Generation of cortical neurons through reprogramming technology

Research output: ThesisDoctoral Thesis (compilation)

Standard

Generation of cortical neurons through reprogramming technology. / Miskinyte, Giedre.

Lund : Lund University: Faculty of Medicine, 2018. 70 p.

Research output: ThesisDoctoral Thesis (compilation)

Harvard

Miskinyte, G 2018, 'Generation of cortical neurons through reprogramming technology', Doctor, Department of Clinical Sciences, Lund, Lund.

APA

Miskinyte, G. (2018). Generation of cortical neurons through reprogramming technology. Lund University: Faculty of Medicine.

CBE

Miskinyte G. 2018. Generation of cortical neurons through reprogramming technology. Lund: Lund University: Faculty of Medicine. 70 p.

MLA

Miskinyte, Giedre Generation of cortical neurons through reprogramming technology Lund: Lund University: Faculty of Medicine. 2018.

Vancouver

Miskinyte G. Generation of cortical neurons through reprogramming technology. Lund: Lund University: Faculty of Medicine, 2018. 70 p. (Lund University, Faculty of Medicine Doctoral Dissertation Series; 157).

Author

Miskinyte, Giedre. / Generation of cortical neurons through reprogramming technology. Lund : Lund University: Faculty of Medicine, 2018. 70 p.

RIS

TY - THES

T1 - Generation of cortical neurons through reprogramming technology

AU - Miskinyte, Giedre

N1 - Defence details Date: 2018-12-19 Time: 13:00 Place: GK-salen, Sölvegatan 19 i Lund External reviewer(s) Name: Falk, Anna Title: professor Affiliation: Karolinska Institutet, Stockholm

PY - 2018

Y1 - 2018

N2 - The human cortex is affected by several debilitating acute and chronic neurodegenerative disorders such as stroke, traumatic brain injury, amyotrophic lateral sclerosis and Alzheimer’s disease, which target specific types of cortical neurons. Emerging evidence indicates that stem cells and reprogrammed cells can be used to generate human cortical neurons both for cell replacement by transplantation, and for disease modeling and drug screening. Several laboratories have established in vitro protocols for the derivation of excitatory pyramidal neurons, the principal type of neuron in the adult cortex, from human pluripotent stem cells (hPSCs). Efficient production of corticofugal projection neurons (CfuPNs) from ES cells has also been reported. Alternatively, human fibroblasts have been directly converted into induced neuronal (iN) cells. However, cortical neurons have not been produced by this method. Also, it remains to be assessed how closely the derived cortical neurons resemble their in vivo counterparts, as well as, whether the generated cells are capable of integrating into human neuronal circuits.The work presented in this thesis demonstrates that cortical neuronal cells can be produced from different types of starting cells: human fibroblasts, human ES cells and human iPSC-derived NSPCs. Regardless the starting cell context and derivation protocol, we have produced in all studies neuronal cells pyramidal in shape, expressing key cortical markers and functional in vitro. More importantly, we showed that these cells are capable of forming synaptic connections with adult human cortical neurons. It remains to be assessed whether cells derived in this thesis are capable of projecting to correct brain regions in vivo. Nonetheless, by providing the first evidence that cortical neurons derived here integrate in adult host neural networks also in a human-to-human grafting situation, this thesis represents an early but important step in the clinical translation of neuronal replacement to promote recovery in the injured brain.

AB - The human cortex is affected by several debilitating acute and chronic neurodegenerative disorders such as stroke, traumatic brain injury, amyotrophic lateral sclerosis and Alzheimer’s disease, which target specific types of cortical neurons. Emerging evidence indicates that stem cells and reprogrammed cells can be used to generate human cortical neurons both for cell replacement by transplantation, and for disease modeling and drug screening. Several laboratories have established in vitro protocols for the derivation of excitatory pyramidal neurons, the principal type of neuron in the adult cortex, from human pluripotent stem cells (hPSCs). Efficient production of corticofugal projection neurons (CfuPNs) from ES cells has also been reported. Alternatively, human fibroblasts have been directly converted into induced neuronal (iN) cells. However, cortical neurons have not been produced by this method. Also, it remains to be assessed how closely the derived cortical neurons resemble their in vivo counterparts, as well as, whether the generated cells are capable of integrating into human neuronal circuits.The work presented in this thesis demonstrates that cortical neuronal cells can be produced from different types of starting cells: human fibroblasts, human ES cells and human iPSC-derived NSPCs. Regardless the starting cell context and derivation protocol, we have produced in all studies neuronal cells pyramidal in shape, expressing key cortical markers and functional in vitro. More importantly, we showed that these cells are capable of forming synaptic connections with adult human cortical neurons. It remains to be assessed whether cells derived in this thesis are capable of projecting to correct brain regions in vivo. Nonetheless, by providing the first evidence that cortical neurons derived here integrate in adult host neural networks also in a human-to-human grafting situation, this thesis represents an early but important step in the clinical translation of neuronal replacement to promote recovery in the injured brain.

KW - Cortex

KW - Reprogramming

KW - human ES cells

KW - transcription factor programming

KW - cortical projection neurons

KW - Human adult cortical slices

M3 - Doctoral Thesis (compilation)

SN - 978-91-7619-726-4

VL - 2018:157

T3 - Lund University, Faculty of Medicine Doctoral Dissertation Series

PB - Lund University: Faculty of Medicine

CY - Lund

ER -