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Frontiers in Cell and Developmental... 2023Nuclei have characteristic shapes dependent on cell type, which are critical for proper cell function, and nuclei lose their distinct shapes in multiple diseases...
Nuclei have characteristic shapes dependent on cell type, which are critical for proper cell function, and nuclei lose their distinct shapes in multiple diseases including cancer, laminopathies, and progeria. Nuclear shapes result from deformations of the sub-nuclear components-nuclear lamina and chromatin. How these structures respond to cytoskeletal forces to form the nuclear shape remains unresolved. Although the mechanisms regulating nuclear shape in human tissues are not fully understood, it is known that different nuclear shapes arise from cumulative nuclear deformations post-mitosis, ranging from the rounded morphologies that develop immediately after mitosis to the various nuclear shapes that roughly correspond to cell shape ( elongated nuclei in elongated cells, flat nuclei in flat cells). We formulated a mathematical model to predict nuclear shapes of cells in various contexts under the geometric constraints of fixed cell volume, nuclear volume and lamina surface area. Nuclear shapes were predicted and compared to experiments for cells in various geometries, including isolated on a flat surface, on patterned rectangles and lines, within a monolayer, isolated in a well, or when the nucleus is impinging against a slender obstacle. The close agreement between predicted and experimental shapes demonstrates a simple geometric principle of nuclear shaping: the excess surface area of the nuclear lamina (relative to that of a sphere of the same volume) permits a wide range of highly deformed nuclear shapes under the constraints of constant surface area and constant volume. When the lamina is smooth (tensed), the nuclear shape can be predicted entirely from these geometric constraints alone for a given cell shape. This principle explains why flattened nuclear shapes in fully spread cells are insensitive to the magnitude of the cytoskeletal forces. Also, the surface tension in the nuclear lamina and nuclear pressure can be estimated from the predicted cell and nuclear shapes when the cell cortical tension is known, and the predictions are consistent with measured forces. These results show that excess surface area of the nuclear lamina is the key determinant of nuclear shapes. When the lamina is smooth (tensed), the nuclear shape can be determined purely by the geometric constraints of constant (but excess) nuclear surface area, nuclear volume, and cell volume, for a given cell adhesion footprint, independent of the magnitude of the cytoskeletal forces involved.
PubMed: 37397244
DOI: 10.3389/fcell.2023.1058727 -
Archives of Medical Research Jul 2023In humans, aging is characterized by a gradual decline of physical and psychological functions, with the concomitant onset of chronic-degenerative diseases, which... (Review)
Review
In humans, aging is characterized by a gradual decline of physical and psychological functions, with the concomitant onset of chronic-degenerative diseases, which ultimately lead to death. The study of Hutchinson-Gilford progeria syndrome (HGPS), a premature aging disorder that recapitulates several features of natural aging, has provided important insights into deciphering the aging process. The genetic origin of HGPS is a de novo point mutation in the LMNA gene that drives the synthesis of progerin, mutant version of lamin A. Progerin is aberrantly anchored to the nuclear envelope disrupting a plethora of molecular processes; nonetheless, how progerin exerts a cascade of deleterious alterations at the cellular and systemic levels is not fully understood. Over the past decade, the use of different cellular and animal models for HGPS has allowed the identification of the molecular mechanisms underlying HGPS, paving the way towards the development of therapeutic treatments against the disease. In this review, we present an updated overview of the biology of HGPS, including its clinical features, description of key cellular processes affected by progerin (nuclear morphology and function, nucleolar activity, mitochondrial function, protein nucleocytoplasmic trafficking and telomere homeostasis), as well as discussion of the therapeutic strategies under development.
Topics: Animals; Humans; Progeria; Aging; Mitochondria
PubMed: 37390702
DOI: 10.1016/j.arcmed.2023.06.002 -
Aging Cell Sep 2023Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most individuals with HGPS harbor a de novo...
Hutchinson-Gilford progeria syndrome (HGPS) is a premature aging disorder affecting tissues of mesenchymal origin. Most individuals with HGPS harbor a de novo c.1824C > T (p.G608G) mutation in the gene encoding lamin A (LMNA), which activates a cryptic splice donor site resulting in production of the toxic "progerin" protein. Clinical manifestations include growth deficiency, lipodystrophy, sclerotic dermis, cardiovascular defects, and bone dysplasia. Here we utilized the Lmna knock-in (KI) mouse model of HGPS to further define mechanisms of bone loss associated with normal and premature aging disorders. Newborn skeletal staining of KI mice revealed altered rib cage shape and spinal curvature, and delayed calvarial mineralization with increased craniofacial and mandibular cartilage content. MicroCT analysis and mechanical testing of adult femurs indicated increased fragility associated with reduced bone mass, recapitulating the progressive bone deterioration that occurs in HGPS patients. We investigated mechanisms of bone loss in KI mice at the cellular level in bone cell populations. Formation of wild-type and KI osteoclasts from marrow-derived precursors was inhibited by KI osteoblast-conditioned media in vitro, suggesting a secreted factor(s) responsible for decreased osteoclasts on KI trabecular surfaces in vivo. Cultured KI osteoblasts exhibited abnormal differentiation characterized by reduced deposition and mineralization of extracellular matrix with increased lipid accumulation compared to wild-type, providing a mechanism for altered bone formation. Furthermore, quantitative analyses of KI transcripts confirmed upregulation of adipogenic genes both in vitro and in vivo. Thus, osteoblast phenotypic plasticity, inflammation and altered cellular cross-talk contribute to abnormal bone formation in HGPS mice.
Topics: Mice; Animals; Progeria; Aging, Premature; Mutation; Lamin Type A; Cell Differentiation; Bone Diseases, Developmental
PubMed: 37365004
DOI: 10.1111/acel.13903 -
Aging Jun 2023Hutchinson-Gilford progeria syndrome (HGPS) is a rare human disease characterised by accelerated biological ageing. Current treatments are limited, and most patients die...
Hutchinson-Gilford progeria syndrome (HGPS) is a rare human disease characterised by accelerated biological ageing. Current treatments are limited, and most patients die before 15 years of age. Hydrogen sulfide (HS) is an important gaseous signalling molecule that it central to multiple cellular homeostasis mechanisms. Dysregulation of tissue HS levels is thought to contribute to an ageing phenotype in many tissues across animal models. Whether HS is altered in HGPS is unknown. We investigated hepatic HS production capacity and transcript, protein and enzymatic activity of proteins that regulate hepatic HS production and disposal in a mouse model of HGPS (G609G mice, mutated Lmna gene equivalent to a causative mutation in HGPS patients). G609G mice were maintained on either regular chow (RC) or high fat diet (HFD), as HFD has been previously shown to significantly extend lifespan of G609G mice, and compared to wild type (WT) mice maintained on RC. RC fed G609G mice had significantly reduced hepatic HS production capacity relative to WT mice, with a compensatory elevation in mRNA transcripts associated with several HS production enzymes, including cystathionine-γ-lyase (CSE). HS levels and CSE protein were partially rescued in HFD fed G609G mice. As current treatments for patients with HGPS have failed to confer significant improvements to symptoms or longevity, the need for novel therapeutic targets is acute and the regulation of HS through dietary or pharmacological means may be a promising new avenue for research.
Topics: Humans; Mice; Animals; Progeria; Hydrogen Sulfide; Disease Models, Animal; Aging; Longevity; Lamin Type A
PubMed: 37354210
DOI: 10.18632/aging.204835 -
Skin Appendage Disorders Jun 2023Onychodystrophy has been described in association with certain bone disorders, including Nail-Patella Syndrome, Hutchinson-Gilford Progeria Syndrome, Coffin-Siris...
INTRODUCTION
Onychodystrophy has been described in association with certain bone disorders, including Nail-Patella Syndrome, Hutchinson-Gilford Progeria Syndrome, Coffin-Siris Syndrome, and congenital brachydactyly. However, nail changes associated with multiple epiphyseal dysplasia (MED) has not been documented.
CASE PRESENTATION
An 11-year-old male with history of MED presented with thickened, dystrophic appearing fingernails. Physical examination was significant for fingernail longitudinal ridges and grooves, thinning, and distal splitting. Dermoscopy revealed superficial desquamation. Nail clippings were negative for microbial pathogens. Hand X-rays showed brachydactyly, shortening of the metacarpals, and sclerotic epiphyses of the bilateral 5th distal phalanges and right 2nd distal phalanx.
CONCLUSION
This is the first documented case of MED with onychodystrophy, supporting the link between phalangeal formation and nail development. It is important to perform a careful examination of the nail units in patients with skeletal dysplasia and screen patients with characteristic and unexplained nail changes for bony changes. Living with skeletal disease is extremely challenging, and treatment of associated nail disease can improve quality of life for these patients.
PubMed: 37325279
DOI: 10.1159/000528474 -
Indian Journal of Anaesthesia Apr 2023
PubMed: 37303874
DOI: 10.4103/ija.ija_1055_21 -
Annual Review of Biomedical Engineering Jun 2023The process of aging manifests from a highly interconnected network of biological cascades resulting in the degradation and breakdown of every living organism over time.... (Review)
Review
The process of aging manifests from a highly interconnected network of biological cascades resulting in the degradation and breakdown of every living organism over time. This natural development increases risk for numerous diseases and can be debilitating. Academic and industrial investigators have long sought to impede, or potentially reverse, aging in the hopes of alleviating clinical burden, restoring functionality, and promoting longevity. Despite widespread investigation, identifying impactful therapeutics has been hindered by narrow experimental validation and the lack of rigorous study design. In this review, we explore the current understanding of the biological mechanisms of aging and how this understanding both informs and limits interpreting data from experimental models based on these mechanisms. We also discuss select therapeutic strategies that have yielded promising data in these model systems with potential clinical translation. Lastly, we propose a unifying approach needed to rigorously vet current and future therapeutics and guide evaluation toward efficacious therapies.
Topics: Humans; Aging; Longevity; Models, Biological; Models, Theoretical; Rejuvenation
PubMed: 37289554
DOI: 10.1146/annurev-bioeng-120122-123054 -
Free Neuropathology Jan 2022In this update we present a series of papers focused on topics that have emerged in vascular disease over the prior year. The first two papers focus on the pathogenesis...
In this update we present a series of papers focused on topics that have emerged in vascular disease over the prior year. The first two papers focus on the pathogenesis of vascular malformations, the first on brain arteriovenous malformations, and the second on cerebral cavernous malformations. These disorders can lead to significant brain injuries from intracerebral hemorrhage (if they rupture) or other neurological complications, including seizures. The next set of papers reflects work that has advanced our understanding of how the brain and the immune system "communicate" after brain injury, including stroke (papers 3-6). The first of these shows that T cells are involved in white matter repair after ischemic injury, an effect dependent on microglia, demonstrating the important cross-talk between innate and adaptive immunity. The next two papers focus on B cells, which have been relatively understudied in the context of brain injury. The contribution of antigen-experienced B cells from the meninges and skull bone marrow, rather than blood-derived B cells in neuroinflammation opens up a very novel area of investigation. The possibility that antibody secreting B cells may contribute to vascular dementia will certainly be an active area for future investigations. Similarly, in paper 6, investigators found that CNS-infiltrating myeloid cells can originate from brain borders tissues. These cells have unique transcriptional signatures that are distinct from their blood-derived counterparts, and likely contribute to myeloid cell infiltration from bone-marrow niches in close proximity to the brain. The contribution of microglia, the primary innate immune cell of the brain, to amyloid deposition and propagation is then discussed, followed by work on how perivascular Aβ is potentially cleared along the cerebral vessels in patients with cerebral amyloid angiopathy. The final two papers focus on the contribution of senescent endothelial cells and pericytes. The first used a model of accelerated senescence (Hutchinson-Gilford progeria syndrome; HGPS) and shows the translational potential of an approach to reduce telomere shortening to slow aging. The final paper demonstrates how capillary pericytes contribute to basal blood flow resistance and slow modulation of blood flow throughout the brain. Interestingly, several of the papers identified therapeutic strategies that could be potentially translated into clinical populations.
PubMed: 37284161
DOI: 10.17879/freeneuropathology-2022-3910 -
Calcified Tissue International Jul 2023Senescence is a complex cell state characterized by stable cell cycle arrest and a unique secretory pattern known as the senescence-associated secretory phenotype... (Review)
Review
Senescence is a complex cell state characterized by stable cell cycle arrest and a unique secretory pattern known as the senescence-associated secretory phenotype (SASP). The SASP factors, which are heterogeneous and tissue specific, normally include chemokines, cytokines, growth factors, adhesion molecules, and lipid components that can lead to multiple age-associated disorders by eliciting local and systemic consequences. The skeleton is a highly dynamic organ that changes constantly in shape and composition. Senescent cells in bone and bone marrow produce diverse SASP factors that induce alterations of the skeleton through paracrine effects. Herein, we refer to bone cell-associated SASP as "bone-SASP." In this review, we describe current knowledge of cellular senescence and SASP, focusing on the role of senescent cells in mediating bone pathologies during natural aging and premature aging syndromes. We also summarize the role of cellular senescence and the bone-SASP in glucocorticoids-induced bone damage. In addition, we discuss the role of bone-SASP in the development of osteoarthritis, highlighting the mechanisms by which bone-SASP drives subchondral bone changes in metabolic syndrome-associated osteoarthritis.
Topics: Cellular Senescence; Bone and Bones; Osteocytes; Cytokines; Phenotype
PubMed: 37256358
DOI: 10.1007/s00223-023-01100-4 -
GeroScience Feb 2024Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease caused by expression of progerin, a lamin A variant that is also expressed at low levels...
Hutchinson-Gilford progeria syndrome (HGPS) is an extremely rare genetic disease caused by expression of progerin, a lamin A variant that is also expressed at low levels in non-HGPS individuals. Although HGPS patients die predominantly from myocardial infarction and stroke, the mechanisms that provoke pathological alterations in the coronary and cerebral arteries in HGPS remain ill defined. Here, we assessed vascular function in the coronary arteries (CorAs) and carotid arteries (CarAs) of progerin-expressing Lmna mice (G609G), both in resting conditions and after hypoxic stimulus. Wire myography, pharmacological screening, and gene expression studies demonstrated vascular atony and stenosis, as well as other functional alterations in progeroid CorAs and CarAs and aorta. These defects were associated with loss of vascular smooth muscle cells and overexpression of the K7 family of voltage-dependent potassium channels. Compared with wild-type controls, G609G mice showed reduced median survival upon chronic isoproterenol exposure, a baseline state of chronic cardiac hypoxia characterized by overexpression of hypoxia-inducible factor 1α and 3α genes, and increased cardiac vascularization. Our results shed light on the mechanisms underlying progerin-induced coronary and carotid artery disease and identify K7 channels as a candidate target for the treatment of HGPS.
Topics: Humans; Mice; Animals; Progeria; Carotid Arteries; Hypoxia
PubMed: 37233881
DOI: 10.1007/s11357-023-00808-3