Establishing iPSCs as a method to model neurodevelopment in Down’s syndrome

Sammanfattning: The derivation of pluripotent stem cells (now termed induced pluripotent stem cells, iPSC) from mature somatic cells was a finding of seminal importance to fundamental cell biology. Thus established iPSC technology has been predicted to advance fields that previously relied on the ethically disputed use of embryonic stem cells. Being pluripotent (able to differentiate into every cell type present in the human body) and sharing most other characteristics with embryonic stem cells, but being much readier obtainable and their derivation free from ethical restraints, human induced pluripotent stem cells (hiPSC) provide access to cell types and insights into cell processes previously unattainable to researches. For this thesis, a hiPSC line was established from a skin biopsy donated by a Down’s syndrome patient. Most of what is known today about the molecular neurobiology behind this disease has been gathered from mice models or human post mortem studies, but this has a limited extrapolation potential to early human brain development in DS patients, as Down’s syndrome is an inherently human disease whose defining phenotype is established early during embryonic development. Having access to human pluripotent cells able to recapitulate the events of early neurogenesis is thus invaluable to the understanding of the mechanisms of this disorder. In parallel, work has been performed on optimizing iPSC reprogramming protocol. By exchanging one of the transcription factors used for reprogramming with a reporter gene, genomic integration of reprogramming factors has become possible to be traced visually, enabling more efficient selection of reprogrammed iPSC colonies.