Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model
Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta, which leads to the motor control deficits. Recently, cell transplantation is a cutting-edge technique for the therapy of PD. Nevertheless, one key bottleneck to realizing such potential i...
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MDPI AG
2022-06-01
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| Online Access: | https://www.mdpi.com/2227-9059/10/6/1446 |
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| author | Kuan-Yin Tseng Jui-Sheng Wu Yuan-Hao Chen Mikko Airavaara Cheng-Yi Cheng Kuo-Hsing Ma |
| author_facet | Kuan-Yin Tseng Jui-Sheng Wu Yuan-Hao Chen Mikko Airavaara Cheng-Yi Cheng Kuo-Hsing Ma |
| author_sort | Kuan-Yin Tseng |
| collection | DOAJ |
| description | Parkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta, which leads to the motor control deficits. Recently, cell transplantation is a cutting-edge technique for the therapy of PD. Nevertheless, one key bottleneck to realizing such potential is allogenic immune reaction of tissue grafts by recipients. Cerebral dopamine neurotrophic factor (CDNF) was shown to possess immune-modulatory properties that benefit neurodegenerative diseases. We hypothesized that co-administration of CDNF with fetal ventral mesencephalic (VM) tissue can improve the success of VM replacement therapies by attenuating immune responses. Hemiparkinsonian rats were generated by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats, with/without CDNF administration. Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small-animal positron emission tomography (PET) coupled with [<sup>18</sup>F] DOPA or [<sup>18</sup>F] FE-PE2I, respectively. In addition, transplantation-related inflammatory response was determined by uptake of [<sup>18</sup>F] FEPPA in the grafted side of striatum. Immunohistochemistry (IHC) examination was used to determine the survival of the grated dopaminergic neurons in the striatum and to investigate immune-modulatory effects of CDNF. The modulation of inflammatory responses caused by CDNF might involve enhancing M2 subset polarization and increasing fractal dimensions of 6-OHDA-treated BV2 microglial cell line. Analysis of CDNF-induced changes to gene expressions of 6-OHDA-stimulated BV2 cells implies that these alternations of the biomarkers and microglial morphology are implicated in the upregulation of protein kinase B signaling as well as regulation of catalytic, transferase, and protein serine/threonine kinase activity. The effects of CDNF on 6-OHDA-induced alternation of the canonical pathway in BV2 microglial cells is highly associated with PI3K-mediated phagosome formation. Our results are the first to show that CDNF administration enhances the survival of the grafted dopaminergic neurons and improves functional recovery in PD animal model. Modulation of the polarization, morphological characteristics, and transcriptional profiles of 6-OHDA-stimualted microglia by CDNF may possess these properties in transplantation-based regenerative therapies. |
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| spelling | doaj.art-37a0438611424aefbf2303293fc0d1902023-11-23T15:44:58ZengMDPI AGBiomedicines2227-90592022-06-01106144610.3390/biomedicines10061446Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat ModelKuan-Yin Tseng0Jui-Sheng Wu1Yuan-Hao Chen2Mikko Airavaara3Cheng-Yi Cheng4Kuo-Hsing Ma5Department of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, TaiwanDepartment of Biology and Anatomy, National Defense Medical Center, Taipei 114, TaiwanDepartment of Neurological Surgery, Tri-Service General Hospital, National Defense Medical Center, Taipei 114, TaiwanDrug Research Program, Faculty of Pharmacy, University of Helsinki, Viikinkaari 5E, 00014 Helsinki, FinlandDepartment of Nuclear Medicine, Tri-Service General Hospital, Taipei 114, TaiwanDepartment of Biology and Anatomy, National Defense Medical Center, Taipei 114, TaiwanParkinson’s disease (PD) is characterized by the loss of dopaminergic neurons in substantia nigra pars compacta, which leads to the motor control deficits. Recently, cell transplantation is a cutting-edge technique for the therapy of PD. Nevertheless, one key bottleneck to realizing such potential is allogenic immune reaction of tissue grafts by recipients. Cerebral dopamine neurotrophic factor (CDNF) was shown to possess immune-modulatory properties that benefit neurodegenerative diseases. We hypothesized that co-administration of CDNF with fetal ventral mesencephalic (VM) tissue can improve the success of VM replacement therapies by attenuating immune responses. Hemiparkinsonian rats were generated by injecting 6-hydroxydopamine (6-OHDA) into the right medial forebrain bundle of Sprague Dawley (SD) rats. The rats were then intrastriatally transplanted with VM tissue from rats, with/without CDNF administration. Recovery of dopaminergic function and survival of the grafts were evaluated using the apomorphine-induced rotation test and small-animal positron emission tomography (PET) coupled with [<sup>18</sup>F] DOPA or [<sup>18</sup>F] FE-PE2I, respectively. In addition, transplantation-related inflammatory response was determined by uptake of [<sup>18</sup>F] FEPPA in the grafted side of striatum. Immunohistochemistry (IHC) examination was used to determine the survival of the grated dopaminergic neurons in the striatum and to investigate immune-modulatory effects of CDNF. The modulation of inflammatory responses caused by CDNF might involve enhancing M2 subset polarization and increasing fractal dimensions of 6-OHDA-treated BV2 microglial cell line. Analysis of CDNF-induced changes to gene expressions of 6-OHDA-stimulated BV2 cells implies that these alternations of the biomarkers and microglial morphology are implicated in the upregulation of protein kinase B signaling as well as regulation of catalytic, transferase, and protein serine/threonine kinase activity. The effects of CDNF on 6-OHDA-induced alternation of the canonical pathway in BV2 microglial cells is highly associated with PI3K-mediated phagosome formation. Our results are the first to show that CDNF administration enhances the survival of the grafted dopaminergic neurons and improves functional recovery in PD animal model. Modulation of the polarization, morphological characteristics, and transcriptional profiles of 6-OHDA-stimualted microglia by CDNF may possess these properties in transplantation-based regenerative therapies.https://www.mdpi.com/2227-9059/10/6/1446cerebral dopamine neurotrophic factor (CDNF)ventral mesencephalic tissuetransplantationpositron emission tomographyParkinson’s diseasemicroglia activation |
| spellingShingle | Kuan-Yin Tseng Jui-Sheng Wu Yuan-Hao Chen Mikko Airavaara Cheng-Yi Cheng Kuo-Hsing Ma Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model Biomedicines cerebral dopamine neurotrophic factor (CDNF) ventral mesencephalic tissue transplantation positron emission tomography Parkinson’s disease microglia activation |
| title | Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model |
| title_full | Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model |
| title_fullStr | Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model |
| title_full_unstemmed | Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model |
| title_short | Modulating Microglia/Macrophage Activation by CDNF Promotes Transplantation of Fetal Ventral Mesencephalic Graft Survival and Function in a Hemiparkinsonian Rat Model |
| title_sort | modulating microglia macrophage activation by cdnf promotes transplantation of fetal ventral mesencephalic graft survival and function in a hemiparkinsonian rat model |
| topic | cerebral dopamine neurotrophic factor (CDNF) ventral mesencephalic tissue transplantation positron emission tomography Parkinson’s disease microglia activation |
| url | https://www.mdpi.com/2227-9059/10/6/1446 |
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