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Neurogenin-1 Overexpression Increases the Therapeutic Effects of Mesenchymal Stem Cells through Enhanced Engraftment in an Ischemic Rat Brain.

ABSTRACT: Background and Objectives:Stem cell therapy is a promising strategy for treating neurological diseases but its effectiveness is influenced by the route of administration and the characteristics of the stem cells. We determined whether neural induction of mesenchymal stem cells (MSCs) was beneficial when the cells were delivered intra-arterially through the carotid artery. Methods and Results:MSCs were neurally induced using a retroviral vector expressing the neurogenic transcription factor neurogenin-1 (Ngn1). The LacZ gene encoding bacterial ?-galactosidase was used as a control. Ischemic stroke was induced by transluminal occlusion of the middle cerebral artery and 3 days later the MSCs were delivered intra-arterially through the internal carotid artery. Magnetic resonance imaging analysis indicated that compared to MSCs expressing LacZ (MSCs/LacZ), MSCs expressing Ngn1 (MSCs/Ngn1) exhibited increased recruitment to the ischemic region and populated this area for a longer duration. Immunohistochemical analysis indicated that compared to MSCs/LacZ, MSCs/Ngn1 more effectively alleviated neurological dysfunction by blocking secondary damage associated with neuronal cell death and brain inflammation. Microarray and real-time PCR analysis indicated that MSCs/Ngn1 exhibited increased expression of chemotactic cytokine receptors, adherence to endothelial cells, and migration ability. Conclusions:Neural induction with Ngn1 increases the homing ability of MSCs, enhancing their engraftment efficiency in the ischemic rat brain. Intra-arterial delivery of neurally induced MSCs/Ngn1 3 days after ischemic injury blocks neuronal cell death and inflammation, and improves functional recovery. Thus, intra-arterial administration of stem cells with neural properties may be a novel therapy for the treatment of ischemic stroke.

SUBMITTER: Kim GH

PROVIDER: S-EPMC7119213 | biostudies-literature | 2020 Mar

REPOSITORIES: biostudies-literature

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Neurogenin-1 Overexpression Increases the Therapeutic Effects of Mesenchymal Stem Cells through Enhanced Engraftment in an Ischemic Rat Brain.

Kim Gyu-Hee GH Subash Marasini M Yoon Jeong Seon JS Jo Darong D Han Jihun J Hong Ji Man JM Kim Sung-Soo SS Suh-Kim Haeyoung H

International journal of stem cells 20200301 1

<h4>Background and objectives</h4>Stem cell therapy is a promising strategy for treating neurological diseases but its effectiveness is influenced by the route of administration and the characteristics of the stem cells. We determined whether neural induction of mesenchymal stem cells (MSCs) was beneficial when the cells were delivered intra-arterially through the carotid artery.<h4>Methods and results</h4>MSCs were neurally induced using a retroviral vector expressing the neurogenic transcripti ...[more]

PMID: 31887850

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Project description:Neurogenic erectile dysfunction (NED) is a common and serious complication after pelvic surgery. The clinical translation of adipose-derived mesenchymal stem cell (ADSC) therapies in NED remains a major challenge due to their low survival rate and limited therapeutic effect. Peroxiredoxin 2 (PRDX2) is a member of the peroxidase family that exerts its therapeutic effects by inhibiting oxidative stress (OS) and ferroptosis, and PRDX2 is expected to enhance the therapeutic effect of ADSCs in treating NED. The purpose of this study was to investigate whether PRDX2 could improve the survival of ADSCs and determine whether overexpression of PRDX2 in ADSCs (PRDX2-ADSCs) could enhance the therapeutic effect of NED. This study investigated the potential role of PRDX2-ADSCs through a NED model induced by bilateral cavernous nerve injury (BCNI) and three in vitro models established by H2O2-stimulated ADSCs, H2O2-stimulated corpus cavernosum smooth muscle cells (CCSMCs), and RSL3-stimulated CCSMCs. We found that PRDX2 could significantly improve the viability of ADSCs by suppressing apoptosis and OS in H2O2-stimulated ADSCs. We also found that BCNI triggered ferroptosis of the corpus cavernosum, which was manifested by increased reactive oxygen species (ROS), total iron content, and MDA as well as decreased SOD and GSH. Our results further demonstrated changes in the expression of key proteins (GPX4 and ACSL4) in the ferroptosis pathway, whereas PRDX2-ADSCs ameliorated BCNI-induced erectile dysfunction and ferroptosis of the corpus cavernosum in NED rats. Consistently, PRDX2-ADSCs attenuated OS in H2O2-stimulated CCSMCs and inhibited ferroptosis in RSL3-stimulated CCSMCs, as evidenced by the decrease in ROS, total iron content, and MDA and the increase in SOD and GSH together with changes in ferroptosis-related protein (GPX4 and ACSL4) expression. In conclusion, overexpression of PRDX2 in ADSCs enhanced the therapeutic effect in a rat model of neurogenic erectile dysfunction by inhibiting ferroptosis via regulation of the GPX4/ACSL4 axis.

Dataset Information

Neurogenin-1 Overexpression Increases the Therapeutic Effects of Mesenchymal Stem Cells through Enhanced Engraftment in an Ischemic Rat Brain.

Publications

Neurogenin-1 Overexpression Increases the Therapeutic Effects of Mesenchymal Stem Cells through Enhanced Engraftment in an Ischemic Rat Brain.

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