Exploring Patient-Specific Cell Replacement Therapy for Parkinson's Disease
Författare
Summary, in English
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.
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.
Avdelning/ar
Publiceringsår
2021
Språk
Engelska
Publikation/Tidskrift/Serie
Lund University, Faculty of Medicine Doctoral Dissertation Series
Issue
2021:20
Fulltext
- Available as PDF - 21 MB
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Dokumenttyp
Doktorsavhandling
Förlag
Lund University, Faculty of Medicine
Ämne
- Neurosciences
Nyckelord
- dopaminergic neurons
- Parkinson's disease
- cell replacement therapy
- cellular reprogramming
- alpha-synuclein
Status
Published
Forskningsgrupp
- Developmental and Regenerative Neurobiology
Handledare
- Malin Parmar
- Cecilia Lundberg
- Deirdre Hoban
ISBN/ISSN/Övrigt
- ISSN: 1652-8220
- ISBN: 978-91-8021-026-3
Försvarsdatum
12 mars 2021
Försvarstid
09:00
Försvarsplats
Segerfalksalen, BMC A10, Sölvegatan 17 i Lund. Join by Zoom: https://lu-se.zoom.us/j/62063710446
Opponent
- Morten Meyer (associate professor)