Leucine-Rich Repeat Kinase 2 Influences Fate Decision of Human Monocytes Differentiated from Induced Pluripotent Stem Cells

PLoS One. 2016 Nov 3;11(11):e0165949. doi: 10.1371/journal.pone.0165949. eCollection 2016.

Abstract

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.

MeSH terms

  • Cell Differentiation* / genetics
  • Cell Line
  • Humans
  • Induced Pluripotent Stem Cells / cytology*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / genetics*
  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2 / metabolism*
  • Monocytes / cytology*
  • Mutation*

Substances

  • Leucine-Rich Repeat Serine-Threonine Protein Kinase-2

Grants and funding

This work was supported by Boehringer Ingelheim Pharma GmbH & Co. KG. The funder provided financial support in the form of authors' salaries [Anna Speidel, Sandra Felk and Frank Gillardon] and research materials, but did not have any additional role in study design, data collection and analysis, decision to publish or preparation of the manuscript.