Synergistic effects of environmental enrichment and transplantation of mesenchymal stem cells in an adult mouse model after neonatal hypoxic-ischemic brain injury

Abstract

[한글]

[영문]For central nervous system injuries, replacement therapy alone using a variety of stem cell types has so far not been sufficient in providing significant functional recovery. Studies have shown that environmental enrichment (EE) can augment the induction of striatal regeneration and consequent functional recovery after transplantation of human adipose-derived mesenchymal stem cells (MSCs) into the striatum of an adult animal model of neonatal hypoxic-ischemic (HI) injury.Permanent brain damage was induced in 7-day-old CD-1® (ICR) mice (P7) by ligation of the right carotid artery and exposure to an 8% hypoxic environment for 90 min. At 6 weeks of age, mice were randomly assigned to 4 groups receiving one of the following treatments: human adipose stem cell transplantation plus EE (ASC-EE), ASC-control, phosphate buffered saline injection plus EE (PBS-EE), or PBS-control. For the mice receiving human ASCs, a total of 1×105 ASCs in 2 μl were transplanted into the striatum of each damaged brain using stereotaxic coordinates. For mice receiving PBS, 2 μl of PBS was injected in the same manner. Behavioral assessments were performed using rotarod, cylinder, and ladder-walking performance tests.Two weeks after each treatment, immunohistochemical analysis revealed a dramatic increase in the number of human nuclei (HuNu) co-staining for the neuronal marker, βIII-tubulin in the neostriata of ASC-EE treated mice, compared to the PBS-control group. Striatal regeneration was also confirmed by transplantation of ASCs prelabeled with 5-bromo-2-deoxyuridine (BrdU) and staining for βIII-tubulin.Eight weeks after treatment, ASC-EE mice exhibited significantly longer rotarod latencies at a constant speed (48 rpm) as well as at accelerating speeds (4-80 rpm), relative to other mouse groups (p<0.05). PBS-control mice performed worse on the forelimb-use asymmetry tests, especially the ladder-walking test, relative to the other mouse groups (p<0.001).In conclusion, induction of neural regeneration in the striatum by transplantation of MSCs can be potentiated by EE. Therefore, this rehabilitative therapy can promote functional recovery in an adult animal model of neonatal HI brain injury, and may offer a promising strategy for the restoration of motor function after cell therapy in adults with cerebral palsy (CP).