Mesenchymal stromal cell treatment attenuates repetitive mild traumatic brain injury-induced persistent cognitive deficits via suppressing ferroptosis

Abstract

The incidence of repetitive mild traumatic brain injury (rmTBI), one of the main risk factors for predicting neurodegenerative disorders, is increasing; however, its underlying mechanism remains unclear. As suggested by several studies, ferroptosis is possibly related to TBI pathophysiology, but its effect on rmTBI is rarely studied. Mesenchymal stromal cells (MSCs), the most studied experimental cells in stem cell therapy, exert many beneficial effects on diseases of the central nervous system, yet evidence regarding the role of MSCs in ferroptosis and post-rmTBI neurodegeneration is unavailable. Our study showed that rmTBI resulted in time-dependent alterations in ferroptosis-related biomarker levels, such as abnormal iron metabolism, glutathione peroxidase (GPx) inactivation, decrease in GPx4 levels, and increase in lipid peroxidation. Furthermore, MSC treatment markedly decreased the aforementioned rmTBI-mediated alterations, neuronal damage, pathological protein deposition, and improved cognitive function compared with vehicle control. Similarly, liproxstatin-1, a ferroptosis inhibitor, showed similar effects. Collectively, based on the above observations, MSCs ameliorate cognitive impairment following rmTBI, partially via suppressing ferroptosis, which could be a therapeutic target for rmTBI.

Human umbilical cord mesenchymal stem cell‐derived exosome suppresses programmed cell death in traumatic brain injury via PINK1/Parkin‐mediated mitophagy

“…For example, Wang et al indicated that repetitive mild traumatic brain injury (rmTBI) caused time‐dependent alterations in ferroptosis‐related biomarker levels. However, treatment of mesenchymal stromal cells (MSCs) markedly decreased the rmTBI‐mediated ferroptosis 36 . Moreover, Cheng et al reported that TBI induced ferroptosis as proved by increased expression of TfR1, decreased levels of MDA, iron homeostatic imbalance and generation of LPO, while treatment of ferristatin II could reduce the expression of TfR1, suppress iron homeostatic imbalance, increase MDA level and attenuate LPO following TBI, suggesting that ferristatin II provided neuroprotection against TBI by inhibiting ferroptosis 37 .…”

Effects of Mesenchymal Stem Cells on Postresuscitation Renal and Intestinal Injuries in a Porcine Cardiac Arrest Model

“…Although no study has explored the potential regulatory effects of MSCs on renal and intestinal ferroptosis after regional or systemic IR injury, two studies have demonstrated that MSCs could ameliorate regional cerebral IR injury by inhibiting cell ferroptosis through regulating the GPX4/cyclooxygenase-2 axis (33) and alleviate systemic cardiac and cerebral IR injuries by suppressing ACSL4/GPX4-mediated cell ferroptosis (18). In addition, MSCs have been shown to produce effective protection through the inhibition of cell ferroptosis in some other diseases including acute spinal cord injury, mild traumatic brain injury, erectile dysfunction, and senescence (34)(35)(36)(37). Based on the evidence mentioned previously, the phenomenon of cell ferroptosis mediated by the ACSL4/GPX4 pathway and its potential regulation by MSCs were investigated in the kidney and intestine after CA/CPR in this study.…”

“…The working parameters of ventilator were as follows: tidal volume (10 mL/kg), peak flow (40 L/min), and oxygen concentration (21%). In addition, the respiratory frequency was adjusted to maintain a normal range of end-tidal CO 2 (35)(36)(37)(38)(39)(40). Electrocardiograms and oxygen saturation were monitored regularly using a patient monitoring system (BeneVision N22; Mindray, Shenzhen, China).…”

Mesenchymal stem cells and ferroptosis: Clinical opportunities and challenges

“…GPX4 inhibits lipid peroxidation by directly reducing hydroperoxides in membrane lipids [ 80 ], exhibiting direct detoxification. Wang et al [ 68 ]found that in mice with repetitive mild traumatic brain injury (RmTBI), GPX inactivation, decrease in GPX4 levels, increase in lipid peroxidation, abnormal iron metabolism, and mitochondrial ultrastructural changes, are key risk factors for neurodegeneration, characterized by increased deposition of Aβ and tau proteins and cognitive impairment [ 81 ]. By reducing pathological protein deposition after RmTBI and promoting glucose metabolism, MSCs can alleviate neuronal degeneration, effectively regulate protein levels related to iron metabolism, inhibit iron accumulation, reduce RmTBI-induced Fer2+ accumulation, regulate iron metabolism, prevent lipid peroxidation by restoring GPX activity and GPX4 content, and inhibit ferroptosis ( Fig.…”