Nanog Reverses the Effects of Organismal Aging on Mesenchymal Stem Cell Proliferation and Myogenic Differentiation Potential

Abstract

Although the therapeutic potential of mesenchymal stem cells (MSC) is widely accepted, loss of cell function due to donor aging or culture senescence are major limiting factors hampering their clinical application. Our laboratory recently showed that MSC originating from older donors suffer from limited proliferative capacity and significantly reduced myogenic differentiation potential. This is a major concern, as the patients most likely to suffer from cardiovascular disease are elderly. Here we tested the hypothesis that a single pluripotency associated transcription factor, namely Nanog, may reverse the proliferation and differentiation potential of BM-MSC from adult donors. Microarray analysis showed that adult (a)BM-MSC expressing Nanog clustered close to Nanog-expressing neonatal cells. Nanog markedly upregulated genes involved in cell cycle, DNA replication and DNA damage repair and enhanced the proliferation rate and clonogenic capacity of aBM-MSC. Notably, Nanog reversed the myogenic differentiation potential and restored the contractile function of aBM-MSC to a similar level as that of neonatal (n)BM-MSC. The effect of Nanog on contractility was mediated – at least in part - through activation of the TGF-β pathway by diffusible factors secreted in the conditioned medium of Nanog-expressing BM-MSC. Overall, our results suggest that Nanog may be used to overcome the effects of organismal aging on aBM-MSC, thereby increasing the potential of MSC from aged donors for cellular therapy and tissue regeneration.

Stromal-Cell-Derived Extracellular Matrix Promotes the Proliferation and Retains the Osteogenic Differentiation Capacity of Mesenchymal Stem Cells on Three-Dimensional Scaffolds

“…Interestingly, this is also supported by the expression of Nanog, which is a transcription factor that inhibits differentiation and maintains the pluripotent capacity of embryonic and adult stem cells. 46 Therefore, a significantly higher Nanog expression implies that at least some of the MSC population still retained their primitive properties when they were maintained on the ECM-Col/HA scaffold. Taken together, these in vitro data suggest that the ECM-Col/HA scaffold promoted the proliferation, while retaining primitive MSCs, similar to the in vivo situation.…”

Magnetofection Mediated Transient NANOG Overexpression Enhances Proliferation and Myogenic Differentiation of Human Hair Follicle Derived Mesenchymal Stem Cells

“…15,16 Whereas ectopic expression of NANOG enhanced proliferation of NIH-3T3 17,18 or bone marrow derived (BM)-MSCs, 19–21 the effects of NANOG on differentiation are unclear and context-dependent. Terminal differentiation of myogenic progenitors into muscle was not affected by NANOG expression but transdifferentiation into osteocytes was impaired.…”

Licensing of DNA replication, cancer, pluripotency and differentiation: An interlinked world?

“…Similarly, the G Model YSCDB-1531; No. of Pages 7 overexpression of Nanog, the other core ES cell pluripotency factor, was found to upregulate genes related to cell cycle control and DNA replication in mesenchymal stem cells, while also dedifferentiating them [72]. Along these lines, when analyzing the Sox2 interactome in ES cells, Gao et al [73] found that this factor is associated with the DNA replication machinery proteins Polb, Rpa1, Rpa2 and Rpa3.…”