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Implantation of the clinical-grade human neural stem cell line, CTX0E03 , rescues the behavioral and pathological deficits in the quinolinic acid-lesioned rodent model of Huntington's disease

Yoon, Yongwoo, Kim, Hyun Sook, Jeon, Iksoo, Noh, Jeong-Eun, Park, Hyun Jung, Lee, Suji, Park, In-Hyun, Stevanato, Lara, Hicks, Caroline, Corteling, Randolph, Barker, Roger A., Sinden, John D., Song, Jihwan·2020·Stem Cells
DOI 10.1002/stem.3191PMC PMC7496241
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Abstract

Huntington's disease (HD) is a devastating, autosomal-dominant neurodegenerative disease, for which there are currently no disease-modifying therapies. Clinical trials to replace the damaged striatal medium spiny neurons (MSNs) have been attempted in the past two decades but have met with only limited success. In this study, we investigated whether a clonal, conditionally immortalized neural stem cell line (CTX0E03), which has already shown safety and signals of efficacy in chronic ischemic stroke patients, could rescue deficits seen in an animal model of HD. After CTX0E03 transplantation into the quinolinic acid-lesioned rat model of HD, behavioral changes were measured using the rotarod, stepping, and staircase tests. In vivo differentiation and neuronal connections of the transplanted CTX0E03 cells were evaluated with immunohistochemical staining and retrograde tracing with Fluoro-Gold. We found that transplantation of CTX0E03 gave rise to a significant behavioral improvement compared with the sham- or fibroblast-transplanted group. Transplanted CTX0E03 formed MSNs (DARPP-32) and GABAergic neurons (GABA, GAD65/67) with BDNF expression in the striatum, while cortically transplanted cells formed Tbr1-positive neurons. Using a retrograde label, we also found stable engraftment and connection of the transplanted cells with host brain tissues. CTX0E03 transplantation also reduced glial scar formation and inflammation, as well as increasing endogenous neurogenesis and angiogenesis. Overall, our results demonstrate that CTX0E03, a clinical-grade neural stem cell line, is effective for preclinical test in HD, and, therefore, will be useful for clinical development in the treatment of HD patients.

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FIGURE 1 CTX cells significantly improve the behavioral deficits induced by quinolinic acid (QA) lesioning of the striatum. Marked improvement of locomotor activity was observed in the QA‐lesioned rats transplanted with CTX between 8 and 12 weeks post‐transplantation (**P < .001 Sham vs CTX; ##P < .001 Fibroblast vs CTX) on rotarod (A) and stepping (B) tests. In the staircase test (C), significant behavioral improvement was observed in the QA‐lesioned rats with CTX between 8 and 12 weeks after transplantation (*P < .05 Sham vs CTX; #P < .05 Fibroblast vs CTX). Prescore represents the animals before receiving QA and the baseline score represents 7 days after QA lesioning. Subsequent scores represent animals after CTX transplantation
FIGURE 1 CTX cells significantly improve the behavioral deficits induced by quinolinic acid (QA) lesioning of the striatum. Marked improvement of locomotor activity was observed in the QA‐lesioned rats transplanted with CTX between 8 and 12 weeks post‐transplantation (**P < .001 Sham vs CTX; ##P < .001 Fibroblast vs CTX) on rotarod (A) and stepping (B) tests. In the staircase test (C), significant behavioral improvement was observed in the QA‐lesioned rats with CTX between 8 and 12 weeks after transplantation (*P < .05 Sham vs CTX; #P < .05 Fibroblast vs CTX). Prescore represents the animals before receiving QA and the baseline score represents 7 days after QA lesioning. Subsequent scores represent animals after CTX transplantationCC BY-NC-ND · PubMed Central
FIGURE 2 CTX cells can survive and differentiate into striatal neurons in the striatum of quinolinic acid (QA)‐lesioned brain 13 weeks after transplantation. A, Widespread distribution of survived CTX cells were detected using a human nuclei antibody (hNu) and visualized with DAB (3,3′‐diaminobenzidine) in the QA‐lesioned striatum. Scale bar = 50 μm. B‐E, Neuronal differentiation of CTX cells transplanted into the striatum (arrows) was identified by hNu colocalized with neuronal markers, including DARPP‐32 (B), GABA (C), GAD 65/67 (D), and BDNF (E). Scale bar = 50 μm
FIGURE 2 CTX cells can survive and differentiate into striatal neurons in the striatum of quinolinic acid (QA)‐lesioned brain 13 weeks after transplantation. A, Widespread distribution of survived CTX cells were detected using a human nuclei antibody (hNu) and visualized with DAB (3,3′‐diaminobenzidine) in the QA‐lesioned striatum. Scale bar = 50 μm. B‐E, Neuronal differentiation of CTX cells transplanted into the striatum (arrows) was identified by hNu colocalized with neuronal markers, including DARPP‐32 (B), GABA (C), GAD 65/67 (D), and BDNF (E). Scale bar = 50 μmCC BY-NC-ND · PubMed Central
FIGURE 3 CTX cells implanted in the cortex can differentiate into cortical neurons. Colocalization (yellow) of hNu and Trb1 demonstrates neuronal differentiation of CTX cells in the cortex 13 weeks after transplantation (arrows). Scale bar = 50 μm
FIGURE 3 CTX cells implanted in the cortex can differentiate into cortical neurons. Colocalization (yellow) of hNu and Trb1 demonstrates neuronal differentiation of CTX cells in the cortex 13 weeks after transplantation (arrows). Scale bar = 50 μmCC BY-NC-ND · PubMed Central
FIGURE 4 CTX cells can establish striato‐pallidal connection in the quinolinic acid (QA)‐lesioned striatum. Colocalization (yellow) of Fluoro‐Gold (FG) and human nuclei in CTX cells (arrows) within the stratum suggests some restoration of local circuitry. Scale bar = 50 μm
FIGURE 4 CTX cells can establish striato‐pallidal connection in the quinolinic acid (QA)‐lesioned striatum. Colocalization (yellow) of Fluoro‐Gold (FG) and human nuclei in CTX cells (arrows) within the stratum suggests some restoration of local circuitry. Scale bar = 50 μmCC BY-NC-ND · PubMed Central
FIGURE 5 CTX cells decrease gliosis and proinflammatory responses in the quinolinic acid (QA)‐lesioned striatum. A, GFAP staining was significantly reduced in CTX‐implanted brains compared with Sham (Media) and Fibroblast (FB) injected brains (CTX vs Sham P = .004; CTX vs FB P = .014). Scale bar = 50 μm. B, CTX cells reduce a M1 proinflammatory phenotype of macrophage in the QA‐lesioned striatum. The percentage of iNOS/ED1 was reduced in CTX treated brains compared with Sham (Media) and Fibroblast grafted brains (CTX vs Sham P < .001, CTX vs FB P = .017). C, CTX cells increase an M2 anti‐inflammatory phenotype in the QA‐lesioned striatum. CD206/ED1 increased in CTX treated brains compared with Sham (Media) and Fibroblast injected brains (CTX vs Sham P < .001, CTX vs FB P < .001). Scale bar = 50 μm
FIGURE 5 CTX cells decrease gliosis and proinflammatory responses in the quinolinic acid (QA)‐lesioned striatum. A, GFAP staining was significantly reduced in CTX‐implanted brains compared with Sham (Media) and Fibroblast (FB) injected brains (CTX vs Sham P = .004; CTX vs FB P = .014). Scale bar = 50 μm. B, CTX cells reduce a M1 proinflammatory phenotype of macrophage in the QA‐lesioned striatum. The percentage of iNOS/ED1 was reduced in CTX treated brains compared with Sham (Media) and Fibroblast grafted brains (CTX vs Sham P < .001, CTX vs FB P = .017). C, CTX cells increase an M2 anti‐inflammatory phenotype in the QA‐lesioned striatum. CD206/ED1 increased in CTX treated brains compared with Sham (Media) and Fibroblast injected brains (CTX vs Sham P < .001, CTX vs FB P < .001). Scale bar = 50 μmCC BY-NC-ND · PubMed Central
FIGURE 6 CTX cells promote neurogenesis in the quinolinic acid (QA)‐lesioned brain. Compared with Sham (Media) and Fibroblast injected brains, the proportion of both BrdU and DCX stained cells was increased markedly in the SVZ of CTX treated brains (BrdU/DAPI CTX vs Sham P < .001, CTX vs FB P < .001; DCX/DAPI CTX vs Sham P < .001, CTX vs FB P = .002). The percentage of DCX expressing cells in BrdU‐positive cells in the SVZ was also significantly increased in CTX treated brains (DCX/BrdU CTX vs Sham P = .025, CTX vs FB P = .029). Scale bar = 100 μm
FIGURE 6 CTX cells promote neurogenesis in the quinolinic acid (QA)‐lesioned brain. Compared with Sham (Media) and Fibroblast injected brains, the proportion of both BrdU and DCX stained cells was increased markedly in the SVZ of CTX treated brains (BrdU/DAPI CTX vs Sham P < .001, CTX vs FB P < .001; DCX/DAPI CTX vs Sham P < .001, CTX vs FB P = .002). The percentage of DCX expressing cells in BrdU‐positive cells in the SVZ was also significantly increased in CTX treated brains (DCX/BrdU CTX vs Sham P = .025, CTX vs FB P = .029). Scale bar = 100 μmCC BY-NC-ND · PubMed Central
FIGURE 7 CTX cells promote angiogenesis in the quinolinic acid (QA)‐lesioned brain. RECA‐1 staining demonstrates that the number of branch points and microvessels was all significantly increased in CTX‐implanted brains compared with Sham (Media) and Fibroblast injected brains (P < .001 CTX vs Sham; P < .001 CTX vs FB; branch points P = .019 CTX vs Sham; P < .001 CTX vs FB; microvessels P < .001 CTX vs Sham; P < .001 CTX vs FB). Scale bar = 50 μm
FIGURE 7 CTX cells promote angiogenesis in the quinolinic acid (QA)‐lesioned brain. RECA‐1 staining demonstrates that the number of branch points and microvessels was all significantly increased in CTX‐implanted brains compared with Sham (Media) and Fibroblast injected brains (P < .001 CTX vs Sham; P < .001 CTX vs FB; branch points P = .019 CTX vs Sham; P < .001 CTX vs FB; microvessels P < .001 CTX vs Sham; P < .001 CTX vs FB). Scale bar = 50 μmCC BY-NC-ND · PubMed Central

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Cited by

Metadata

Authors
Yoon, Y., Kim, H. S., Jeon, I., Noh, J.-E., Park, H. J., Lee, S., Park, I.-H., Stevanato, L., Hicks, C., Corteling, R., Barker, R. A., Sinden, J. D., & Song, J.
Affiliations
  • 1 Department of Biomedical Science, CHA Stem Cell Institute, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea
  • 2 Department of Neurology, CHA Bundang Medical Center, CHA University, Seongnam-si, Gyeonggi-do, Republic of Korea
  • 3 Department of Genetics, Yale Stem Cell Center, Yale School of Medicine, New Haven, Connecticut, USA
  • 4 ReNeuron, Pencoed Business Park, Bridgend, UK
  • 5 John van Geest Cambridge Centre for Brain Repair, Department of Clinical Neuroscience, University of Cambridge, Cambridge, UK
ORCID
Song, Jihwan
Venue
Stem Cells
Publisher
Oxford University Press (OUP)
Published
2020-05-06
Volume
38
Issue
8
Pages
936-947
ISSN
  • 1066-5099
  • 1549-4918
DOI
10.1002/stem.3191
PMC
PMC7496241
Cited by
34
References
2
Language
en
Licence
Funders
  • National Research Foundation of Korea (NRF-2017M3A9B4061407, NRF‐2017M3A9B4061407)
  • iPS Bio, Inc
  • ReNeuron, United Kingdom

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