Abstract
IntroductionLoss 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.MethodsWe 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.ResultsOur 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.ConclusionsThese 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.
Highlights
Loss of adult stem cell function during aging contributes to impaired tissue regeneration
muscle-derived stem/progenitor cell (MDSPC) from accelerated aged mice show defect in prelamin A processing and stem cell marker expression To determine whether a defect in lamin A/C processing, previously reported in Zmpste24-deficient mice [7,10], affects our stem/progenitor cells, MDSPCs isolated from 8-week-old WT and Zmpste24-deficient mice were evaluated for expression and distribution of lamin A/C and prelamin A (Figure 1A)
An antibody specific to prelamin A and lamin A/C revealed accumulation of prelamin Aand an absence of lamin A expression in the Zmpste24-/MDSPCs in comparison with WT MDSPCs. These results confirm the lack of prelamin A processing in Zmpste24deficient MDSPCs, as previously reported in other cells isolated from these mutant mice [9,29]
Summary
Loss of adult stem cell function during aging contributes to impaired tissue regeneration. We tested the aging-related decline in regeneration potential of adult stem cells residing in the skeletal muscle. Hutchinson-Gilford progeria syndrome (HGPS) is an autosomal dominant disease that involves premature aging, causing early death in childhood due to stroke or myocardial infarction. A point mutation of the lamin A gene (LMNA), which encodes lamin A protein, was found to be the main cause of HGPS [2,3]. Lamin A is a nuclear envelope protein that gives structural support to the nucleus and is involved in various cellular roles, such as gene expression and DNA replication [4,5]. Murine models of HGPS have been created by altering posttranslational modification steps of lamin A [6,7,8]. Young and colleagues [6] developed Zmpste knockout mice with many features common to HGPS [6]
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