BDNF-Overexpressing Engineered Mesenchymal Stem Cells Enhances Their Therapeutic Efficacy against Severe Neonatal Hypoxic Ischemic Brain Injury.

So Yoon Ahn,Yun Sil Chang,Hyo-Jin Kim,Se In Sung,Soon Min Lee,Young Eun Kim,Won Soon Park,Dong Kyung Sung

doi:10.3390/ijms222111395

Abstract

We investigated whether irradiated brain-derived neurotropic factor (BDNF)-overexpressing engineered human mesenchymal stem cells (BDNF-eMSCs) improve paracrine efficiency and, thus, the beneficial potency of naïve MSCs against severe hypoxic ischemic (HI) brain injury in newborn rats. Irradiated BDNF-eMSCs hyper-secreted BDNF > 10 fold and were >5 fold more effective than naïve MSCs in attenuating the oxygen-glucose deprivation-induced increase in cytotoxicity, oxidative stress, and cell death in vitro. Only the irradiated BDNF-eMSCs, but not naïve MSCs, showed significant attenuating effects on severe neonatal HI-induced short-term brain injury scores, long-term progress of brain infarct, increased apoptotic cell death, astrogliosis and inflammatory responses, and impaired negative geotaxis and rotarod tests in vivo. Our data, showing better paracrine potency and the resultant better therapeutic efficacy of the irradiated BDNF-eMSCs, compared to naïve MSCs, suggest that MSCs transfected with the BDNF gene might represent a better, new therapeutic strategy against severe neonatal HI brain injury.

Highlights

Despite recent improvements in perinatal and neonatal intensive care medicine, neonatal hypoxic ischemic encephalopathy (HIE) remains a major cause of neonatal mortality and long-term neurologic morbidities, such as intellectual disability, cerebral palsy, and epilepsy in survivors [1,2]
These findings suggest that mesenchymal stem cell (MSC) transplantation might be a novel clinically effective therapy in addition to therapeutic hypothermia to improve the outcome of currently intractable severe neonatal
We investigated whether genetically modifying engineered human MSCs to secrete more brain-derived neurotropic factor (BDNF) enhances the therapeutic efficacy of naïve human MSCs in vitro for oxygen glucose deprivation (OGD) and in vivo in newborn rats received therapeutic hypothermia after severe HI brain injury

Summary

Introduction

Despite recent improvements in perinatal and neonatal intensive care medicine, neonatal hypoxic ischemic encephalopathy (HIE) remains a major cause of neonatal mortality and long-term neurologic morbidities, such as intellectual disability, cerebral palsy, and epilepsy in survivors [1,2]. While therapeutic hypothermia is the only currently applicable therapeutic option in clinical practice to improve the outcomes of neonatal HIE [3,4], more than half of infants with HIE expire or develop severe neurologic problems, especially in severe HIE [5,6]. We showed that concurrent or delayed MSC injection with hypothermia treatment synergistically improved severe HI brain injury in contrast to hypothermia-alone therapy [12,13]. These findings suggest that MSC transplantation might be a novel clinically effective therapy in addition to therapeutic hypothermia to improve the outcome of currently intractable severe neonatal

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