Inhibition of Nuclear Nox4 Activity by Plumbagin: Effect on Proliferative Capacity in Human Amniotic Stem Cells

Abstract

Human amniotic fluid stem cells (AFSC) with multilineage differentiation potential are novel source for cell therapy. However, in vitro expansion leads to senescence affecting differentiation and proliferative capacities. Reactive oxygen species (ROS) have been involved in the regulation of stem cell pluripotency, proliferation, and differentiation. Redox-regulated signal transduction is coordinated by spatially controlled production of ROS within subcellular compartments. NAD(P)H oxidase family, in particular Nox4, has been known to produce ROS in the nucleus; however, the mechanisms and the meaning of this function remain largely unknown. In the present study, we show that Nox4 nuclear expression (nNox4) increases during culture passages up to cell cycle arrest and the serum starvation causes the same effect. With the decrease of Nox4 activity, obtained with plumbagin, a decline of nuclear ROS production and of DNA damage occurs. Moreover, plumbagin exposure reduces the binding between nNox4 and nucleoskeleton components, as Matrin 3. The same effect was observed also for the binding with phospho-ERK, although nuclear ERK and P-ERK are unchanged. Taken together, we suggest that nNox4 regulation may have important pathophysiologic effects in stem cell proliferation through modulation of nuclear signaling and DNA damage.

Development of a novel method for amniotic fluid stem cell storage

“…3A), that is a critical point to be investigated one by one, in order to find a correlation between the hAFSCs profile and the physio-pathological feature of the donor. We purpose that an intrinsic ROS homeostasis, depending on specific ROS sources, is an important modulator in stem cell power, independently on the age and the oxygen tension present during cultivation in vitro [3,27].…”

Nox2 and Nox4 regulate self-renewal of murine induced-pluripotent stem cells

“…One of the primary cellular mechanisms of ROS production involves the oxidation of nicotinamide adenine dinucleotide phosphate (NADPH) by NADPH oxidase (Nox) . Of the several Nox homologs expressed in stem cells, Nox2 and Nox4 are the most abundant ( ) , and the ROS produced by Nox2/Nox4 have been linked to many aspects of stem cell biology, including the proliferation of neural stem cells , stemness and proliferation in amniotic‐fluid stem cells , the mobilization of bone‐marrow progenitor cells in response to ischemic injury, chondrogenic , and neural‐stem cell differentiation , and the differentiation of cardiac precursor cells into smooth‐muscle cells and cardiomyocytes . Nox‐mediated ROS production also regulates migration and gene expression in stem cells , but the role of Nox2 and Nox4 in stem cell self‐renewal has yet to be thoroughly studied.…”

Response Proliferative Capacity of Undifferentiated Stem Cells of Obtained Human Adult Dental Follicle

“…The accumulation of ROS is common in senescent cells. ROS have been related to the regulation of stem cell pluripotency, proliferation, and differentiation, besides being a critical factor which regulates the quiescent state of MSC [42]- [45]. The results obtained in this study showed that MDA levels obtained during the growth of stem cells from dental follicle of third molars had a significant increase between the 6th and 12th day of culture, accompanied by a high rate of cell growth.…”