Transplanted Oligodendrocyte Progenitor Cells Survive in the Brain ofa Rat Neonatal White Matter Injury Model but Less Mature in Comparison with theNormal Brain

摘要

Preterm infants have a high risk of neonatal white matter injury (WMI) caused byhypoxia-ischemia. Cell-based therapies are promising strategies for neonatal WMIby providing trophic substances and replacing lost cells. Using a rat model ofneonatal WMI in which oligodendrocyte progenitors (OPCs) are predominantlydamaged, we investigated whether insulin-like growth factor 2 (IGF2) has trophiceffects on OPCs in vitro and whether OPC transplantation haspotential as a cell replacement therapy. Enhanced expression ofIgf2 mRNA was first confirmed in the brain of P5 model ratsby real-time polymerase chain reaction. Immunostaining for IGF2 and its receptorIGF2 R revealed that both proteins were co-expressed in OLIG2-positive andGFAP-positive cells in the corpus callosum (CC), indicating autocrine andparacrine effects of IGF2. To investigate the in vitro effectof IGF2 on OPCs, IGF2 (100 ng/ml) was added to the differentiation mediumcontaining ciliary neurotrophic factor (10 ng/ml) and triiodothyronine (20ng/ml), and IGF2 promoted the differentiation of OPCs into matureoligodendrocytes. We next transplanted rat-derived OPCs that express greenfluorescent protein into the CC of neonatal WMI model rats withoutimmunosuppression and investigated the survival of grafted cells for 8 weeks.Although many OPCs survived for at least 8 weeks, the number of matureoligodendrocytes was unexpectedly small in the CC of the model compared withthat in the sham-operated control. These findings suggest that the mechanism inthe brain that inhibits differentiation should be solved in cell replacementtherapy for neonatal WMI as same as trophic support from IGF2.