Dopamine transporter neuroimaging accurately assesses the maturation of dopamine neurons in a preclinical model of Parkinson’s disease
Abstract Background Significant developments in stem cell therapy for Parkinson’s disease (PD) have already been achieved; however, methods for reliable assessment of dopamine neuron maturation in vivo are lacking. Establishing the efficacy of new cellular therapies using non-invasive methodologies...
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| Format: | Article |
| Language: | English |
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BMC
2020-08-01
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| Series: | Stem Cell Research & Therapy |
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| Online Access: | http://link.springer.com/article/10.1186/s13287-020-01868-4 |
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| author | Julian L. Goggi Lifeng Qiu Mei Chih Liao Shivashankar Khanapur Lingfan Jiang Ramasamy Boominathan Siddesh V. Hartimath Peter Cheng Fui Fong Yong Vanessa Soh Xiaozhou Deng Youshan Melissa Lin Anna Haslop Peng Wen Tan Xiaoxia Zeng Jolene W. L. Lee Zhiwei Zhang Pragalath Sadasivam Eng King Tan Sajinder K. Luthra William D. Shingleton Steve K. W. Oh Li Zeng Edward G. Robins |
| author_facet | Julian L. Goggi Lifeng Qiu Mei Chih Liao Shivashankar Khanapur Lingfan Jiang Ramasamy Boominathan Siddesh V. Hartimath Peter Cheng Fui Fong Yong Vanessa Soh Xiaozhou Deng Youshan Melissa Lin Anna Haslop Peng Wen Tan Xiaoxia Zeng Jolene W. L. Lee Zhiwei Zhang Pragalath Sadasivam Eng King Tan Sajinder K. Luthra William D. Shingleton Steve K. W. Oh Li Zeng Edward G. Robins |
| author_sort | Julian L. Goggi |
| collection | DOAJ |
| description | Abstract Background Significant developments in stem cell therapy for Parkinson’s disease (PD) have already been achieved; however, methods for reliable assessment of dopamine neuron maturation in vivo are lacking. Establishing the efficacy of new cellular therapies using non-invasive methodologies will be critical for future regulatory approval and application. The current study examines the utility of neuroimaging to characterise the in vivo maturation, innervation and functional dopamine release of transplanted human embryonic stem cell-derived midbrain dopaminergic neurons (hESC-mDAs) in a preclinical model of PD. Methods Female NIH RNu rats received a unilateral stereotaxic injection of 6-OHDA into the left medial forebrain bundle to create the PD lesion. hESC-mDA cell and sham transplantations were carried out 1 month post-lesion, with treated animals receiving approximately 4 × 105 cells per transplantation. Behavioural analysis, [18F]FBCTT and [18F]fallypride microPET/CT, was conducted at 1, 3 and 6 months post-transplantation and compared with histological characterisation at 6 months. Results PET imaging revealed transplant survival and maturation into functional dopaminergic neurons. [18F]FBCTT-PET/CT dopamine transporter (DAT) imaging demonstrated pre-synaptic restoration and [18F]fallypride-PET/CT indicated functional dopamine release, whilst amphetamine-induced rotation showed significant behavioural recovery. Moreover, histology revealed that the grafted cells matured differently in vivo producing high- and low-tyrosine hydroxylase (TH) expressing cohorts, and only [18F]FBCTT uptake was well correlated with differentiation. Conclusions This study provides further evidence for the value of in vivo functional imaging for the assessment of cell therapies and highlights the utility of DAT imaging for the determination of early post-transplant cell maturation and differentiation of hESC-mDAs. |
| first_indexed | 2024-12-13T17:39:35Z |
| format | Article |
| id | doaj.art-7b3a51c8d38643008824b7f536251784 |
| institution | Directory Open Access Journal |
| issn | 1757-6512 |
| language | English |
| last_indexed | 2024-12-13T17:39:35Z |
| publishDate | 2020-08-01 |
| publisher | BMC |
| record_format | Article |
| series | Stem Cell Research & Therapy |
| spelling | doaj.art-7b3a51c8d38643008824b7f5362517842022-12-21T23:36:48ZengBMCStem Cell Research & Therapy1757-65122020-08-0111111410.1186/s13287-020-01868-4Dopamine transporter neuroimaging accurately assesses the maturation of dopamine neurons in a preclinical model of Parkinson’s diseaseJulian L. Goggi0Lifeng Qiu1Mei Chih Liao2Shivashankar Khanapur3Lingfan Jiang4Ramasamy Boominathan5Siddesh V. Hartimath6Peter Cheng7Fui Fong Yong8Vanessa Soh9Xiaozhou Deng10Youshan Melissa Lin11Anna Haslop12Peng Wen Tan13Xiaoxia Zeng14Jolene W. L. Lee15Zhiwei Zhang16Pragalath Sadasivam17Eng King Tan18Sajinder K. Luthra19William D. Shingleton20Steve K. W. Oh21Li Zeng22Edward G. Robins23Singapore Bioimaging Consortium, A*STARNeural Stem Cell Research Lab, Research Department, National Neuroscience InstituteBioprocessing Technology Institute, A*STARSingapore Bioimaging Consortium, A*STARSingapore Bioimaging Consortium, A*STARSingapore Bioimaging Consortium, A*STARSingapore Bioimaging Consortium, A*STARSingapore Bioimaging Consortium, A*STARSingapore Bioimaging Consortium, A*STARSingapore Bioimaging Consortium, A*STARSingapore Bioimaging Consortium, A*STARBioprocessing Technology Institute, A*STARSingapore Bioimaging Consortium, A*STARSingapore Bioimaging Consortium, A*STARNeural Stem Cell Research Lab, Research Department, National Neuroscience InstituteNeural Stem Cell Research Lab, Research Department, National Neuroscience InstituteNeural Stem Cell Research Lab, Research Department, National Neuroscience InstituteSingapore Bioimaging Consortium, A*STARResearch Department, National Neuroscience InstituteGE Healthcare Life SciencesGE Healthcare Life SciencesBioprocessing Technology Institute, A*STARNeural Stem Cell Research Lab, Research Department, National Neuroscience InstituteSingapore Bioimaging Consortium, A*STARAbstract Background Significant developments in stem cell therapy for Parkinson’s disease (PD) have already been achieved; however, methods for reliable assessment of dopamine neuron maturation in vivo are lacking. Establishing the efficacy of new cellular therapies using non-invasive methodologies will be critical for future regulatory approval and application. The current study examines the utility of neuroimaging to characterise the in vivo maturation, innervation and functional dopamine release of transplanted human embryonic stem cell-derived midbrain dopaminergic neurons (hESC-mDAs) in a preclinical model of PD. Methods Female NIH RNu rats received a unilateral stereotaxic injection of 6-OHDA into the left medial forebrain bundle to create the PD lesion. hESC-mDA cell and sham transplantations were carried out 1 month post-lesion, with treated animals receiving approximately 4 × 105 cells per transplantation. Behavioural analysis, [18F]FBCTT and [18F]fallypride microPET/CT, was conducted at 1, 3 and 6 months post-transplantation and compared with histological characterisation at 6 months. Results PET imaging revealed transplant survival and maturation into functional dopaminergic neurons. [18F]FBCTT-PET/CT dopamine transporter (DAT) imaging demonstrated pre-synaptic restoration and [18F]fallypride-PET/CT indicated functional dopamine release, whilst amphetamine-induced rotation showed significant behavioural recovery. Moreover, histology revealed that the grafted cells matured differently in vivo producing high- and low-tyrosine hydroxylase (TH) expressing cohorts, and only [18F]FBCTT uptake was well correlated with differentiation. Conclusions This study provides further evidence for the value of in vivo functional imaging for the assessment of cell therapies and highlights the utility of DAT imaging for the determination of early post-transplant cell maturation and differentiation of hESC-mDAs.http://link.springer.com/article/10.1186/s13287-020-01868-4Parkinson’s diseaseDopaminergic neuronCell therapyPET imagingDAT |
| spellingShingle | Julian L. Goggi Lifeng Qiu Mei Chih Liao Shivashankar Khanapur Lingfan Jiang Ramasamy Boominathan Siddesh V. Hartimath Peter Cheng Fui Fong Yong Vanessa Soh Xiaozhou Deng Youshan Melissa Lin Anna Haslop Peng Wen Tan Xiaoxia Zeng Jolene W. L. Lee Zhiwei Zhang Pragalath Sadasivam Eng King Tan Sajinder K. Luthra William D. Shingleton Steve K. W. Oh Li Zeng Edward G. Robins Dopamine transporter neuroimaging accurately assesses the maturation of dopamine neurons in a preclinical model of Parkinson’s disease Stem Cell Research & Therapy Parkinson’s disease Dopaminergic neuron Cell therapy PET imaging DAT |
| title | Dopamine transporter neuroimaging accurately assesses the maturation of dopamine neurons in a preclinical model of Parkinson’s disease |
| title_full | Dopamine transporter neuroimaging accurately assesses the maturation of dopamine neurons in a preclinical model of Parkinson’s disease |
| title_fullStr | Dopamine transporter neuroimaging accurately assesses the maturation of dopamine neurons in a preclinical model of Parkinson’s disease |
| title_full_unstemmed | Dopamine transporter neuroimaging accurately assesses the maturation of dopamine neurons in a preclinical model of Parkinson’s disease |
| title_short | Dopamine transporter neuroimaging accurately assesses the maturation of dopamine neurons in a preclinical model of Parkinson’s disease |
| title_sort | dopamine transporter neuroimaging accurately assesses the maturation of dopamine neurons in a preclinical model of parkinson s disease |
| topic | Parkinson’s disease Dopaminergic neuron Cell therapy PET imaging DAT |
| url | http://link.springer.com/article/10.1186/s13287-020-01868-4 |
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