In spite of recent progress in perinatal and neonatal intensive care medicine, neonatal brain injury due to various disorders including intraventricular hemorrhage (IVH), hypoxic ischemic encephalopathy (HIE), neonatal stroke and bacterial meningitis still remains a major cause of death and morbidities in survivors1. Since few effective treatments are currently available to improve the outcome of these intractable and devastating neonatal brain disorders, developing a new and effective therapeutic modality would be an urgent big issue.

Recently, various preclinical studies have shown the benefits of stem cell therapy for attenuating neonatal brain injury in the newborn animal models of intraventricular hemorrhage (IVH)2, 3, 4, 5, 6, 7, 8, 9, hypoxic ischemic encephalopathy (HIE)10,11, neonatal stroke12 and bacterial meningitis13. Phase I clinical trials in newborn infants for severe IVH4 and HIE14 have demonstrated stem cell therapy to be safe, feasible and potentially efficacious. Moreover, considering the pleiotropic anti-apoptotic, anti-oxidative, anti-inflammatory, anti-fibrotic and anti-bacterial effects15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, stem cell therapy could be a novel therapeutic candidate for neonatal brain injury due to the currently intractable and devastating neonatal disorders with complex multifactorial etiology. Here, we discuss recent progress in stem cell therapy, specifically mesenchymal stem cells (MSCs) transplantation, for various neonatal intractable brain disorders with focus on the preclinical data concerning the important issues for clinical translation including the protective mechanisms, determining the ideal cells, optimal route, timing and dose of MSCs transplantation.