Demonstrating translational relevance of organoid and multicellular tissues for preclinical models of human disease
Myleoid cells play critical roles in adaptive and innate immunity and dysregulation can result in disease pathology, such as neurodegeneration. However, a detailed mechanistic understanding of human myeloid biology has been hampered by the lack of robust and scalable models for cellular and genetic studies. Conventional approaches rely upon immortalised cells that lack biological relevance or primary cells which are limited in number, reproducibility, and genetic perturbation. To overcome these challenges, we developed and industrialised a human induced pluripotent stem cell (iPSC)-derived myeloid platform that permits a robust and continuous supply of progenitors that are subsequently differentiated into macrophage or microglia. Since each iPSC line retains the genetic information of the donor this provides an opportunity to harness human genetics to investigate in vitro disease mechanisms.
We performed extensive transcriptomic, epigenetic, proteomic and metabolomic analyses with concomitant phenotypic (e.g. flow cytometry, image analysis) and functional assays (e.g. phagocytosis, cytokine secretion) to support their use as a model to primary counterparts. Here, we demonstrate a combination of conventional and innovative technologies to generate and validate iPSC-derived target cell types as an unlimited source of patient genotype-specific cells to study. We describe implementation of such disease relevant models to enable large scale (epi)genomic functional modelling for improved novel target ID.
The human biological samples were sourced ethically and their research use was in accord with the terms of the informed consents under an IRB/EC approved protocol.