Varga, R. et al. Progressive vascular smooth muscle cell defects in a mouse model of Hutchinson-Gilford progeria syndrome. Proc. Natl Acad. Sci. USA 103, 3250-3255

Genome Technology Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892, USA.
Proceedings of the National Academy of Sciences (Impact Factor: 9.67). 03/2006; 103(9):3250-5. DOI: 10.1073/pnas.0600012103
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Children with Hutchinson-Gilford progeria syndrome (HGPS) suffer from dramatic acceleration of some symptoms associated with normal aging, most notably cardiovascular disease that eventually leads to death from myocardial infarction and/or stroke usually in their second decade of life. For the vast majority of cases, a de novo point mutation in the lamin A (LMNA) gene is the cause of HGPS. This missense mutation creates a cryptic splice donor site that produces a mutant lamin A protein, termed "progerin," which carries a 50-aa deletion near its C terminus. We have created a mouse model for progeria by generating transgenics carrying a human bacterial artificial chromosome that harbors the common HGPS mutation. These mice develop progressive loss of vascular smooth muscle cells in the medial layer of large arteries, in a pattern very similar to that seen in children with HGPS. This mouse model should prove valuable for testing experimental therapies for this devastating disorder and for exploring cardiovascular disease in general.

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    • "These tet-ON or tet-OFF expression systems allow for the control of target gene expression in a specific tissue at different time points and are reversible [11], [12]. Several mouse models have been developed to study the underlying causes of HGPS [10], and two animal models are currently available to study the cardiovascular pathology of HGPS [8], [13]; however, none of these models is inducible or tissue-specific. Our goal was to induce the pathology of HGPS in arteries by developing an inducible, tissue-specific expression system based on the tet-ON system [11], under the control of the vascular smooth muscle cell specific promoter (sm22α) that is expressed during mouse embryogenesis (from embryonic day 9.5) and continuously active in postnatal vascular smooth muscle cells [14]–[15]. "
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    ABSTRACT: Hutchinson-Gilford progeria syndrome (HGPS) is a genetic disease with multiple features that are suggestive of premature aging. Most patients with HGPS carry a mutation on one of their copies of the LMNA gene. The LMNA gene encodes the lamin A and lamin C proteins, which are the major proteins of the nuclear lamina. The organs of the cardiovascular system are amongst those that are most severely affected in HGPS, undergoing a progressive depletion of vascular smooth muscle cells, and most children with HGPS die in their early teens from cardio-vascular disease and other complications from atherosclerosis. In this study, we developed a transgenic mouse model based on the tet-ON system to increase the understanding of the molecular mechanisms leading to the most lethal aspect of HGPS. To induce the expression of the most common HGPS mutation, LMNA c.1824C>T; p.G608G, in the vascular smooth muscle cells of the aortic arch and thoracic aorta, we used the previously described reverse tetracycline-controlled transactivator, sm22α-rtTA. However, the expression of the reverse sm22α-transactivator was barely detectable in the arteries, and this low level of expression was not sufficient to induce the expression of the target human lamin A minigene. The results from this study are important because they suggest caution during the use of previously functional transgenic animal models and emphasize the importance of assessing transgene expression over time.
    PLoS ONE 08/2014; 9(8):e104098. DOI:10.1371/journal.pone.0104098 · 3.23 Impact Factor
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    • "A mouse model of HGPS was generated using a bacterial artificial chromosome (BAC) in the laboratory of Dr. Francis S. Collins [8]. In brief, the BAC was engineered to carry the single nucleotide mutation at G608G of the human lamin A gene coding for the dysfunctional protein, progerin, which is responsible for the progeria syndrome in children [8]. All mice were genotyped using primers 5′-GTGTCTGGGTGCCCTACTCTGGTAAGGA-3′ and 5′-GTAGGGCAGCAGGCATGCACTATTA-3′. "
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    ABSTRACT: A mouse model of progeria derived by insertion of the human mutant LMNA gene (mLMNA), producing mutant lamin A, shows loss of smooth muscle cells in the media of the ascending aorta. We hypothesized that high shear stress, in the presence of mutant lamin A, induces this vasculopathy and tried to define the molecular and cellular basis for aortic vasculopathy. Ascending and descending aorta from wild type (WT) and mLMNA+ mice were compared using proteomics, western blots, PCR and immunostaining. To determine whether high fluidic shear stress, known to occur in the ascending aorta, contributed to the vasculopathy, we exposed descending aortas of mLMNA+ mice, with no apparent vasculopathy, to 75 dynes/cm2 shear stress for 30-minutes using a microfluidic system. At one year of life, expression of several mechanotransduction proteins in ascending aorta, including vimentin, decreased in mLMNA+ mice but no decrease occurred in the descending aorta. High fluidic shear stress produced a significant reduction in vimentin of mLMNA+ mice but not in similarly treated WT mice. The occurrence of mutant lamin A and high shear stress correlate with a reduction in the level of mechanotransduction proteins in smooth muscle cells of the media. Reduction of these proteins may contribute over time to development of the vasculopathy in the ascending aorta in progeria syndrome.
    Stem Cell Research & Therapy 03/2014; 5(2):41. DOI:10.1186/scrt429 · 3.37 Impact Factor
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    • "Numerous studies have reported that mutation of lamin A, a major component of the nuclear envelope, has an adverse effect on skeletal muscle function and myoblast differentiation [7,9,11-14,34]; however, no studies examined earlier muscle stem/progenitor cells residing in muscle tissue. Because degenerative changes associated with progeroid syndromes may have a strong impact on stem cells, we hypothesized that the dysfunction of muscle stems cells in Zmpste24-/- progeroid mice may contribute to the loss of the cells' ability to regenerate skeletal muscle. "
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    ABSTRACT: Introduction Loss of adult stem cell function during aging contributes to impaired tissue regeneration. Here, we tested the aging-related decline in regeneration potential of adult stem cells residing in the skeletal muscle. Methods We isolated muscle-derived stem/progenitor cells (MDSPCs) from progeroid Zmpste24-deficient mice (Zmpste24-/-) with accelerated aging phenotypes to investigate whether mutation in lamin A has an adverse effect on muscle stem/progenitor cell function. Results Our results indicate that MDSPCs isolated from Zmpste24-/- mice show reduced proliferation and myogenic differentiation. In addition, Zmpste24-/- MDSPCs showed impaired muscle regeneration, with a limited engraftment potential when transplanted into dystrophic muscle, compared with wild-type (WT) MDSPCs. Exposure of progeroid Zmpste24-/- MDSPCs to WT MDSPCs rescued the myogenic differentiation defect in vitro. Conclusions These results demonstrate that adult stem/progenitor cell dysfunction contributes to impairment of tissue regeneration and suggest that factors secreted by functional cells are indeed important for the therapeutic effect of adult stem cells.
    Stem Cell Research & Therapy 03/2013; 4(2):33. DOI:10.1186/scrt183 · 3.37 Impact Factor
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