THERAPEUTIC EFFECT OF AN EXOSOME RICHCONDITIONED MEDIUM DERIVED FROM AMNIOTIC MEMBRANE STEM CELLS IN AN ANIMAL MODEL OF CEREBRAL PALSY

초록

Background and Aims: Cerebral palsy (CP) resulting from perinatal cerebral hypoxia is one of the most-devastating neurological diseases in children exhibiting diverse neurobehavioral symptoms including motor and cognitive disorders. Methods: An exosome rich-conditioned medium (ERCM) was prepared under a hypoxic culture (2% O2) from human amniotic membrane stem cells (AMSCs), and its neuroprotective effects were investigated in human neural stem cells (NSCs) and oligodendrocyte progenitor cells (OPCs) as well as in an animal model of CP. Results: The ERCM was confirmed to contain much more exosome particles and greater amounts of growth and neurotrophic factors (GFs/NFs) than normoxic culture (20% O2) medium (NCM). In vitro study, ERCM protected NSCs and OPCs against lipopolysaccharide and KCN exposure by inhibiting apoptosis and inflammatory responses. Also, ERCM facilitated the differentiation and maturation of OPCs to oligodendrocytes by increasing related-gene expression. CM-DiI-labeled exosomes were found to enter the brains of normal and CP-induced animals, reaching peak levels 2-3 hours after intravenous (IV) injection. Single or repeated IV treatment of ERCM (1.5 × 1010 and 6.0 × 1010 exosomes/rat) recovered the neurobehavioral and cognitive functions of CP animals. As shown in cell study, ERCM suppressed apoptotic signal and inflammatory response, while increased oligodendrocyte makers in the CP brain. ERCM also attenuated demyelination and facilitated remyelination in the corpus callosum and periventricular zone, regions highly vulnerable to CP. Conclusions: It is suggested that AMSC-ERCM containing large amounts of GFs/NFs exert CP-therapeutic effects by preserving NSCs and OPCs via regulation of apoptotic signaling, inflammatory response, and remyelination.