TY - JOUR
T1 - 3D Cultures of Parkinson's Disease-Specific Dopaminergic Neurons for High Content Phenotyping and Drug Testing
AU - Bolognin, Silvia
AU - Fossépré, Marie
AU - Qing, Xiaobing
AU - Jarazo, Javier
AU - Ščančar, Janez
AU - Moreno, Edinson Lucumi
AU - Nickels, Sarah L.
AU - Wasner, Kobi
AU - Ouzren, Nassima
AU - Walter, Jonas
AU - Grünewald, Anne
AU - Glaab, Enrico
AU - Salamanca, Luis
AU - Fleming, Ronan M.T.
AU - Antony, Paul M.A.
AU - Schwamborn, Jens C.
PY - 2019/1/9
Y1 - 2019/1/9
N2 - Parkinson's disease (PD)-specific neurons, grown in standard 2D cultures, typically only display weak endophenotypes. The cultivation of PD patient-specific neurons, derived from induced pluripotent stem cells carrying the LRRK2-G2019S mutation, is optimized in 3D microfluidics. The automated image analysis algorithms are implemented to enable pharmacophenomics in disease-relevant conditions. In contrast to 2D cultures, this 3D approach reveals robust endophenotypes. High-content imaging data show decreased dopaminergic differentiation and branching complexity, altered mitochondrial morphology, and increased cell death in LRRK2-G2019S neurons compared to isogenic lines without using stressor agents. Treatment with the LRRK2 inhibitor 2 (Inh2) rescues LRRK2-G2019S-dependent dopaminergic phenotypes. Strikingly, a holistic analysis of all studied features shows that the genetic background of the PD patients, and not the LRRK2-G2019S mutation, constitutes the strongest contribution to the phenotypes. These data support the use of advanced in vitro models for future patient stratification and personalized drug development.
AB - Parkinson's disease (PD)-specific neurons, grown in standard 2D cultures, typically only display weak endophenotypes. The cultivation of PD patient-specific neurons, derived from induced pluripotent stem cells carrying the LRRK2-G2019S mutation, is optimized in 3D microfluidics. The automated image analysis algorithms are implemented to enable pharmacophenomics in disease-relevant conditions. In contrast to 2D cultures, this 3D approach reveals robust endophenotypes. High-content imaging data show decreased dopaminergic differentiation and branching complexity, altered mitochondrial morphology, and increased cell death in LRRK2-G2019S neurons compared to isogenic lines without using stressor agents. Treatment with the LRRK2 inhibitor 2 (Inh2) rescues LRRK2-G2019S-dependent dopaminergic phenotypes. Strikingly, a holistic analysis of all studied features shows that the genetic background of the PD patients, and not the LRRK2-G2019S mutation, constitutes the strongest contribution to the phenotypes. These data support the use of advanced in vitro models for future patient stratification and personalized drug development.
UR - http://www.scopus.com/inward/record.url?scp=85056763127&partnerID=8YFLogxK
U2 - 10.1002/advs.201800927
DO - 10.1002/advs.201800927
M3 - Journal articles
AN - SCOPUS:85056763127
SN - 2198-3844
VL - 6
JO - Advanced Science
JF - Advanced Science
IS - 1
M1 - 1800927
ER -
