Overexpression of fibroblast growth factor‐21 (FGF‐21) protects mesenchymal stem cells against caspase‐dependent apoptosis induced by oxidative stress and inflammation

Abstract

The clinical application of stem cells offers great promise as a potential avenue for therapeutic use in neurodegenerative diseases. However, cell loss after transplantation remains a major challenge, which currently plagues the field. On the basis of our previous findings that fibroblast growth factor 21 (FGF‐21) protected neurons from glutamate excitotoxicity and that upregulation of FGF‐21 in a rat model of ischemic stroke was associated with neuroprotection, we proposed that overexpression of FGF‐21 protects bone marrow‐derived mesenchymal stem cells (MSCs) from apoptosis. To test this hypothesis, we examined whether the detrimental effects of apoptosis can be mitigated by the transgenic overexpression of FGF‐21 in MSCs. FGF‐21 was transduced into MSCs by lentivirus and its overexpression was confirmed by quantitative polymerase chain reaction. Moreover, FGF‐21 overexpression did not stimulate the expression of other FGF family members, suggesting it does not activate a positive feedback system. The effects of hydrogen peroxide (H2O2), tumor necrosis factor‐α (TNF‐α), and staurosporine, known inducers of apoptosis, were evaluated in FGF‐21 overexpressing MSCs and mCherry control MSCs. Caspases 3 and 7 activity was markedly and dose‐dependently increased by all three stimuli in mCherry MSCs. FGF‐21 overexpression robustly suppressed caspase activation induced by H2O2 and TNF‐α, but not staurosporine. Moreover, the assessment of apoptotic morphological changes confirmed the protective effects of FGF‐21 overexpression. Taken together, these results provide compelling evidence that FGF‐21 plays a crucial role in protecting MSCs from apoptosis induced by oxidative stress and inflammation and merits further investigation as a strategy for enhancing the therapeutic efficacy of stem cell‐based therapies.

Progress in Mesenchymal Stem Cell Therapy for Ischemic Stroke

“…Ghazavi et al investigated the effect of AD-MSCs transfected with FGF1 and found that compared with normal AD-MSCs, the former could increase the level of FGF1 in the ischemic lesions, reduce apoptotic cells, and infarct size more significantly [61]. In addition, Linares et al found that FGF21 transfected MSCs have strong antiapoptotic ability in vitro in the face of oxidative stress and inflammatory environment, which suggests that FGF21 transfected MSCs may have stronger survival ability and neuroprotective ability in infarcted lesions [168]. LV et al found that transplanted MSCs overexpressing HIF-1α had increased viability in ischemic lesions and showed a more significant reduction of infarct size and recovery of neurobehavior, which was related to the further decrease of proinflammatory cytokines and increase of neurotrophic factors [169].…”

Fibroblast growth factor 21 is associated with increased serum total antioxidant capacity and oxidized lipoproteins in humans with different stages of chronic kidney disease

“…To date, evidence suggests that OS stimulates FGF21 production, 8,12,13 and other studies have demonstrated that FGF21 protects cells from OS injury and death in cardiac cells exposed to hydrogen peroxide; 42 neuroblastoma cells (SH-SY5Y) exposed to amyloid-beta 1-42 ; 43 mesenchymal stem cells exposed to hydrogen peroxide and tumor necrosis factor alpha (TNFa); 44 and in vivo in a rodent model of sciatic crush injury, 45 FGF21 has shown an antioxidant and protective effect.…”

Stem Cell Therapy in Treating Epilepsy

“…MSCs possess self-renewal capacities and are able to differentiate into many specialized cell types including neurons (Tropel et al, 2006 ). Recently, several preclinical animal and clinical studies have investigated the applications of MSCs for the treatment of epilepsy and appear potentials to ameliorate the severity of epilepsy and attenuate epilepsy-induced excitotoxicity, oxidative stress, and neuroinflammation (Fukumura et al, 2018 ; Milczarek et al, 2018 ; Papazian et al, 2018 ; Kodali et al, 2019 ; Xian et al, 2019 ; Linares et al, 2020 ). Furthermore, stem cell therapy using MSCs allows either allogeneic or autologous transplantation that extends the clinical feasibility.…”