Abstract
Nitro-oleic acid (NO2-OA), pluripotent cell-signaling mediator, was recently described as a modulator of the signal transducer and activator of transcription 3 (STAT3) activity. In our study, we discovered new aspects of NO2-OA involvement in the regulation of stem cell pluripotency and differentiation. Murine embryonic stem cells (mESC) or mESC-derived embryoid bodies (EBs) were exposed to NO2-OA or oleic acid (OA) for selected time periods. Our results showed that NO2-OA but not OA caused the loss of pluripotency of mESC cultivated in leukemia inhibitory factor (LIF) rich medium via the decrease of pluripotency markers (NANOG, sex-determining region Y-box 1 transcription factor (SOX2), and octamer-binding transcription factor 4 (OCT4)). The effects of NO2-OA on mESC correlated with reduced phosphorylation of STAT3. Subsequent differentiation led to an increase of the ectodermal marker orthodenticle homolog 2 (Otx2). Similarly, treatment of mESC-derived EBs by NO2-OA resulted in the up-regulation of both neural markers Nestin and β-Tubulin class III (Tubb3). Interestingly, the expression of cardiac-specific genes and beating of EBs were significantly decreased. In conclusion, NO2-OA is able to modulate pluripotency of mESC via the regulation of STAT3 phosphorylation. Further, it attenuates cardiac differentiation on the one hand, and on the other hand, it directs mESC into neural fate.
Highlights
With regards to cardiomyocytes in vitro, beating embryoid bodies (EBs) are characterized by higher levels of phosphorylated signal transducer and activator of transcription 3 (STAT3) compared to non-beating EBs, and Stat3-/- mouse embryonic stem cells (mESC)-derived EBs resulted in lack of the expression of several cardiac-specific genes (e.g., alpha-actin, NK2 Homeobox 5 (Nkx2.5)) [10]
Gene expressions of all cardio-specific markers (myosin heavy chain 7 (Myh7), myosin light chain 7 (Myl7), and cardiac troponin T) as well as the percentage of beating EBs were significantly reduced after NO2 -oleic acid (OA) treatment at day 15 (Figure 4B–E)
We have described a previously unknown effect of NO2 -OA in the regulation of leukemia inhibitory factor (LIF)-associated pluripotency in mESC
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. There has been an increasing interest in deciphering the mechanisms responsible for the regulation of ESC pluripotency and differentiation, especially due to the possible use of stem cells in the therapy [13,14,15]. Many of these studies were focused on the direct or indirect regulation of STAT3 signaling pathway [9,10]. While the role of fatty acids in the regulation of stem cell pluripotency and differentiation was already studied [2,23], the effects of NO2 -FAs, especially NO2 -OA, in this process remain unclear
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