Reversing stem cell aging: Implications for vascular regeneration
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Organismal aging is associated with vascular dysfunction and the emergence of vascular diseases such as hypertension and atherosclerosis. Characteristics of the aged vasculature include vascular stiffness, dilatation of the lumen, intimal thickening, inflammation and cellular senescence. To a large extent vascular aging is attributed to Smooth Muscle Cells (SMC), which line the media of the blood vessels and their primary role is to regulate the vascular tone. However, during aging, SMC become dysfunctional, due to intracellular and extracellular changes that eventual lead to proliferation, hyper-contractility, vascular remodeling, senescence and apoptosis. In the current study we propose the use of Mesenchymal Stem Cells (MSC) as a cell source for vascular regeneration. MSC are highly proliferative and multipotent stem cells that can effectively differentiate into functional SMC. They also exhibit other important antiaging functions. They are immunosuppressive and can effectively deposit collagen and elastin. These properties make MSC as an ideal cell source for vascular regeneration. However, aging severely affects the properties of MSC. In the second chapter of the present thesis we evaluated the effect of cellular aging on the proliferative and differentiation capacity of human MSC. Our results clearly indicated that the MSC potential decreases with replicative senescence highlighting the importance of identifying strategies to rejuvenate the aged stem cells. To this end, on the third chapter we hypothesized that expression of a single pluripotent factor, NANOG, into aged stem cells is sufficient to reverse cellular aging. To address this intriguing hypothesis, we employed a tetracycline regulatable system through which we expressed NANOG on myogenic progenitors derived from two different senescent models: a) replicative or culture senescence and b) progeroid disease. Our results showed that NANOG reversed cellular aging and restored completely the ability to generate contractile force. To elicit its effects, NANOG enabled reactivation of the ROCK and TGF-beta pathways – both of which were impaired in senescent cells - leading to ACTIN polymerization, MRTF-A translocation into the nucleus and SRF-dependent myogenic gene expression. Collectively, our study provides a novel strategy to reverse the effects of aging on stem cell function which may have broad applications in vascular regeneration and anti-aging treatments.