Functional Analysis and Transcriptomic Profiling of IPSC-derived Macrophages and Their Application in Modeling Mendelian Disease

Overview

Journal Circ Res

Specialty Cardiology & Vascular Diseases

Date 2015 Apr 24

PMID 25904599

Citations 77

Authors

Hanrui Zhang

Chenyi Xue

Rhia Shah

Kate Bermingham

Christine C Hinkle

Wenjun Li

Amrith Rodrigues

Jennifer Tabita-Martinez

John S Millar

Marina Cuchel

Evanthia E Pashos

Ying Liu

Ruilan Yan

Wenli Yang

Sager J Gosai

Daniel VanDorn

Stella T Chou

Brian D Gregory

Edward E Morrisey

Mingyao Li

Daniel J Rader

Muredach P Reilly

Affiliations

Soon will be listed here.

Abstract

Rationale: An efficient and reproducible source of genotype-specific human macrophages is essential for study of human macrophage biology and related diseases.

Objective: To perform integrated functional and transcriptome analyses of human induced pluripotent stem cell-derived macrophages (IPSDMs) and their isogenic human peripheral blood mononuclear cell-derived macrophage (HMDM) counterparts and assess the application of IPSDM in modeling macrophage polarization and Mendelian disease.

Methods And Results: We developed an efficient protocol for differentiation of IPSDM, which expressed macrophage-specific markers and took up modified lipoproteins in a similar manner to HMDM. Like HMDM, IPSDM revealed reduction in phagocytosis, increase in cholesterol efflux capacity and characteristic secretion of inflammatory cytokines in response to M1 (lipopolysaccharide+interferon-γ) activation. RNA-Seq revealed that nonpolarized (M0) as well as M1 or M2 (interleukin-4) polarized IPSDM shared transcriptomic profiles with their isogenic HMDM counterparts while also revealing novel markers of macrophage polarization. Relative to IPSDM and HMDM of control individuals, patterns of defective cholesterol efflux to apolipoprotein A-I and high-density lipoprotein-3 were qualitatively and quantitatively similar in IPSDM and HMDM of patients with Tangier disease, an autosomal recessive disorder because of mutations in ATP-binding cassette transporter AI. Tangier disease-IPSDM also revealed novel defects of enhanced proinflammatory response to lipopolysaccharide stimulus.

Conclusions: Our protocol-derived IPSDM are comparable with HMDM at phenotypic, functional, and transcriptomic levels. Tangier disease-IPSDM recapitulated hallmark features observed in HMDM and revealed novel inflammatory phenotypes. IPSDMs provide a powerful tool for study of macrophage-specific function in human genetic disorders as well as molecular studies of human macrophage activation and polarization.

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