Human Induced Pluripotent Stem Cell–Derived Macrophages for Unraveling Human Macrophage Biology

Abstract

Despite a substantial appreciation for the critical role of macrophages in cardiometabolic diseases, understanding of human macrophage biology has been hampered by the lack of reliable and scalable models for cellular and genetic studies. Human iPSC-derived macrophages (IPSDM), as an unlimited source of subject genotype-specific cells, will undoubtedly play an important role in advancing our understanding of the role of macrophages in human diseases. In this Review, we summarize current literature in the differentiation and characterization of IPSDM at phenotypic, functional and transcriptomic levels. We emphasize the progress in differentiating iPSC to tissue resident macrophages, and in understanding the ontogeny of in vitro differentiated IPSDM that resembles primitive hematopoiesis, rather than adult definitive hematopoiesis. We review the application of IPSDM in modeling both Mendelian genetic disorders and host-pathogen interactions. Finally, we highlighted the potential areas of research using IPSDM in functional validation of coronary artery disease loci in genome-wide association studies, functional genomic analyses, drug testing and cell therapeutics in cardiovascular diseases.

Cellular Models and Assays to Study NLRP3 Inflammasome Biology

“…For these reasons, several research groups have begun to establish macrophages from induced-pluripotent stem cells (iPS). Currently, different protocols have been tested to efficiently reprogram iPS into mature macrophages, and some of them nicely demonstrated how the iPS-DM showed similarities with hMDMs, including morphology, expression of surface markers, transcriptional and cytokine release profiles, and functional abilities, such as phagocytosis [ 105 , 106 , 107 , 108 , 109 , 110 ]. These studies opened the possibility of using iPS-DMs derived from healthy subjects as well as from patients for drug discovery purposes.…”

Differentiation of Human‐Induced Pluripotent Stem Cells to Macrophages for Disease Modeling and Functional Genomics

“…Prior protocols to differentiate pluripotent stem cells to macrophages have been summarized in our recently published review article (Zhang & Reilly, ). Briefly, in addition to earlier protocols for differentiation of human embryonic stem cells to macrophages (Karlsson et al., ; Subramanian et al., ), recent protocols for IPSDM generation have used three approaches: (1) co‐culture with OP9 mouse stromal cell (Choi, Vodyanik, & Slukvin, ; Senju et al., ; Vanhee et al., ); (2) monolayer‐based differentiation in 2D culture (Yanagimachi et al., ); and (3) EB‐based differentiation (Alasoo et al., ; Buchrieser, James, & Moore, ; Lachmann et al., ; Panicker et al., ; van Wilgenburg, Browne, Vowles, & Cowley, ; Zhang et al., ).…”

Alpha lipoic acid promotes development of hematopoietic progenitors derived from human embryonic stem cells by antagonizing ROS signals

“…11 Small molecules that can regulate ROS levels play an important role in differentiation of hematopoietic stem/progenitor cells from human pluripotent stem cells (hPSCs), especially in the serum-and stroma cell-free hematopoietic differentiation system. 12 Modulation of ROS level enhances development of CD34 + cells derived from hPSCs, 13 indicating that high ROS levels might cause apoptosis of hemogenic from hPSCs such as NK cells, 15 T lymphocytes, 16 erythrocytes, 17 neutrophils, 18,19 and M s 20 has been reported widely, recent research has focused on the molecular regulation and applications of hematopoietic cell differentiation from hPSCs. Two main methods are used for hematopoietic differentiation of human pluripotent stem cells: coculture with stroma cells and embryoid body formation.…”

“…While regeneration of functional hematopoietic cells derived from hPSCs such as NK cells, 15 T lymphocytes, 16 erythrocytes, 17 neutrophils, 18,19 and Mϕs 20 has been reported widely, recent research has focused on the molecular regulation and applications of hematopoietic cell differentiation from hPSCs. Two main methods are used for hematopoietic differentiation of human pluripotent stem cells: coculture with stroma cells and embryoid body formation.…”