hESC-Derived Dopaminergic Transplants Integrate into Basal Ganglia Circuitry in a Preclinical Model of Parkinson's Disease
(2019) In Cell Reports 28(13). p.5-3473- Abstract
Cell replacement is currently being explored as a therapeutic approach for neurodegenerative disease. Using stem cells as a source, transplantable progenitors can now be generated under conditions compliant with clinical application in patients. In this study, we elucidate factors controlling target-appropriate innervation and circuitry integration of human embryonic stem cell (hESC)-derived grafts after transplantation to the adult brain. We show that cell-intrinsic factors determine graft-derived axonal innervation, whereas synaptic inputs from host neurons primarily reflect the graft location. Furthermore, we provide evidence that hESC-derived dopaminergic grafts transplanted in a long-term preclinical rat model of Parkinson's... (More)
Cell replacement is currently being explored as a therapeutic approach for neurodegenerative disease. Using stem cells as a source, transplantable progenitors can now be generated under conditions compliant with clinical application in patients. In this study, we elucidate factors controlling target-appropriate innervation and circuitry integration of human embryonic stem cell (hESC)-derived grafts after transplantation to the adult brain. We show that cell-intrinsic factors determine graft-derived axonal innervation, whereas synaptic inputs from host neurons primarily reflect the graft location. Furthermore, we provide evidence that hESC-derived dopaminergic grafts transplanted in a long-term preclinical rat model of Parkinson's disease (PD) receive synaptic input from subtypes of host cortical, striatal, and pallidal neurons that are known to regulate the function of endogenous nigral dopamine neurons. This refined understanding of how graft neurons integrate with host circuitry will be important for the design of clinical stem-cell-based replacement therapies for PD, as well as for other neurodegenerative diseases. Adler et al. graft hESC-derived dopaminergic progenitors into a rat model of Parkinson's disease. They find grafts correctly innervate host targets and receive appropriate synaptic input after intranigral and intrastriatal placement. Furthermore, the same host neurons projecting toward endogenous dopamine neurons are found to also connect to the grafts.
(Less)
- author
- Adler, Andrew F. LU ; Cardoso, Tiago LU ; Nolbrant, Sara LU ; Mattsson, Bengt LU ; Hoban, Deirdre B. LU ; Jarl, Ulla LU ; Wahlestedt, Jenny Nelander LU ; Grealish, Shane LU ; Björklund, Anders LU and Parmar, Malin LU
- organization
- publishing date
- 2019-09-24
- type
- Contribution to journal
- publication status
- published
- subject
- keywords
- brain repair, cell replacement therapy, cell transplantation, grafting, monosynaptic tracing, Parkinson's disease, stem cells
- in
- Cell Reports
- volume
- 28
- issue
- 13
- pages
- 5 - 3473
- publisher
- Cell Press
- external identifiers
-
- scopus:85072215148
- pmid:31553914
- ISSN
- 2211-1247
- DOI
- 10.1016/j.celrep.2019.08.058
- language
- English
- LU publication?
- yes
- id
- d7cc793e-dd63-45ea-a490-cdd90247354e
- date added to LUP
- 2019-09-27 12:56:22
- date last changed
- 2024-07-11 05:39:23
@article{d7cc793e-dd63-45ea-a490-cdd90247354e, abstract = {{<p>Cell replacement is currently being explored as a therapeutic approach for neurodegenerative disease. Using stem cells as a source, transplantable progenitors can now be generated under conditions compliant with clinical application in patients. In this study, we elucidate factors controlling target-appropriate innervation and circuitry integration of human embryonic stem cell (hESC)-derived grafts after transplantation to the adult brain. We show that cell-intrinsic factors determine graft-derived axonal innervation, whereas synaptic inputs from host neurons primarily reflect the graft location. Furthermore, we provide evidence that hESC-derived dopaminergic grafts transplanted in a long-term preclinical rat model of Parkinson's disease (PD) receive synaptic input from subtypes of host cortical, striatal, and pallidal neurons that are known to regulate the function of endogenous nigral dopamine neurons. This refined understanding of how graft neurons integrate with host circuitry will be important for the design of clinical stem-cell-based replacement therapies for PD, as well as for other neurodegenerative diseases. Adler et al. graft hESC-derived dopaminergic progenitors into a rat model of Parkinson's disease. They find grafts correctly innervate host targets and receive appropriate synaptic input after intranigral and intrastriatal placement. Furthermore, the same host neurons projecting toward endogenous dopamine neurons are found to also connect to the grafts.</p>}}, author = {{Adler, Andrew F. and Cardoso, Tiago and Nolbrant, Sara and Mattsson, Bengt and Hoban, Deirdre B. and Jarl, Ulla and Wahlestedt, Jenny Nelander and Grealish, Shane and Björklund, Anders and Parmar, Malin}}, issn = {{2211-1247}}, keywords = {{brain repair; cell replacement therapy; cell transplantation; grafting; monosynaptic tracing; Parkinson's disease; stem cells}}, language = {{eng}}, month = {{09}}, number = {{13}}, pages = {{5--3473}}, publisher = {{Cell Press}}, series = {{Cell Reports}}, title = {{hESC-Derived Dopaminergic Transplants Integrate into Basal Ganglia Circuitry in a Preclinical Model of Parkinson's Disease}}, url = {{https://lup.lub.lu.se/search/files/100829204/ADLER_PDF_publication_in_cell_reports.pdf}}, doi = {{10.1016/j.celrep.2019.08.058}}, volume = {{28}}, year = {{2019}}, }