Leucine-Rich Repeat Kinase 2 Influences Fate Decision of Human Monocytes Differentiated from Induced Pluripotent Stem Cells.
Mutations in Leucine-rich repeat kinase 2 (LRRK2) are strongly associated with familial Parkinson's disease (PD). High expression levels in immune cells suggest a role of LRRK2 in regulating the immune system. In this study, we investigated the effect of the LRRK2 (G2019S) mutation in monocytes, using a human stem cell-derived model expressing LRRK2 at endogenous levels. We discovered alterations in the differentiation pattern of LRRK2 mutant, compared to non-mutant isogenic controls, leading to accelerated monocyte production and a reduction in the non-classical CD14+CD16+ monocyte subpopulation in the LRRK2 mutant cells. LPS-treatment of the iPSC-derived monocytes significantly increased the release of pro-inflammatory cytokines, demonstrating a functional response without revealing any significant differences between the genotypes. Assessment of the migrational capacity of the differentiated monocytes revealed moderate deficits in LRRK2 mutant cells, compared to their respective controls. Our findings indicate a pivotal role of LRRK2 in hematopoietic fate decision, endorsing the involvement of the immune system in the development of PD.
CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Anna
http://orcid.org/0000-0002-6741-3091
A
Speidel
CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Sandra
S
Felk
CRTD / DFG-Center for Regenerative Therapies Dresden, Dresden, Germany.
Peter
P
Reinhardt
CRTD / DFG-Center for Regenerative Therapies Dresden, Dresden, Germany.
Jared
J
Sterneckert
CNS Diseases Research, Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach an der Riss, Germany.
Frank
F
Gillardon
D002454:Cell Differentiation / Q000235:genetics; D002460:Cell Line; D006801:Humans; D057026:Induced Pluripotent Stem Cells / Q000166:cytology*; D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / Q000235:genetics* / Q000378:metabolism*; D009000:Monocytes / Q000166:cytology*; D009154:Mutation
D000071158:Leucine-Rich Repeat Serine-Threonine Protein Kinase-2