Induced Pluripotent Stem Cell-Derived Monocytes/Macrophages in Autoinflammatory Diseases

Abstract

The concept of autoinflammation, first proposed in 1999, refers to a seemingly unprovoked episode of sterile inflammation manifesting as unexplained fever, skin rashes, and arthralgia. Autoinflammatory diseases are caused mainly by hereditary abnormalities of innate immunity, without the production of autoantibodies or autoreactive T cells. The revolutionary discovery of induced pluripotent stem cells (iPSCs), whereby a patient's somatic cells can be reprogrammed into an embryonic pluripotent state by forced expression of a defined set of transcription factors, has the transformative potential to enable in vitro disease modeling and drug candidate screening, as well as to provide a resource for cell replacement therapy. Recent reports demonstrate that recapitulating a disease phenotype in vitro is feasible for numerous monogenic diseases, including autoinflammatory diseases. In this review, we provide a comprehensive overview of current advances in research into autoinflammatory diseases involving iPSC-derived monocytes/macrophages. This review may aid in the planning of new studies of autoinflammatory diseases.

Keywords: autoinflammatory diseases; disease modeling; drug screening; induced pluripotent stem cells; macrophages; monocytes.

Figure 1

In vitro culture of primary monocytes for 7 days in the presence of macrophage colony-stimulating factor (M-CSF) gives rise to adherent monocyte-derived macrophages (MDMs). Sequential stimulation with VEGF, BMP4, bFGF, SCF, TPO, IL-3, FL, and M-CSF differentiates induced pluripotent stem cells (iPSCs) into floating monocyte-like cells. After introduction of three transgenes, namely, cMYC, MBI1, and MDM2, into the floating cells, PSC-derived immortalized myeloid cell lines (PSC-MLs) begin to proliferate. In vitro culture of PSC-MLs for 7 days in the presence of M-CSF gives rise to adherent PSC-derived macrophages (PSC-MPs). Scale bars, 20 µm. VEGF, vascular endothelial growth factor; BMP4, bone morphogenic protein type 4; bFGF, basic fibroblast growth factor; SCF, stem cell factor; TPO, thrombopoietin; IL-3, interleukin-3; FL, FLT3 ligand.