Exploring Direct Conversion of Human Glia into Therapeutic Neurons
(2022) In Lund University, Faculty of Medicine Doctoral Dissertation Series- Abstract
- Direct neuronal reprogramming of a somatic cell into therapeutic neurons, without a transient pluripotent state, provides new promise for the large number of individuals afflicted by neurodegenerative diseases or brain injury. This approach could be potentially applied directly in the brain by targeting resident cells as a source of new neurons. Direct neuronal conversion of resident glial cells is advantageous since they are ubiquitously distributed brain cells able to self-renew and replenish their number, making them ideal candidates for endogenous repair.
In this thesis, human glia-to-neuron direct conversion and engineered viral vectors are explored using pre-clinical in vitro and ex vivo models. The first part of the thesis... (More) - Direct neuronal reprogramming of a somatic cell into therapeutic neurons, without a transient pluripotent state, provides new promise for the large number of individuals afflicted by neurodegenerative diseases or brain injury. This approach could be potentially applied directly in the brain by targeting resident cells as a source of new neurons. Direct neuronal conversion of resident glial cells is advantageous since they are ubiquitously distributed brain cells able to self-renew and replenish their number, making them ideal candidates for endogenous repair.
In this thesis, human glia-to-neuron direct conversion and engineered viral vectors are explored using pre-clinical in vitro and ex vivo models. The first part of the thesis (Paper I, II, III) shows the development and improvement of a hESC-based system of for virus-mediated direct reprogramming of human glial progenitor cells into both induced dopaminergic neurons (iDANs) and GABAergic interneurons. An extensive functional and molecular analysis confirms the maturation and properties of these neurons and we show the expression of subtype-specific markers in vitro. We have also increased our understanding on the reprogramming process by employing single-nucleus RNA sequencing for assessment of cell composition before and after conversion into iDANs. The last part of the thesis (Paper IV) is aimed at investigating a better targeting strategy for future in vivo conversion applications and demonstrates that selective infection of human glia transplanted in the rodent brain can be achieved by engineering the AAV capsid surface.
Collectively, the work thereby presented contributes to better understanding of the potential of this technique and further advanced the development of therapeutic reprogramming strategies as a future avenue for brain repair. (Less)
Please use this url to cite or link to this publication:
https://lup.lub.lu.se/record/8749cf70-af61-4973-9dfd-2cf72f99019b
- author
- Giacomoni, Jessica LU
- supervisor
-
- Malin Parmar LU
- Daniella Ottosson LU
- Johan Jakobsson LU
- opponent
-
- Professor Karow, Marisa, Biochemistry and Molecular Neuroscience, Institute of Biochemistry,
- organization
- publishing date
- 2022
- type
- Thesis
- publication status
- published
- subject
- keywords
- human embryonic stem cells, glial progenitor cells, neuronal reprogramming, induced neurons, spheroids, brain slice cultures, neurodegenerative disorders
- in
- Lund University, Faculty of Medicine Doctoral Dissertation Series
- issue
- 2022:133
- pages
- 82 pages
- publisher
- Lund University, Faculty of Medicine
- defense location
- Segerfalksalen, BMC A10, Sölvegatan 17 i Lund
- defense date
- 2022-10-14 09:00:00
- ISSN
- 1652-8220
- ISBN
- 978-91-8021-295-3
- language
- English
- LU publication?
- yes
- id
- 8749cf70-af61-4973-9dfd-2cf72f99019b
- date added to LUP
- 2022-09-22 13:34:31
- date last changed
- 2022-09-27 14:18:53
@phdthesis{8749cf70-af61-4973-9dfd-2cf72f99019b,
abstract = {{Direct neuronal reprogramming of a somatic cell into therapeutic neurons, without a transient pluripotent state, provides new promise for the large number of individuals afflicted by neurodegenerative diseases or brain injury. This approach could be potentially applied directly in the brain by targeting resident cells as a source of new neurons. Direct neuronal conversion of resident glial cells is advantageous since they are ubiquitously distributed brain cells able to self-renew and replenish their number, making them ideal candidates for endogenous repair.<br/>In this thesis, human glia-to-neuron direct conversion and engineered viral vectors are explored using pre-clinical in vitro and ex vivo models. The first part of the thesis (Paper I, II, III) shows the development and improvement of a hESC-based system of for virus-mediated direct reprogramming of human glial progenitor cells into both induced dopaminergic neurons (iDANs) and GABAergic interneurons. An extensive functional and molecular analysis confirms the maturation and properties of these neurons and we show the expression of subtype-specific markers in vitro. We have also increased our understanding on the reprogramming process by employing single-nucleus RNA sequencing for assessment of cell composition before and after conversion into iDANs. The last part of the thesis (Paper IV) is aimed at investigating a better targeting strategy for future in vivo conversion applications and demonstrates that selective infection of human glia transplanted in the rodent brain can be achieved by engineering the AAV capsid surface.<br/>Collectively, the work thereby presented contributes to better understanding of the potential of this technique and further advanced the development of therapeutic reprogramming strategies as a future avenue for brain repair.}},
author = {{Giacomoni, Jessica}},
isbn = {{978-91-8021-295-3}},
issn = {{1652-8220}},
keywords = {{human embryonic stem cells; glial progenitor cells; neuronal reprogramming; induced neurons; spheroids; brain slice cultures; neurodegenerative disorders}},
language = {{eng}},
number = {{2022:133}},
publisher = {{Lund University, Faculty of Medicine}},
school = {{Lund University}},
series = {{Lund University, Faculty of Medicine Doctoral Dissertation Series}},
title = {{Exploring Direct Conversion of Human Glia into Therapeutic Neurons}},
year = {{2022}},
}