Human Induced Pluripotent Stem Cell-Derived Macrophages Share Ontogeny with MYB-Independent Tissue-Resident Macrophages

Buchrieser, Julian; James, William; Moore, Michael D.

doi:10.1016/j.stemcr.2016.12.020

Cited by 154 publications

(224 citation statements)

References 48 publications

(57 reference statements)

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“…16 Vanhee et al used a reporter hESC line with MYB-eGFP , a marker for hematopoietic stem cell (HSC)-dependent hematopoiesis, and confirmed the absence of in vitro generation of MYB + HSC during EB-based IPSDM differentiation. 16 The results were further validated in human iPSCs, 17 showing that knockout of MYB in iPSC by CRISPR/Cas9 did not impact IPSDM differentiation. 12 In contrast, when SPI1 and RUNX1 , important transcription factors in yolk sac (YS) hematopoiesis, were knocked out, iPSCs were unable to produce CD14 + macrophages.…”

Section: Generation Functional Feature and Molecular Profiling Of Ipsdmmentioning

confidence: 91%

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

Zhang

Reilly

2017

ATVB

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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.

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Section: Generation Functional Feature and Molecular Profiling Of Ipsdmmentioning

confidence: 91%

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

Zhang

Reilly

2017

ATVB

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“…To recapitulate the development of yolk sac-derived macrophages, we use our previously established, straightforward, highly efficient, serum- and feeder-free protocol for deriving PSC macrophages (Karlsson et al., 2008, van Wilgenburg et al., 2013). We have recently directly demonstrated that these derive from MYB -independent, RUNX1- and PU.1 -dependent precursors, characteristic of yolk sac-derived macrophages (Buchrieser et al., 2017, Vanhee et al., 2015). Here, we co-culture them with iPSC cortical neurons (Shi et al., 2012), in medium optimized for survival and functionality of both neurons and microglia.…”

Section: Introductionmentioning

confidence: 99%

A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response

et al. 2017

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SummaryMicroglia are increasingly implicated in brain pathology, particularly neurodegenerative disease, with many genes implicated in Alzheimer's, Parkinson's, and motor neuron disease expressed in microglia. There is, therefore, a need for authentic, efficient in vitro models to study human microglial pathological mechanisms. Microglia originate from the yolk sac as MYB-independent macrophages, migrating into the developing brain to complete differentiation. Here, we recapitulate microglial ontogeny by highly efficient differentiation of embryonic MYB-independent iPSC-derived macrophages then co-culture them with iPSC-derived cortical neurons. Co-cultures retain neuronal maturity and functionality for many weeks. Co-culture microglia express key microglia-specific markers and neurodegenerative disease-relevant genes, develop highly dynamic ramifications, and are phagocytic. Upon activation they become more ameboid, releasing multiple microglia-relevant cytokines. Importantly, co-culture microglia downregulate pathogen-response pathways, upregulate homeostatic function pathways, and promote a more anti-inflammatory and pro-remodeling cytokine response than corresponding monocultures, demonstrating that co-cultures are preferable for modeling authentic microglial physiology.

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“…Although our initial studies used HSPCs derived from murine bone marrow or human cord blood, also iPSC-derived macrophages represent a highly interesting source for cell therapy strategies in diseases related to macrophage dysfunction [13,14]. Here, the embryonic origin of the cells may even serve as an advantage [15], and the transplantation of iPSC-derived macrophages potentially may be superior to the transplantation of adult CD34+ HSC-derived macrophages. Consequently, a combination of hematopoietic cell-based gene therapy applications with the unique potential of iPSCs has been explored for quite some time.…”

Section: Resultsmentioning

confidence: 99%

Ex vivo Generation of Genetically Modified Macrophages from Human Induced Pluripotent Stem Cells

Ackermann

Kuhn

Kunkiel

et al. 2017

Transfus Med Hemother

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Background: Pluripotent stem cells, including induced pluripotent stem cells (iPSCs), have the capacity to differentiate towards all three germ layers and have been highlighted as an attractive cell source for the field of regenerative medicine. Thus, stable expression of therapeutic transgenes in iPSCs, as well as thereof derived progeny of hematopoietic lineage, may lay the foundation for innovative cell replacement therapies. Methods: We have utilized human iPSC lines genetically modified by lentiviral vector technology or targeted integration of reporter genes to evaluate transgene expression during hematopoietic specification and differentiation towards macrophages. Results: Use of lentiviral vectors equipped with an ubiquitous chromatin opening element (CBX3-UCOE) as well as zinc finger nuclease-mediated targeting of an expression cassette into the human adeno-associated virus integration site 1 (AAVS1) safe harbor resulted in stable transgene expression in iPSCs. When iPSCs were differentiated along the myeloid pathway into macrophages, both strategies yielded sustained transgene expression during the hematopoietic specification process including mature CD14+ and CD11b+ macrophages. Conclusion: Combination of human iPSC technology with either lentiviral vector technology or designer nuclease-based genome editing allows for the generation of transgenic iPSC-derived macrophages with stable transgene expression which may be useful for novel cell and gene replacement therapies.

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Human Induced Pluripotent Stem Cell-Derived Macrophages Share Ontogeny with MYB-Independent Tissue-Resident Macrophages

Cited by 154 publications

References 48 publications

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

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

A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response

Ex vivo Generation of Genetically Modified Macrophages from Human Induced Pluripotent Stem Cells

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