Neural Stem Cells Expressing bFGF Reduce Brain Damage and Restore Sensorimotor Function after Neonatal Hypoxia-Ischemia

Abstract

Background/Aims: Neonatal hypoxia-ischemia (HI) causes severe brain damage and significantly increases neonatal morbidity and mortality. Increasing evidences have verified that stem cell-based therapy has the potential to rescue the ischemic tissue and restore function via secreting growth factors after HI. Here, we had investigated whether intranasal neural stem cells (NSCs) treatment improves the recovery of neonatal HI, and NSCs overexpressing basic fibroblast growth factor (bFGF) has a better therapeutic effect for recovery than NSCs treatment only. Methods: We performed permanent occlusion of the right common carotid artery in 9-day old ICR mice as animal model of neonatal hypoxia-ischemia. At 3 days post-HI, NSC, NSC-GFP, NSC-bFGF and vehicle were delivered intranasally. To determine the effect of intranasal NSC, NSC-GFP and NSC-bFGF treatment on recovery after HI, we analyzed brain damage, sensor-motor function and cell differentiation. Results: It was observed that intranasal NSC, NSC-GFP and NSC-bFGF treatment decreased gray and white matter loss area in comparison with vehicle-treated mouse. NSC, NSC-GFP and NSC-bFGF treatment also significantly improved sensor motor function in cylinder rearing test and adhesive removal test, however, NSC-bFGF-treatment was more effective than NSC-treatment in the improvement of somatosensory function. Furthermore, compared with NSC and NSC-GFP, NSC-bFGF treatment group appeared to differentiate into more neurons. Conclusion: Taken together, intranasal administration of NSCs is a promising therapy for treatment of neonatal HI, but NSCs overexpressing bFGF promotes the survival and differentiation of NSCs, and consequently achieves a better therapeutic effect in improving recovery after neonatal HI.

Cell motility and migration as determinants of stem cell efficacy

“…However, a closer look at the mechanisms and pathways of intranasal cell delivery discovered by us 11 years ago, reveals that cells use nearly the same delivery mechanisms (besides active migration) as described for peptides and growth factors [43]. This is evidenced by their rapid appearance within the brain, just a few hours after administration as shown by us for MSC [10,44] or within a day as reported by other groups for NSC [45,46]. Hereby, it is suggested that besides active migration promoting the cell distribution within the brain, a complex of tools such as bulk flow, vessel pulsation when the cells move along perivascular spaces, as well as nose-to-brain interconnection of lymphatic and cerebrospinal fluid systems contribute to their rapid entry into the brain and further distribution to different brain areas [43,44].…”

TNF-α Pretreatment Improves the Survival and Function of Transplanted Human Neural Progenitor Cells Following Hypoxic-Ischemic Brain Injury

“…In the current study, TNF-α-pretreated-hNPCs and non-pretreated hNPCs were injected 3 days after induction of HI brain injury. In animal models of HI brain injury, stem cells have been transplanted between the first hour and 7 days after brain injury, with different degrees of beneficial outcome [14,[39][40][41]. Most of these studies have a variety of types, including transplant cell types, injury models, evaluation methods, etc., making it difficult to determine the best time for stem/progenitor cell therapy.…”

The Regenerative Potential of bFGF in Dental Pulp Repair and Regeneration

“…The bFGF is an important neurotrophin which possesses superior properties to promote neural stem cell (NSC) migration, proliferation, and self-renewal ( Yeoh and de Haan, 2007 ). Ye et al further informed that the bFGF could promote the survival and differentiation of NSCs to reduce brain damage and restore sensorimotor function after neonatal hypoxia-ischemia ( Ye et al, 2018 ). The bFGF has also been reported to be able to maintain the survival of neuronal and glial cells, probably by protecting neurons from ROS-induced cell death and antagonizing the neuronal apoptosis induced by glutamate ( Liu and Zhu, 1999 ).…”

“…In summary, the results from the aforementioned studies emphasize the important role of the bFGF in neural differentiation and promise new therapeutic strategies by using the bFGF to treat neurological diseases and repair neuronal damage, such as spinal cord injury (SCI), Parkinson’s disease, neonatal hypoxia-ischemia (NHI), and Alzheimer’s disease ( Barzilay et al, 2008 ; Zhang et al, 2014 ; Luo et al, 2018a ; Ye et al, 2018 ). However, achieving the neurite growth in root canals with the treatment of the bFGF needs more experimental reports.…”