Bone marrow mesenchymal stem cells overexpressing hepatocyte growth factor ameliorate hypoxic–ischemic brain damage in neonatal rats

Abstract

Objectives Hypoxic–ischemic brain damage (HIBD) is a major cause of brain injury in neonates. Bone marrow mesenchymal stem cells (BMSCs) show therapeutic potential for HIBD, and genetic modification may enhance their neuroprotective effects. The goal of this study was to investigate the neuroprotective effects of hepatocyte growth factor (HGF)-overexpressing BMSCs (BMSCs-HGF) against HIBD and their underlying mechanisms. Methods: BMSCs were transfected with HGF using adenoviral vectors. HIBD models were established and then BMSCs were transplanted into the brains of HIBD rats via intraventricular injection. 2,3,5-Triphenyltetrazolium chloride (TTC) staining was used to measure cerebral infarction volumes. In vitro, primary cultured cortical neurons were co-cultured with BMSCs in a Transwell plate system. Oxygen–glucose deprivation (OGD) was applied to imitate hypoxic–ischemic insult, and PD98059 was added to the culture medium to block the phosphorylation of extracellular signal-regulated kinase (ERK). Cell apoptosis was determined using TUNEL staining. The expression of HGF was measured by immunofluorescence, real-time quantitative PCR (RT-qPCR), and western blots. The expression of phosphorylated ERK (p-ERK) and B-cell lymphoma-2 (Bcl-2) was measured by western blots. Results HGF-gene transfection promoted BMSC proliferation. Moreover, BMSCs-HGF decreased HIBD-induced cerebral infarction volumes and enhanced the protective effects of the BMSCs against HIBD. BMSCs-HGF also increased expression of HGF, p-ERK, and Bcl-2 in brain tissues. In vitro, BMSC-HGF protected neurons against OGD-induced apoptosis. Inhibition of ERK phosphorylation abolished the neuroprotective effect of BMSCs-HGF against OGD. Conclusions BMSCs-HGF is a potential treatment for HIBD and that the ERK/Bcl-2 pathway is involved in the underlying neuroprotective mechanism.

Aconitum coreanum alleviates cerebral ischemic stroke through the PI3K/Akt signaling pathway in gerbils model

“…The gerbils after modeling had severe cerebral ischemia and exhibited significant neurological deficits such as facial paralysis, limb weakness, and abnormal movement. In this study, permanent ligation of the right carotid artery in gerbils was used as modeling method, prolonged ischemia time could also lead to gradual ischemia of the contralateral brain [ 42 , 43 ]. This discovery suggested that for sudden CIS, timely treatment should be taken to avoid worsening of cerebral ischemia.…”

Intra-individual variability in the neuroprotective and promyelinating properties of conditioned culture medium obtained from human adipose mesenchymal stromal cells

“…Even more surprising was the negative correlation we observed between OGD neuroprotection and HGF concentration, HGF having recently been indicated as a key factor in preventing neuronal death and promoting survival through pro-angiogenic, anti-inflammatory, and immune-modulatory mechanisms in vivo [ 62 ]. Bone marrow-derived MSCs transfected with HGF also protected neurons against OGD-induced apoptosis [ 63 , 64 ].…”