Grafts Derived from an α-Synuclein Triplication Patient Mediate Functional Recovery but Develop Disease-Associated Pathology in the 6-OHDA Model of Parkinson's Disease
Shrigley, Shelby LU
; Nilsson, Fredrik
LU
; Mattsson, Bengt
LU
; Fiorenzano, Alessandro
LU
; Mudannayake, Janitha
LU
; Bruzelius, Andreas
LU
; Ottosson, Daniella Rylander
LU
; Björklund, Anders
LU
; Hoban, Deirdre B
LU
and Parmar, Malin
LU
(2021)
In Journal of Parkinson's Disease
11(2).
p.515-528
- Abstract
BACKGROUND: Human induced pluripotent stem cells (hiPSCs) have been proposed as an alternative source for cell replacement therapy for Parkinson's disease (PD) and they provide the option of using the patient's own cells. A few studies have investigated transplantation of patient-derived dopaminergic (DA) neurons in preclinical models; however, little is known about the long-term integrity and function of grafts derived from patients with PD.
OBJECTIVE: To assess the viability and function of DA neuron grafts derived from a patient hiPSC line with an α-synuclein gene triplication (AST18), using a clinical grade human embryonic stem cell (hESC) line (RC17) as a reference control.
METHODS: Cells were differentiated into... (More)
BACKGROUND: Human induced pluripotent stem cells (hiPSCs) have been proposed as an alternative source for cell replacement therapy for Parkinson's disease (PD) and they provide the option of using the patient's own cells. A few studies have investigated transplantation of patient-derived dopaminergic (DA) neurons in preclinical models; however, little is known about the long-term integrity and function of grafts derived from patients with PD.
OBJECTIVE: To assess the viability and function of DA neuron grafts derived from a patient hiPSC line with an α-synuclein gene triplication (AST18), using a clinical grade human embryonic stem cell (hESC) line (RC17) as a reference control.
METHODS: Cells were differentiated into ventral mesencephalic (VM)-patterned DA progenitors using an established GMP protocol. The progenitors were then either terminally differentiated to mature DA neurons in vitro or transplanted into 6-hydroxydopamine (6-OHDA) lesioned rats and their survival, maturation, function, and propensity to develop α-synuclein related pathology, were assessed in vivo.
RESULTS: Both cell lines generated functional neurons with DA properties in vitro. AST18-derived VM progenitor cells survived transplantation and matured into neuron-rich grafts similar to the RC17 cells. After 24 weeks, both cell lines produced DA-rich grafts that mediated full functional recovery; however, pathological changes were only observed in grafts derived from the α-synuclein triplication patient line.
CONCLUSION: This data shows proof-of-principle for survival and functional recovery with familial PD patient-derived cells in the 6-OHDA model of PD. However, signs of slowly developing pathology warrants further investigation before use of autologous grafts in patients.
(Less)
- author
- Shrigley, Shelby
LU
; Nilsson, Fredrik
LU
; Mattsson, Bengt
LU
; Fiorenzano, Alessandro
LU
; Mudannayake, Janitha
LU
; Bruzelius, Andreas
LU
; Ottosson, Daniella Rylander
LU
; Björklund, Anders
LU
; Hoban, Deirdre B
LU
and Parmar, Malin
LU
- organization
- publishing date
- 2021-04-13
- type
- Contribution to journal
- publication status
- published
- subject
- in
- Journal of Parkinson's Disease
- volume
- 11
- issue
- 2
- pages
- 515 - 528
- publisher
- IOS Press
- external identifiers
-
- pmid:33361611
- scopus:85104331818
- ISSN
- 1877-718X
- DOI
- 10.3233/JPD-202366
- language
- English
- LU publication?
- yes
- additional info
- These authors contributed equally to this work: H. Deirdre and M. Parmar
- id
- be0b8167-2b21-4ed3-95fc-fdbb9c2cd3b3
- date added to LUP
- 2021-01-14 13:59:41
- date last changed
- 2024-06-13 05:11:18
@article{be0b8167-2b21-4ed3-95fc-fdbb9c2cd3b3,
abstract = {{<p>BACKGROUND: Human induced pluripotent stem cells (hiPSCs) have been proposed as an alternative source for cell replacement therapy for Parkinson's disease (PD) and they provide the option of using the patient's own cells. A few studies have investigated transplantation of patient-derived dopaminergic (DA) neurons in preclinical models; however, little is known about the long-term integrity and function of grafts derived from patients with PD.</p><p>OBJECTIVE: To assess the viability and function of DA neuron grafts derived from a patient hiPSC line with an α-synuclein gene triplication (AST18), using a clinical grade human embryonic stem cell (hESC) line (RC17) as a reference control.</p><p>METHODS: Cells were differentiated into ventral mesencephalic (VM)-patterned DA progenitors using an established GMP protocol. The progenitors were then either terminally differentiated to mature DA neurons in vitro or transplanted into 6-hydroxydopamine (6-OHDA) lesioned rats and their survival, maturation, function, and propensity to develop α-synuclein related pathology, were assessed in vivo.</p><p>RESULTS: Both cell lines generated functional neurons with DA properties in vitro. AST18-derived VM progenitor cells survived transplantation and matured into neuron-rich grafts similar to the RC17 cells. After 24 weeks, both cell lines produced DA-rich grafts that mediated full functional recovery; however, pathological changes were only observed in grafts derived from the α-synuclein triplication patient line.</p><p>CONCLUSION: This data shows proof-of-principle for survival and functional recovery with familial PD patient-derived cells in the 6-OHDA model of PD. However, signs of slowly developing pathology warrants further investigation before use of autologous grafts in patients.</p>}},
author = {{Shrigley, Shelby and Nilsson, Fredrik and Mattsson, Bengt and Fiorenzano, Alessandro and Mudannayake, Janitha and Bruzelius, Andreas and Ottosson, Daniella Rylander and Björklund, Anders and Hoban, Deirdre B and Parmar, Malin}},
issn = {{1877-718X}},
language = {{eng}},
month = {{04}},
number = {{2}},
pages = {{515--528}},
publisher = {{IOS Press}},
series = {{Journal of Parkinson's Disease}},
title = {{Grafts Derived from an α-Synuclein Triplication Patient Mediate Functional Recovery but Develop Disease-Associated Pathology in the 6-OHDA Model of Parkinson's Disease}},
url = {{https://lup.lub.lu.se/search/files/100827590/SHRIGLEY_PDF_publication_in_Journal_of_Parkinson_s_Disease.pdf}},
doi = {{10.3233/JPD-202366}},
volume = {{11}},
year = {{2021}},
}