NANOG Restores Contractility of Mesenchymal Stem Cell-Based Senescent Microtissues

Shahini, Aref; Mistriotis, Panagiotis; Asmani, Mohammadnabi; Zhao, Ruogang; Andreadis, Stelios T.

doi:10.1089/ten.tea.2016.0494

Cited by 22 publications

(15 citation statements)

References 53 publications

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“…We have previously demonstrated that the pluripotent factor NANOG was sufficient to reverse cellular aging and to completely restore the diminished differentiation capacity of aged MSCs and the contractile function of MSC-derived SMCs (1,2,18,19). Here, we report that NANOG also restored the effects of aging on collagen production in both senescent MSCs and HGPS-derived myofibroblasts as shown in traditional cultures and 3-dimensional vascular tissue mimetics.…”

Section: Discussionsupporting

confidence: 55%

“…We also discovered that ectopic expression of the pluripotent factor NANOG (Nanog homeobox) was sufficient to reverse cellular aging and restore the diminished contractile capacity of aged myogenic progenitors using 3 different models of aging: 1) organismal aging; 2) replicative senescence; and 3) Hutchinson-Gilford progeria syndrome (HGPS) or premature aging (18). In addition, we reported that NANOG restored ACTIN polymerization, and induced myocardinrelated transcription factor A (MRTF-A) translocation to the nucleus and serum response factor (SRF)-dependent myogenic gene expression (18), ultimately restoring the force generation ability of senescent MSCs and HGPS cells (19). Here we report that NANOG also reversed the impaired production of COL3 in senescent MSCs and HGPS cells by reactivating the impaired TGF-b1 pathway through transcriptional control of several genes, including mothers against decapentaplegic (SMAD)2 and SMAD3.…”

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confidence: 99%

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Restoring extracellular matrix synthesis in senescent stem cells

Mistriotis

Wang

et al. 2019

FASEB j.

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Collagen type III (COL3) is one of the 3 major collagens in the body, and loss of expression or mutations in the COL3 gene have been associated with the onset of vascular diseases such the Ehlers‐Danlos syndrome. Previous work reported a significant reduction of COL3 in tissues such as skin and vessels with aging. In agreement, we found that COL3 was significantly reduced in senescent human mesenchymal stem cells and myofibroblasts derived from patients with Hutchinson‐Gilford progeria syndrome, a premature aging syndrome. Most notably, we discovered that ectopic expression of the embryonic transcription factor Nanog homeobox (NANOG) restored COL3 expression by restoring the activity of the TGF‐β pathway that was impaired in senescent cells. RNA sequencing analysis showed that genes associated with the activation of the TGF‐β pathway were up‐regulated, whereas negative regulators of the pathway were down‐regulated upon NANOG expression. Chromatin immunoprecipitation sequencing and immunoprecipitation experiments revealed that NANOG bound to the mothers against decapentaplegic (SMAD)2 and SMAD3 promoters, in agreement with increased expression and phosphorylation levels of both proteins. Using chemical inhibition, short hairpin RNA knockdown, and gain of function approaches, we established that both SMAD2 and SMAD3 were necessary to mediate the effects of NANOG, but SMAD3 overexpression was also sufficient for COL3 production. In summary, NANOG restored production of COL3, which was impaired by cellular aging, suggesting novel strategies to restore the impaired extracellular matrix production and biomechanical function of aged tissues, with potential implications for regenerative medicine and anti‐aging treatments.—Rong, N., Mistriotis, P., Wang, X., Tseropoulos, G., Rajabian, N., Zhang, Y., Wang, J., Liu, S., Andreadis, S. T. Restoring extracellular matrix synthesis in senescent stem cells. FASEB J. 33, 10954–10965 (2019). http://www.fasebj.org

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Section: Discussionsupporting

confidence: 55%

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confidence: 99%

Restoring extracellular matrix synthesis in senescent stem cells

Mistriotis

Wang

et al. 2019

FASEB j.

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“…Administration of rapamycin, an inhibitor of the mTOR signaling pathway, raised the expression level of NANOG, postponed replicative arrest, and enhanced the lifespan increment of BM-MSCs[ 116 ]. NANOG, an embryonic transcription factor, is a pluripotency marker that facilitates myogenic differentiation and restores the contractile function of senescent MSCs[ 117 ]. Additionally, a high number of potential regulators involved in senescent MSC rejuvenation have been screened and investigated in vitro .…”

Section: Cellular Rejuvenation Strategiesmentioning

confidence: 99%

Senescent mesenchymal stem/stromal cells and restoring their cellular functions

Meng¹,

Liu²,

Lu³

et al. 2020

WJSC

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Mesenchymal stem/stromal cells (MSCs) have various properties that make them promising candidates for stem cell-based therapies in clinical settings. These include self-renewal, multilineage differentiation, and immunoregulation. However, recent studies have confirmed that aging is a vital factor that limits their function and therapeutic properties as standardized clinical products. Understanding the features of senescence and exploration of cell rejuvenation methods are necessary to develop effective strategies that can overcome the shortage and instability of MSCs. This review will summarize the current knowledge on characteristics and functional changes of aged MSCs. Additionally, it will highlight cell rejuvenation strategies such as molecular regulation, non-coding RNA modifications, and microenvironment controls that may enhance the therapeutic potential of MSCs in clinical settings.

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“…In particular, the pluripotency factor NANOG is essential for maintaining the self-renewal of ESCs over many population doublings (19). Although overexpression of NANOG does not confer pluripotency to somatic cells, it has been shown to restore several cellular functions that are compromised by aging including proliferation and differentiation of senescent fibroblasts and mesenchymal stem cells (20)(21)(22). In vivo endogenous expression of this transcription factor in stratified epithelia of adult mice showed that systemic overexpression of NANOG induces hyperplasia without initiating tumors (23)(24)(25)(26).…”

Section: Introductionmentioning

confidence: 99%

Ameliorating the hallmarks of cellular senescence in skeletal muscle myogenic progenitors in vitro and in vivo

et al. 2021

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Senescence of myogenic progenitors impedes skeletal muscle regeneration. Here, we show that overexpression of the transcription factor NANOG in senescent myoblasts can overcome the effects of cellular senescence and confer a youthful phenotype to senescent cells. NANOG ameliorated primary hallmarks of cellular senescence including genomic instability, loss of proteostasis, and mitochondrial dysfunction. The rejuvenating effects of NANOG included restoration of DNA damage response via up-regulation of DNA repair proteins, recovery of heterochromatin marks via up-regulation of histones, and reactivation of autophagy and mitochondrial energetics via up-regulation of AMP-activated protein kinase (AMPK). Expression of NANOG in the skeletal muscle of a mouse model of premature aging restored the number of myogenic progenitors and induced formation of eMyHC + myofibers. This work demonstrates the feasibility of reversing the effects of cellular senescence in vitro and in vivo, with no need for reprogramming to the pluripotent state.

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NANOG Restores Contractility of Mesenchymal Stem Cell-Based Senescent Microtissues

Cited by 22 publications

References 53 publications

Restoring extracellular matrix synthesis in senescent stem cells

Restoring extracellular matrix synthesis in senescent stem cells

Senescent mesenchymal stem/stromal cells and restoring their cellular functions

Ameliorating the hallmarks of cellular senescence in skeletal muscle myogenic progenitors in vitro and in vivo

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