Protective effect of human umbilical cord blood mesenchymal stem cells on the rat’s blood-brain barrier after traumatic brain injury

doi:10.3969/j.issn.2095-4344.2109

Abstract

Abstract:

BACKGROUND: Human umbilical cord mesenchymal stem cells play a vital role in the repair of the blood-brain barrier after traumatic brain injury.

OBJECTIVE: To investigate the protective effect of human umbilical cord blood mesenchymal stem cell transplantation on the blood-brain barrier after traumatic brain injury in rats and its possible mechanism.

METHODS: Sixty Sprague-Dawley rats were randomly divided into sham operation group, injury control group (model group), cell transplantation group and Sunitinib group, with 15 rats in each group. Traumatic brain injury model was established by improved hydraulic impact method in all the groups except for the sham operation group. Rats in the sham operation group and model group were injected with 1 mL of normal saline, and those in the cell transplantation group were injected with 1 mL of 2×109 /L human umbilical cord blood mesenchymal stem cells. The injection was done via the tail vein at 0.5, 24, and 48 hours after modeling. In the Sunitinib inhibitor group, the rats were given oral PDGFR-β pathway inhibitor, Sunitinib (80 mg/kg), from 1 day before modeling until being executed. Three days after modeling, the water content in brain tissue was measured by dry-wet specific gravity method, the permeability of the blood-brain barrier was measured by Evans blue method, expression of GFAP and vWF was observed by immunofluorescence staining and the expression of blood-brain barrier related proteins and PDGFR-β pathway proteins was detected by western blot method.

RESULTS AND CONCLUSION: Compared with the sham operation group, the brain water content of the model group increased significantly (P < 0.05), while that of the cell transplantation group was significantly lower than that of the model group (P < 0.05). The Evans blue content in the model group was significantly higher than that in the sham operation group (P < 0.05), while the Evans blue content in the cell transplantation group was significantly lower than that in the model group (P < 0.05). Compared with the sham operation group, the expression of vWF and GFAP increased significantly in the model group (P < 0.05), while compared with the model group, the expression was significantly reduced in the cell transplantation group (P < 0.05). Western blot showed that ZO-1, Oclaudin-5, and PDGFR-β protein expressions in the model group were significantly lower than those in the sham operation group (P < 0.05), while these expressions were significantly increased in the cell transplantation group as compared with the model group (P < 0.05). To conclude, intravenous injection of human umbilical cord mesenchymal stem cells through the tail ein can reduce the permeability of blood-brain barrier and play a neuroprotective role in rats with traumatic brain injury. Its possible mechanism is related to the promotion of PDGFR-β expression in the injured area.

Key words:

human umbilical cord mesenchymal stem cells, traumatic brain injury, blood-brain barrier, brain water content, PDGFR-β

pathway

CLC Number:

Chen Jianglong, Shi Xinyu, Cheng Jun, Ye Yichao, Zhang Zhenwen, Li Xiaohong, Sun Hongtao. Protective effect of human umbilical cord blood mesenchymal stem cells on the rat’s blood-brain barrier after traumatic brain injury[J]. Chinese Journal of Tissue Engineering Research, 2020, 24(25): 3947-3952.

Figures/Tables 7

References

[1]PERUZZARO ST, ANDREWS MMM, AL-GHARAIBEH A, et al. Transplantation of mesenchymal stem cells genetically engineered to overexpress interleukin-10 promotes alternative inflammatory response in rat model of traumatic brain injury. J Neuroinflammation.2019;16(1):2.
[2]LI T, XIA M, GAO Y, et al. Human umbilical cord mesenchymal stem cells: an overview of their potential in cell-based therapy. Expert Opin Biol Ther. 2015;15(9):1293-1306.
[3]HYDER AA, WUNDERLICH CA, PUVANACHANDRA P, et al. The impact of traumatic brain injuries: a global perspective. NeuroRehabilitation.2007;22(5):341-353.
[4]OBERMEIER B, DANEMAN R, RANSOHOFF RM. Development, maintenance and disruption of the blood-brain barrier. Nat Med.2013;19(12):1584-1596.
[5]NEUWELT E, ABBOTT NJ, ABREY L, et al. Strategies to advance translational research into brain barriers. Lancet Neurol. 2008;7(1):84-96.
[6]SUN P, LIU DZ, JICKLING GC, et al. MicroRNA-based therapeutics in central nervous system injuries. J Cereb Blood Flow Metab. 2018;38(7):1125-1148.
[7]BLENNOW K, HARDY J, ZETTERBERG H. The neuropathology and neurobiology of traumatic brain injury. Neuron. 2012;76(5):886-899.
[8]韩潇,白海,赵强,等.人脐带间充质干细胞体外分离培养及其生物学特性的研究[J].重庆医学,2016,45(7):876-879.
[9]DONG HJ, ZHAO ML, LI XH, et al. Hypothermia-Modulating Matrix Elasticity of Injured Brain Promoted Neural Lineage Specification of Mesenchymal Stem Cells. Neuroscience. 2018;377:1-11.
[10]傅兴宁,刘丽冰,张志杰,等.CART肽抑制缺血再灌注小鼠脑组织水通道蛋白4表达并减轻脑水肿[J].中国病理生理杂志, 2018, 34(8):1363-1367.
[11]BELL L, KOENIGER T, TACKE S, et al. Characterization of blood-brain barrier integrity in a B-cell-dependent mouse model of multiple sclerosis. Histochem Cell Biol. 2019;151(6): 489-499.
[12]LORENZO MF, THOMAS SC, KANI Y, et al. Temporal Characterization of Blood-Brain Barrier Disruption with High-Frequency Electroporation. Cancers (Basel). 2019; 11(12). pii: E1850.
[13]YOU Q, GONG Q, HAN YQ, et al. Role of miR-124 in the regulation of retinoic acid-induced Neuro-2A cell differentiation. Neural Regen Res. 2020;15(6):1133-1139.
[14]许泽艳,杨志贤,廖承德,等.创伤性脑损伤与血脑屏障关系的研究进展[J].山东医药,2018,58(41):110-112.
[15]SHEN Q, YIN Y, XIA QJ, et al. Bone Marrow Stromal Cells Promote Neuronal Restoration in Rats with Traumatic Brain Injury: Involvement of GDNF Regulating BAD and BAX Signaling. Cell Physiol Biochem. 2016;38(2):748-762.
[16]PISCHIUTTA F, BRUNELLI L, ROMELE P, et al. Protection of Brain Injury by Amniotic Mesenchymal Stromal Cell-Secreted Metabolites. Crit Care Med. 2016;44(11):e1118-e1131.
[17]LUO SY, LI R, LE ZY, et al. Anfibatide protects against rat cerebral ischemia/reperfusion injury via TLR4/JNK/caspase-3 pathway. Eur J Pharmacol. 2017;807:127-137.
[18]王义义,杨卓.血脑屏障的结构和功能[J].天津医药, 2010,38(3): 200.
[19]张合鹏,杜爱玲,李磊,等. AG490对大鼠脑损伤后血-脑屏障通透性及白细胞介素6和肿瘤坏死因子α表达的影响[J].中国脑血管病杂志, 2015,12(3):134-139.
[20]GONÇALVES J, LEITÃO RA, HIGUERA-MATAS A, et al. Extended-access methamphetamine self-administration elicits neuroinflammatory response along with blood-brain barrier breakdown. Brain Behav Immun. 2017;62:306-317.
[21]ZHU X, CAO Y, WEI L, et al. von Willebrand factor contributes to poor outcome in a mouse model of intracerebral haemorrhage. Sci Rep.2016;6:35901.
[22]KUROSE T, TAKAHASHI S, OTSUKA T, et al. Simulated microgravity-cultured mesenchymal stem cells improve recovery following spinal cord ischemia in rats. Stem Cell Res. 2019;41:101601.
[23]SHIM AH, LIU H, FOCIA PJ, et al. Structures of a platelet-derived growth factor/propeptide complex and a platelet-derived growth factor/receptor complex. Proc Natl Acad Sci U S A. 2010;107(25):11307-11312.
[24]GERHARDT H, BETSHOLTZ C. Endothelial-pericyte interactions in angiogenesis. Cell Tissue Res.2003;314(1): 15-23.
[25]SHEN J, ISHII Y, XU G, et al. PDGFR-β as a positive regulator of tissue repair in a mouse model of focal cerebral ischemia. J Cereb Blood Flow Metab.2012;32(2):353-367.
[26]ARMULIK A, GENOVÉ G, BETSHOLTZ C. Pericytes: developmental, physiological, and pathological perspectives, problems, and promises. Dev Cell. 2011;21(2):193-215.
[27]DANEMAN R, ZHOU L, KEBEDE AA, et al. Pericytes are required for blood-brain barrier integrity during embryogenesis. Nature. 2010;468(7323):562-566.
[28]FARSHORI P, KACHAR B. Redistribution and phosphorylation of occludin during opening and resealing of tight junctions in cultured epithelial cells. J Membr Biol.1999; 170(2):147-156.
[29]BHOWMICK S, D'MELLO V, CARUSO D, et al. Impairment of pericyte-endothelium crosstalk leads to blood-brain barrier dysfunction following traumatic brain injury. Exp Neurol. 2019; 317:260-270.