Abstract
Improving the effects of human adipose tissue-derived mesenchymal stem cells (ASCs) on the demyelination and neurobehavioral function was investigated in an experimental model of neonatal hypoxic-ischemic encephalopathy (HIE). Seven-day-old male rats were subjected to hypoxia-ischemia-lipopolysaccharide and intracerebroventricularly transplanted with human ASCs (4 × 10(5) cells/rat) once at postnatal day 10 (PND10) or repeatedly at PND10, 17, 27, and 37. Neurobehavioral abnormalities (at PND20, 30, and 40) and cognitive functions (at PND41-44) were evaluated using multiple test systems. Human ASCs recovered the using ratio of forelimb contralateral to the injured brain, improved locomotor activity, and restored rota-rod performance of HIE animals, in addition to showing a marked improvement of cognitive functions. It was confirmed that transplanted human ASCs migrated to injured areas and differentiated into oligodendrocytes expressing myelin basic protein (MBP). Moreover, transplanted ASCs restored production of growth and neurotrophic factors and expression of decreased inflammatory cytokines, leading to attenuation of host MBP loss. The results indicate that transplanted ASCs restored neurobehavioral functions by producing MBP as well as by preserving host myelins, which might be mediated by ASCs' anti-inflammatory activity and release of growth and neurotrophic factors.