Abstract

Aims: Hypoxic-Ischaemic Brain Damage (HIBD) remains a common sequelae of various nervous system diseases. Human Umbilical Cord derived Mesenchymal Stem Cells (hUC-MSCs) transplantation was considered to be promising in treating HIBD. However, the best route of administration to transplant hUC-MSCs remains open. In this study, we systematically compared the three routes of administration. The Intravenous (IV), Intracerebral (IC) and Intranasal (IN) administration for the first time to guide the best clinical practice.

Methods: The HIBD rat models were built on the 7^th (PN7) day after birth of rats. The three routes of administration of hUC-MSCs were conducted on the 14^th day (PN14) after birth of rats. And these three groups (HIBD+IV, HIBD+IN, HIBD+IC) were compared with HIBD and sham group on motor function learning and memory function improvement by hanging wire, vertical pole test and Morris Water Maze (MWM) test on 10th (PN10) and 21^st (PN21) day after birth of rats. Moreover, the pathological tests were used to compare the pathological repair effects of three routes of administration: The morphological changes of brain tissue were tested by Haematoxylin and Eosin staining (HE staining); the proliferation of reactive astrocytes were compared by detecting the expression of Glial Fibrillar Acidic Protein (GFAP) by immunohistochemistry; and the number of neuronal apoptosis in cortex and hippocampus were compared by TUNEL staining.

Results: The motor function of rats in HIBD group was significantly lower than that in sham group on the PN10, both in hanging wire and vertical pole tests (p<0.0001). This shows the effectiveness of our HIBD model. All of the three routes of administration groups showed significant improvement of motor and learning function, reducing the liquefaction necrosis, GFAP expression and apoptosis rate of nerve cells in cerebral cortex and hippocampus of HIBD rats. Among the three routes of administration groups, the functional improvement and pathological repair effect of Intracerebral (IC) and Intranasal (IN) administration were better than those of Intravenous (IV) administration stem cells. And no significant difference between intracerebral and intranasal administration. As Intranasal (IN) administration is more compliant and convenient in clinical practice than intracerebral (IC) administration, thus we suggest that Intranasal (IN) administration is the best route of administration of hUC-MSCs on HIBD treatment.

Keywords: HIBD; hUC-MSCs; Brain damage; Cell therapy; Administration routes