cardiomyopathy, the relevant interactions that bridge the nucleoskeleton to cytoskeleton are poorly understood in the cardiomyocyte, where cytoskeletal organization is unique. Furthermore, while microtubules and desmin intermediate filaments associate closely with cardiomyocyte nuclei, the importance of these interactions is unknown. Objective: Here, we sought to determine how cytoskeletal interactions with the LINC complex regulate nuclear homeostasis in the cardiomyocyte. Methods and Results: To this end, we acutely disrupted the LINC complex, microtubules, actin, and intermediate filaments and assessed the consequences on nuclear morphology and genome organization in rat ventricular cardiomyocytes via a combination of super-resolution imaging, biophysical, and genomic approaches. We find that a balance of dynamic microtubules and desmin intermediate filaments is required to maintain nuclear shape and the fidelity of the nuclear envelope and lamina. Upon depletion of desmin (or nesprin [nuclear envelope spectrin repeat protein]-3, its binding partner in the LINC complex), polymerizing microtubules collapse the nucleus and drive infolding of the nuclear membrane. This results in DNA damage, a loss of genome organization, and broad transcriptional changes. The collapse in nuclear integrity is concomitant with compromised contractile function and may contribute to the pathophysiological changes observed in desmin-related myopathies. Conclusions: Disrupting the tethering of desmin to the nucleus results in a loss of nuclear homeostasis and rapid alterations to cardiomyocyte function. Our data suggest that a balance of forces imposed by intermediate filaments and microtubules is required to maintain nuclear structure and genome organization in the cardiomyocyte.

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