The Neuroprotective Effects of Human Umbilical Cord Blood Mesenchymal Stem Cells on Cerebral Ischemia-Reperfusion Rats by Activating PI3K/Akt Pathway
FAN Jinjin, DING Li, ZHANG Yueliang, CHEN Jun, ZHANG Bei, LI Xueqing, TONG Xu, WANG Yunfu, AI Zhibing
2023, 18(11):
1289-1297.
DOI: 10.3969/j.issn.1673-5765.2023.11.011
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Objective To discuss the effect of pericyte expression and the change of neurological function of human umbilical cord blood mesenchymal stem cells (hUCBMSCs) on cerebral ischemia-reperfusion injury rats by regulating phosphoinositide3-kinase/protein kinase B (PI3K/Akt) pathway.
Methods A total of 72 male Sprague Dawley rats were randomly divided into sham group, model group, hUCBMSCs group, hUCBMSCs+inhibitor group, with 18 in each group. Except for sham group, the rat models with cerebral ischemia-reperfusion were established in the other groups. After successful modeling, 0.1 mL phosphate-buffered saline (PBS) was injected into the tail vein of the model group, 0.1 mL PBS containing 2×106 hUCBMSCs was injected into the tail vein of the hUCBMSCs group, 0.1 mL PBS containing 2×106 hUCBMSCs was injected into the tail vein of the hUCBMSCs+inhibitor group and PI3K/Akt inhibitor LY294002 (0.03 mg/100 g) was injected intraperitoneally, LY294002 was administered once a day until death. Modified neurological severity scores (mNSS) were measured at 1, 3, 7 and 14 days after operation. After 7 and 14 days of operation, the area of cerebral infarction was measured by 2, 3, 5-triphenyltetrazolium chloride (TTC) staining. The number of normal neurons in ischemic penumbra of cerebral cortex were detected by Nissl staining. The number of platelet derived growth factor receptor-β+ (PDGFRβ+) pericytes in ischemic penumbra of cerebral cortex were detected by immunohistochemistry. The expressions of PI3K/Akt pathway related proteins p-Akt and Akt in ischemic penumbra of cerebral cortex were detected by Western Blot.
Results On the 7th day after operation, there were significant differences in all indexes among the four groups (P<0.001). As compared with sham group, the number of normal neurons (55.42±4.75 vs. 8.50±1.64, P<0.001) and p-Akt/Akt (1.00±0.00 vs. 0.47±0.06, P=0.002) in model group were decreased, however the number of PDGFRβ+ pericytes (1.08±0.29 vs. 13.67±2.47, P<0.001) were increased. As compared with model group, the mNSS (6.33±0.71 vs. 4.78±0.98, P<0.001) and the rate of cerebral infarction (32.66%±1.76% vs. 14.60%±0.52%, P<0.001) in hUCBMSCs group were decreased; however the number of normal neurons (8.50±1.64 vs. 23.17±1.77, P<0.001), the number of PDGFRβ+ pericytes (13.67±2.47 vs. 28.50±3.19, P<0.001) and p-Akt/Akt (0.47±0.06 vs. 0.83±0.18, P=0.017) were increased. As compared with hUCBMSCs group, the mNSS (4.78±0.98 vs. 6.11±0.78, P=0.002) and the rate of cerebral infarction (14.60%±0.52% vs. 27.85%±0.59%, P<0.001) in hUCBMSCs+inhibitor group were increased; however the number of normal neurons (23.17±1.77 vs. 11.83±0.88, P=0.003), the number of PDGFRβ+ pericytes (28.50±3.19 vs. 20.33±1.44, P=0.007) and p-Akt/Akt (0.83±0.18 vs. 0.36±0.11, P=0.003) were decreased. On the 14th day after operation, there were significant differences in all indexes among the four groups (P<0.001). As compared with sham group, the number of normal neurons (57.08±3.79 vs. 11.25±5.52, P<0.001) and p-Akt/Akt (1.00±0.00 vs. 0.53±0.12, P=0.002) in model group were decreased, however the number of PDGFRβ+ pericytes (2.00±0.25 vs. 13.42±1.04, P<0.001) were increased. As compared with model group, the mNSS (4.89±0.78 vs. 2.33±0.87, P<0.001) and the rate of cerebral infarction (32.58%±1.96% vs. 11.78%±1.92%, P<0.001) in hUCBMSCs group were decreased; however the number of normal neurons (11.25±5.52 vs. 31.00±1.89, P<0.001), the number of PDGFRβ+ pericytes (13.42±1.04 vs. 31.42±3.66, P<0.001) and p-Akt/Akt (0.53±0.12 vs. 0.93±0.12, P=0.004) were increased. As compared with hUCBMSCs group, the mNSS (2.33±0.87 vs. 4.44±0.53, P<0.001) and the rate of cerebral infarction (11.78%±1.92% vs. 25.25%±2.76%, P<0.001) in hUCBMSCs+inhibitor group were increased; however the number of normal neurons (31.00±1.89 vs. 13.83±1.04, P=0.002), the number of PDGFRβ+ pericytes (31.42±3.66 vs. 20.67±1.42, P<0.001) and p-Akt/Akt (0.93±0.12 vs. 0.53±0.09, P=0.005) were decreased.
Conclusions hUCBMSCs may play a neuroprotective role by promoting the survival and recruitment of pericytes through the activation of PI3K/Akt pathway, and then promote the recovery of neurological function in rats with cerebral ischemia-reperfusion injury.
