Generation of induced pluripotent stem cell lines from 3 distinct laminopathies bearing heterogeneous mutations in lamin A/C

Ho, Joseph; Zhou, Ting; Lai, Wing‐Hon; Huang, Yinghua; Chan, Yau-Chi; Li, Xingyan; Wong, Ngai Sze; Li, Yanhua; Au, Ka-Wing; Guo, Dongsheng; Xu, Jianyong; Siu, Chung‐Wah; Pei, Duanqing; Tse, Hung‐Fat; Esteban, Miguel A.

doi:10.18632/aging.100277

Cited by 77 publications

(67 citation statements)

References 38 publications

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“…iPSC are used for in vitro development and testing of new therapeutic agents and regimens [457], for high-throughput drug screening [458,459] and imaging in industrial platforms [460]. iPSC have been derived from HGPS [461] and Werner syndrome cells [462]. Adenoviral vectors can be used to provide large genomic regions that correct LMNA mutations in HGPS iPSC and their derived mesenchymal stem cells [463].…”

Section: Induced Pluripotent Stem Cells (Ipsc)mentioning

confidence: 99%

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Cau

Navarro

Harhouri

et al. 2014

Seminars in Cell & Developmental Biology

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Lamin A-related progeroid syndromes are genetically determined, extremely rare and severe. In the past ten years, our knowledge and perspectives for these diseases has widely progressed, through the progressive dissection of their pathophysiological mechanisms leading to precocious and accelerated aging, from the genes mutations discovery until therapeutic trials in affected children. A-type lamins are major actors in several structural and functional activities at the nuclear periphery, as they are major components of the nuclear lamina. However, while this is usually poorly considered, they also play a key role within the rest of the nucleoplasm, whose defects are related to cell senescence. Although nuclear shape and nuclear envelope deformities are obvious and visible events, nuclear matrix disorganization and abnormal composition certainly represent the most important causes of cell defects with dramatic pathological consequences. Therefore, lamin-associated diseases should be better referred as laminopathies instead of envelopathies, this later being too restrictive, considering neither the key structural and functional roles of soluble lamins in the entire nucleoplasm, nor the nuclear matrix contribution to the pathophysiology of lamin-associated disorders and in particular in defective lamin A processing-associated aging diseases. Based on both our understanding of pathophysiological mechanisms and the biological and clinical consequences of progeria and related diseases, therapeutic trials have been conducted in patients and were terminated less than 10 years after the gene discovery, a quite fast issue for a genetic disease. Pharmacological drugs have been repurposed and used to decrease the toxicity of the accumulated, unprocessed and truncated prelaminA in progeria. To date, none of them may be considered as a cure for progeria and these clinical strategies were essentially designed toward reducing a subset of the most dramatic and morbid features associated to progeria. New therapeutic strategies under study, in particular targeting the protein expression pathway at the mRNA level, have shown a remarkable efficacy both in vitro in cells and in vivo in mice models. Strategies intending to clear the toxic accumulated proteins from the nucleus are also under evaluation. However, although exceedingly rare, improving our knowledge of genetic progeroid syndromes and searching for innovative and efficient therapies in these syndromes is of paramount importance as, even before they can be used to save lives, they may significantly (i) expand the affected childrens' lifespan and preserve their quality of life; (ii) improve our understanding of aging-related disorders and other more common diseases; and (iii) expand our fundamental knowledge of physiological aging and its links with major physiological processes such as those involved in oncogenesis.

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Section: Induced Pluripotent Stem Cells (Ipsc)mentioning

confidence: 99%

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Cau

Navarro

Harhouri

et al. 2014

Seminars in Cell & Developmental Biology

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“…Progerin-induced DNA damage signaling is localized to telomeres and induces dysfunction of telomeres, indicative of an accelerated aging phenotype in HGPS cells [62]. Reprogramming of HGPS skin fibroblasts to iPSC has been reported by different groups [63][64][65]. The derived HGPSiPSCs demonstrate absence of progerin expression, normal nuclear structure, and epigenetic markers.…”

Section: Cellular Senescence Accelerated Aging and Reprogrammingmentioning

confidence: 99%

Apoptosis: Reprogramming and the Fate of Mature Cells

2012

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Apoptosis is essential for embryogenesis, organ metamorphosis, and tissue homeostasis. In embryonic stem cells, self-renewal is balanced with proliferative potential, inhibition of differentiation, and prevention of senescence and apoptosis. Growing evidence supports the role of apoptosis in self-renewal, differentiation of pluripotent stem cells, and dedifferentiation (reprogramming) of somatic cells. In this paper we discuss the multiple roles of apoptosis in embryonic stem cells (ESCs) and reprogramming of differentiated cells to pluripotency. The role of caspases and p53 as key effectors in controlling the generation of iPSC is emphasized. Remarkably, the complication of apoptosis arising during reprogramming may provide insights into technical improvements for derivation of iPSC from senescent cells as a tool for modeling aging-related diseases.

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“…Inhibition of beta-catenin signaling leading to proliferative arrest also occurs in postnatal fibroblasts of progeroid mice that express a farnesylated, truncated prelamin A (Hernández et al 2010). Induced pluripotent stem cells derived from dermal fibroblasts of subjects with HGPS express little to no A-type lamins, including progerin, but differentiation into various lineages leads to their re-expression (Ho et al 2011: Liu et al 2011: Zhang et al 2011. Differentiation further leads to abnormal cellular phenotypes with differentiated vascular smooth muscle cells in particular showing premature senescence, DNA damage, and abnormal phenotypes consistent with vascular aging, particular when subjected to hypoxia or stress (Liu et al 2011;Zhang et al 2011).…”

Section: Pathogenic Mechanismsmentioning

confidence: 99%

Inner nuclear membrane proteins: impact on human disease

Méndez-López

Worman

2012

Chromosoma

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In the past decade, the inner nuclear membrane has become a focus of research on inherited diseases. A heterogeneous group of genetic disorders known as laminopathies have been described that result from mutations in genes encoding nuclear lamins, intermediate filament proteins associated with the inner nuclear membrane. Mutations in genes encoding integral inner nuclear membrane proteins, many of which bind to nuclear lamins, also cause diseases that sometimes are very similar to those caused by lamin gene mutations. The pathogenic mechanisms that underlie these diseases, which often selectively affect different tissues or organ systems despite the near-ubiquitous expression of the proteins, are only beginning to be elucidated. The unfolding story of the laminopathies provides a remarkable example of how research in basic cell biology has impacted upon medicine and human health.

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Generation of induced pluripotent stem cell lines from 3 distinct laminopathies bearing heterogeneous mutations in lamin A/C

Cited by 77 publications

References 38 publications

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Nuclear matrix, nuclear envelope and premature aging syndromes in a translational research perspective

Apoptosis: Reprogramming and the Fate of Mature Cells

Inner nuclear membrane proteins: impact on human disease

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