NANOG Reverses the Myogenic Differentiation Potential of Senescent Stem Cells by Restoring ACTIN Filamentous Organization and SRF-Dependent Gene Expression

Mistriotis, Panagiotis; Bajpai, Vivek K.; Wang, Xiaoyan; Na, Rong; Shahini, Aref; Asmani, Mohammadnabi; Liang, Mao‐Shih; Wang, Jianmin; Lei, Pedro; Liu, Song; Zhao, Ruogang; Andreadis, Stelios T.

doi:10.1002/stem.2452

Cited by 32 publications

(40 citation statements)

References 63 publications

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“…Human dermal fibroblasts from patients suffering from HGPS (HGADFN167) and from a healthy donor (CNT, HGADFN168, father of HGADFN167) were obtained from the Progeria Research Foundation (Peabody, MA, USA). Early passage (EP) and late passage (LP) or senescent cells were characterized and defined based on their proliferation and differentiation potential as previously described by Mistriotis et al (18). In general, hHF-MSCs at passage 6-7 were defined as EP and passage 13-16 as LP cells.…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

“…All the media contained 1% (v/v) antibioticantimycotic (Thermo Fisher Scientific). Doxycycline (DOX)-regulated overexpression of NANOG or ZsGreen (control) in the aforementioned cells were previously described by Mistriotis et al (18). To evaluate the effect of NANOG on COL3A1 production, confluent cell monolayers in growth medium were first induced with 1 mg/ml DOX (Milli-poreSigma, Burlington, MA, USA) to overexpress NANOG or ZsGreen for 2 d, before coaxing the cells to differentiate in differentiation medium for 5 d in the continuous presence of DOX.…”

Section: Cell Lines and Cell Culturementioning

confidence: 99%

“…RNA sequencing (RNA-Seq) was performed with the Illumina platform to assess the global gene expression profile upon NANOG expression as previously described by Mistriotis et al (18). Genes that were differentially expressed by .1.5-fold and with an adjusted value of P , 0.05 were analyzed.…”

Section: Rna Sequencing Analysismentioning

confidence: 99%

“…Previous work from our laboratory revealed that the proliferation capacity and contractility of mesenchymal stem cell (MSC)-derived SMCs were greatly diminished with donor aging and culture senescence (17). 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).…”

mentioning

confidence: 99%

“…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: Cell Lines and Cell Culturementioning

confidence: 99%

Section: Cell Lines and Cell Culturementioning

confidence: 99%

Section: Rna Sequencing Analysismentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

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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Cell‐Free Vascular Grafts That Grow with the Host

Nasiri

Row

Smith

et al. 2020

Adv Funct Materials

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Cell-free small diameter vascular grafts, based on small intestinal submucosa functionalized with heparin and vascular endothelial growth factor (VEGF) are manufactured and implanted successfully into the arterial system of neonatal lambs, where they remain patent and grow in size with the host to a similar extent and with similar rate as native arteries. Acellular tissue engineered vessels (A-TEVs) integrate seamlessly into the native vasculature and develop confluent, functional endothelium that affords patency. The medial layer is infiltrated by smooth muscle cells, shows no signs of calcification, and develops contractile function. The vascular wall undergoes remarkable extracellular matrix remodeling exhibiting elastin fibers and even inner elastic lamina within six months. Taken together, the results suggest that VEGF-based A-TEVs may be suitable for treatment of congenital heart disorders to alleviate the need for repeated surgeries, which are currently standard practice.

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Downregulation of YAP Activity Restricts P53 Hyperactivation to Promote Cell Survival in Confinement

Hemmati,

Akinpelu,

Song

et al. 2023

Advanced Science

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Cell migration through confining three dimensional (3D) topographies can lead to loss of nuclear envelope integrity, DNA damage, and genomic instability. Despite these detrimental phenomena, cells transiently exposed to confinement do not usually die. Whether this is also true for cells subjected to long‐term confinement remains unclear at present. To investigate this, photopatterning and microfluidics are employed to fabricate a high‐throughput device that circumvents limitations of previous cell confinement models and enables prolonged culture of single cells in microchannels with physiologically relevant length scales. The results of this study show that continuous exposure to tight confinement can trigger frequent nuclear envelope rupture events, which in turn promote P53 activation and cell apoptosis. Migrating cells eventually adapt to confinement and evade cell death by downregulating YAP activity. Reduced YAP activity, which is the consequence of confinement‐induced YAP1/2 translocation to the cytoplasm, suppresses the incidence of nuclear envelope rupture and abolishes P53‐mediated cell death. Cumulatively, this work establishes advanced, high‐throughput biomimetic models for better understanding cell behavior in health and disease, and underscores the critical role of topographical cues and mechanotransduction pathways in the regulation of cell life and death.

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NANOG Reverses the Myogenic Differentiation Potential of Senescent Stem Cells by Restoring ACTIN Filamentous Organization and SRF-Dependent Gene Expression

Cited by 32 publications

References 63 publications

Restoring extracellular matrix synthesis in senescent stem cells

Restoring extracellular matrix synthesis in senescent stem cells

Cell‐Free Vascular Grafts That Grow with the Host

Downregulation of YAP Activity Restricts P53 Hyperactivation to Promote Cell Survival in Confinement

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