Optimised generation of iPSC-derived macrophages and dendritic cells that are functionally and transcriptionally similar to their primary counterparts

Susan Monkley; Jayendra Kumar Krishnaswamy; Melker Göransson; Maryam Clausen; Johan Meuller; Kristofer Thörn; Ryan Hicks; Stephen Delaney; Louise Stjernborg

doi:10.1371/journal.pone.0243807

Optimised generation of iPSC-derived macrophages and dendritic cells that are functionally and transcriptionally similar to their primary counterparts

PLoS One. 2020 Dec 17;15(12):e0243807. doi: 10.1371/journal.pone.0243807. eCollection 2020.

Authors

Susan Monkley¹, Jayendra Kumar Krishnaswamy², Melker Göransson², Maryam Clausen³, Johan Meuller³, Kristofer Thörn¹, Ryan Hicks⁴, Stephen Delaney², Louise Stjernborg³

Affiliations

¹ Translational Science and Experimental Medicine, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
² Bioscience, Research and Early Development, Respiratory and Immunology (R&I), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
³ Discovery Biology, Discovery Sciences, BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.
⁴ BioPharmaceuticals R&D Cell Therapy, Research and Early Development, Cardiovascular, Renal and Metabolism (CVRM), BioPharmaceuticals R&D, AstraZeneca, Gothenburg, Sweden.

Abstract

Induced pluripotent stem cells (iPSC) offer the possibility to generate diverse disease-relevant cell types, from any genetic background with the use of cellular reprogramming and directed differentiation. This provides a powerful platform for disease modeling, drug screening and cell therapeutics. The critical question is how the differentiated iPSC-derived cells translate to their primary counterparts. Our refinement of a published differentiation protocol produces a CD14+ monocytic lineage at a higher yield, in a smaller format and at a lower cost. These iPSC-derived monocytes can be further differentiated into macrophages or dendritic cells (DC), both with similar morphological and functional profiles as compared to their primary counterparts. Transcriptomic analysis of iPSC-derived cells at different stages of differentiation as well as comparison to their blood-derived counterparts demonstrates a complete switch of iPSCs to cells expressing a monocyte, macrophage or DC specific gene profile. iPSC-derived macrophages respond to LPS treatment by inducing expression of classic macrophage pro-inflammatory response markers. Interestingly, though iPSC-derived DC show similarities to monocyte derived DC, they are more similar transcriptionally to a newly described subpopulation of AXL+ DC. Thus, our study provides a detailed and accurate profile of iPSC-derived monocytic lineage cells.

MeSH terms

Cell Differentiation
Cell Lineage
Dendritic Cells / cytology*
Dendritic Cells / metabolism
Humans
Induced Pluripotent Stem Cells / cytology*
Macrophages / cytology*
Macrophages / metabolism
Transcription, Genetic*

Grants and funding

The author(s) received no specific funding for this work. AstraZeneca provided support in the form of salaries for authors [SM, JKK, MG, MC, JM, KT, RH, SD, LS ], as well as research materials. Employees of AstraZeneca, as authors, participated in the study design, data collection and analysis, decision to publish, or preparation of the manuscript. AstraZeneca reviewed the publication, without influencing the opinions of the authors, to ensure medical and scientific accuracy, and the protection of intellectual property. All authors had access to all data in the study, and approved the decision to submit the manuscript for publication. The specific roles of the authors are articulated in the ‘author contributions’ section.