Human Induced Pluripotent Stem Cell-Derived Macrophages Share Ontogeny with MYB-Independent Tissue-Resident Macrophages
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Tissue-resident macrophages, such as microglia, Kupffer cells, and Langerhans cells, derive from Myb-independent yolk sac (YS) progenitors generated before the emergence of hematopoietic stem cells (HSCs). Myb-independent YS-derived resident macrophages self-renew locally, independently of circulating monocytes and HSCs. In contrast, adult blood monocytes, as well as infiltrating, gut, and dermal macrophages, derive from Myb-dependent HSCs. These findings are derived from the mouse, using gene knockouts and lineage tracing, but their applicability to human development has not been formally demonstrated. Here, we use human induced pluripotent stem cells (iPSCs) as a tool to model human hematopoietic development. By using a CRISPR-Cas9 knockout strategy, we show that human iPSC-derived monocytes/macrophages develop in an MYB-independent, RUNX1-, and SPI1 (PU.1)-dependent fashion. This result makes human iPSC-derived macrophages developmentally related to and a good model for MYB-independent tissue-resident macrophages, such as alveolar and kidney macrophages, microglia, Kupffer cells, and Langerhans cells.
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These cells closely resemble human foetal microglia with regards to transcriptional signature and express high levels of microglial genes.
“These cells closely resemble human foetal microglia with regards to transcriptional signature and express high levels of microglial genes29,30.”
From PLCγ2 regulates TREM2 signalling and integrin-mediated adhesion and migration of human iPSC-derived macrophages (2021) · cites this paper as [30]
The Abstract describes iPSC-derived macrophages as developmentally related to tissue-resident macrophages, including microglia. The Results report a tissue-resident gene-expression pattern compared with adult blood monocytes, but do not compare these cells’ transcriptional signature with human foetal microglia or establish high expression of microglia-specific genes. The Introduction’s foetal comparison concerns liver-derived monocytes/macrophages, not microglia. (LLM, conf=0.87)
Experimental — accuracy not yet measuredPSC macrophages derive from MYB-independent, RUNX1- and PU.1-dependent precursors, characteristic of yolk sac-derived macrophages.
“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).”
From A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response (2017) · cites this paper as Buchrieser et al., 2017
The Results section shows that iPSC-derived monocytes/macrophages develop without MYB but require RUNX1 and SPI1 (PU.1). The Discussion, however, says their derivation from these progenitors is suggested rather than directly established, and notes that other primitive macrophage progenitors cannot be excluded without clonal analysis. (LLM, conf=0.86)
Experimental — accuracy not yet measuredThe protocol produces MYB-independent myeloid cells, recapitulating an embryonic ontogeny.
“Our own work (Buchrieser et al., 2017) and that of others (Hoeffel et al., 2015) indicates that this protocol produces MYB-independent myeloid cells, recapitulating an embryonic ontogeny, and lineage-tracking studies in mouse have demonstrated that microglia derive from primitive, yolk sac macrophages that migrate into the developing brain (Ginhoux et al., 2010, Ginhoux et al., 2013).”
From A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response (2017) · cites this paper as Buchrieser et al., 2017
Only our protocol has direct evidence by gene knockout for producing MYB-independent primitive macrophages.
“However, only our protocol has direct evidence by gene knockout for producing MYB-independent primitive macrophages (Buchrieser et al., 2017).”
From A highly efficient human pluripotent stem cell microglia model displays a neuronal-co-culture-specific expression profile and inflammatory response (2017) · cites this paper as Buchrieser et al., 2017
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Self-citation
- Authors
- Buchrieser, J., James, W., & Moore, M. D.
- Affiliations
- University of Oxford (GB)
- Corresponding author
- Buchrieser, Julian
- Venue
- Stem Cell Reports
- Publisher
- Elsevier BV
- Published
- 2017-02
- Volume
- 8
- Issue
- 2
- Pages
- 334-345
- ISSN
- 2213-6711 (ISSN-L)
- PMC
- PMC5312255
- OpenAlex
- W2575042032
- Cited by
- 215
- References
- 50
- Citations by year
- 2026: 24 · 2025: 18 · 2024: 27 · 2023: 19 · 2022: 25 · 2021: 26 · 2020: 30 · 2019: 15 · 2018: 22 · 2017: 9
- FWCI
- 8.49
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Stem Cell Reports (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Parkinson's UK (2581970, SC037554)
- Research Councils UK
- Wellcome Trust (WTISSF121302)
- National Institute for Health and Care Research (090532/Z/09/Z.)
- Medical Research Council
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Pluripotent Stem Cells Research
- Health Sciences › Medicine › Hematology › Hematopoietic Stem Cell Transplantation
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- tissue-resident macrophages, iPSC-derived macrophages, macrophage ontogeny, hematopoietic development, RUNX1, yolk sac macrophages, microglia, Kupffer cells, Langerhans cells, alveolar macrophages, kidney macrophages, monocytes, CRISPR/Cas9 knockout
- MeSH terms
- Proto-Oncogene Protein Spi-1, Cell Differentiation, Cell Line, Erythrocytes, Granulocytes, Hematopoietic Stem Cells, Humans, Macrophages, Monocytes, Organ Specificity, Phenotype, Proto-Oncogene Proteins, Biomarkers, Trans-Activators, Gene Expression, Gene Expression Regulation, Developmental, Genes, myb, Core Binding Factor Alpha 2 Subunit, Gene Knockout Techniques, Induced Pluripotent Stem Cells, Embryoid Bodies
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