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Exploring Patient-Specific Cell Replacement Therapy for Parkinson's Disease

Shrigley, Shelby LU (2021) In Lund University, Faculty of Medicine Doctoral Dissertation Series
Abstract
Parkinson’s disease (PD) affects over six million people worldwide and is characterised by the progressive loss of dopaminergic (DA) neurons in the substantia nigra, accumulation of pathological alpha-synuclein (αSyn), and inflammation in the brain. This leads to motor impairments including rigidity, akinesia, bradykinesia, resting tremor, and postural instability. Cell replacement therapy aims to replace the midbrain DA neurons which have been lost in the disease to restore normal motor function. Previously, DA cells for transplantation have been derived from fetal mesencephalic tissue or human embryonic stem cells (hESCs). However, an alternative route to generate DA cells is via cellular reprogramming. This is a rapidly emerging field... (More)
Parkinson’s disease (PD) affects over six million people worldwide and is characterised by the progressive loss of dopaminergic (DA) neurons in the substantia nigra, accumulation of pathological alpha-synuclein (αSyn), and inflammation in the brain. This leads to motor impairments including rigidity, akinesia, bradykinesia, resting tremor, and postural instability. Cell replacement therapy aims to replace the midbrain DA neurons which have been lost in the disease to restore normal motor function. Previously, DA cells for transplantation have been derived from fetal mesencephalic tissue or human embryonic stem cells (hESCs). However, an alternative route to generate DA cells is via cellular reprogramming. This is a rapidly emerging field which allows somatic cells to be reprogrammed either into human induced pluripotent stem cells (hiPSCs) or directly into induced neurons (iNs) by forced expression of specific factors. This creates the possibility to use patient-specific cells which could reduce the risk of immune rejection and eliminate ethical concerns.

The overall aim of this thesis is to evaluate if patient-derived cells could be a suitable alternative in cell replacement therapy for PD. Firstly, an efficient protocol to directly reprogram human adult fibroblasts into iNs was developed. Following this, factors that could convert cells specifically towards a DA subtype were investigated and used to examine if cells from healthy donors and PD patients could be reprogrammed with similar efficiency. Next, a new humanized αSyn xenograft model of PD was established to assess the impact of host pathology on grafted cells. Finally, we explored if DA cells derived from a patient hiPSC line harbouring an αSyn triplication mutation could survive intracerebral transplantation and function on par with hESC-derived DA neurons. This patient line was also assessed for the presence of pathological features in different models of PD. These results will help to pave the way for future research assessing the potential of patient-derived cells for brain repair. (Less)
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author
supervisor
opponent
  • associate professor Meyer, Morten, University of Southern Denmark, Odense, Denmark.
organization
publishing date
type
Thesis
publication status
published
subject
keywords
dopaminergic neurons, Parkinson's disease, cell replacement therapy, cellular reprogramming, alpha-synuclein
in
Lund University, Faculty of Medicine Doctoral Dissertation Series
issue
2021:20
pages
87 pages
publisher
Lund University, Faculty of Medicine
defense location
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/62063710446
defense date
2021-03-12 09:00:00
ISSN
1652-8220
ISBN
978-91-8021-026-3
language
English
LU publication?
yes
id
0b75f9f7-9dfb-4aae-bab4-b4d24121afa2
date added to LUP
2021-02-12 12:09:27
date last changed
2021-03-05 15:58:23
@phdthesis{0b75f9f7-9dfb-4aae-bab4-b4d24121afa2,
  abstract     = {Parkinson’s disease (PD) affects over six million people worldwide and is characterised by the progressive loss of dopaminergic (DA) neurons in the substantia nigra, accumulation of pathological alpha-synuclein (αSyn), and inflammation in the brain. This leads to motor impairments including rigidity, akinesia, bradykinesia, resting tremor, and postural instability. Cell replacement therapy aims to replace the midbrain DA neurons which have been lost in the disease to restore normal motor function. Previously, DA cells for transplantation have been derived from fetal mesencephalic tissue or human embryonic stem cells (hESCs). However, an alternative route to generate DA cells is via cellular reprogramming. This is a rapidly emerging field which allows somatic cells to be reprogrammed either into human induced pluripotent stem cells (hiPSCs) or directly into induced neurons (iNs) by forced expression of specific factors. This creates the possibility to use patient-specific cells which could reduce the risk of immune rejection and eliminate ethical concerns.<br/><br/>The overall aim of this thesis is to evaluate if patient-derived cells could be a suitable alternative in cell replacement therapy for PD. Firstly, an efficient protocol to directly reprogram human adult fibroblasts into iNs was developed. Following this, factors that could convert cells specifically towards a DA subtype were investigated and used to examine if cells from healthy donors and PD patients could be reprogrammed with similar efficiency. Next, a new humanized αSyn xenograft model of PD was established to assess the impact of host pathology on grafted cells. Finally, we explored if DA cells derived from a patient hiPSC line harbouring an αSyn triplication mutation could survive intracerebral transplantation and function on par with hESC-derived DA neurons. This patient line was also assessed for the presence of pathological features in different models of PD. These results will help to pave the way for future research assessing the potential of patient-derived cells for brain repair.},
  author       = {Shrigley, Shelby},
  isbn         = {978-91-8021-026-3},
  issn         = {1652-8220},
  language     = {eng},
  number       = {2021:20},
  publisher    = {Lund University, Faculty of Medicine},
  school       = {Lund University},
  series       = {Lund University, Faculty of Medicine Doctoral Dissertation Series},
  title        = {Exploring Patient-Specific Cell Replacement Therapy for Parkinson's Disease},
  url          = {https://lup.lub.lu.se/search/ws/files/91290475/Shelby_Shrigley_Thesis_LUCRIS.pdf},
  year         = {2021},
}