Mitochondria‐targeted antioxidant mito‐TEMPO alleviate oxidative stress induced by antimycin A in human mesenchymal stem cells

Abstract

The cell therapy of damaged tissue, which is linked to hypoxia condition might fail, in large part due to the emergence of oxidative stress (OS) and/or mitochondrial dysfunctions. Thus, the invigoration of stem cells against oxidative stress could be a reliable strategy to improve the cell therapy outcome. Of various antioxidants, mito‐Tempo (mito‐T) is one of the potent antioxidants that could target and neutralize the mitochondrial oxidative stress. In this study, for the induction of hypoxia and oxidative stress in mitochondria of the mesenchymal stem cells (MSCs) isolated from human adipose tissue, antimycin A (AMA) was used and then several parameters were analyzed, including cell viability and cell cycle arrest of MSCs exposed to AMA, mito‐T, antioxidant potential, redox homeostasis, and signaling pathways in MSCs under oxidative stress. Based on our findings, the treated MSCs were found to impose a high resistance to the OS‐induced apoptosis, which correlated with the nuclear factor erythroid 2‐related factor 2 (Nrf2) pathway required to manage OS. Upon exposure of the MSCs to high oxidative stress conditions using AMA, the cells failed to scavenge. The use of mito‐T was found to alleviate the damage induced by oxidative stress through both direct functions of the free radical scavenging and the interplay in terms of cell signaling pathways including the upregulation of the Nrf2 pathway. These findings may pave the way in the stem cell therapy for the hypoxia‐mediated tissue damage.

Designing robust chitosan-based hydrogels for stem cell nesting under oxidative stress

“…Nrf2 is a transcription activator that attaches to the antioxidant response elements in the promoter regions of target antioxidant genes and is critical for the harmonized up-regulation of genes in response to oxidative stress. 20 As shown in Fig. 7 , a decreased profile level of Nrf2 was detected in the cells nested at the CS scaffold ( P = 0.003).…”

“…Decreased oxidative stress leads to MSCs' promoted proliferation besides DNA stability. 20 , 21 Despite high contents of glutathione and an active antioxidant system in MSCs, they endure ROS production as they replicate. Elevated levels of ROS lead to a decreased cell differentiation though in adipose tissue, it is the opposite.…”

Mitohormesis and mitochondrial dynamics in the regulation of stem cell fate

“…In the very low tension of oxygen, 0.5% (anoxia), oxidative stress will be induced and ATP production will be disrupted and the cells will undergo the apoptosis (Barzegari, Nouri, et al, 2020; Guzy & Schumacker, 2006). However, under hypoxia (0.5%–3% O 2 ), physiological ROS production is vital for the bio‐function of stem cells.…”

“…A vast progress in stem cell therapy has held great promise for regenerative medicine; yet, it is limited due to the poor homing and survival of transplanted stem cells owing to higher physiological stresses specially hypoxia‐induced oxidative stress (Barzegari, Nouri, et al, 2020). Transplanted stem cells face an unfavorable environment with low oxygen and nutrient (Abdollahi et al, 2011).…”

Reply:

“…Interestingly, Barzegari et al (2020) reported that the mitochondria‐targeted antioxidant mito‐TEMPO activates Nrf2. ( 5 ) However, the contribution of Nrf2 to the regulation of mitochondrial oxidant stress in APAP‐induced liver injury remains unclear and warrants further study.…”