Generating tissue-resident macrophages from pluripotent stem cells: Lessons learned from microglia

Area of Science:

• Neuroscience
• Immunology
• Stem Cell Biology

Background:

• Tissue-resident macrophages, like microglia in the brain, are vital in various pathologies.
• Primary microglia lose tissue-specific features rapidly in vitro, complicating research.
• Generating tissue-resident macrophages from pluripotent stem cells (PSCs) is challenging due to limited knowledge of developmental pathways and niche factors.

Purpose of the Study:

• To review current approaches for generating human microglia in vitro from PSCs.
• To analyze the origin and in vivo resemblance of these derived cells.
• To discuss factors for improving future differentiation protocols.

Main Methods:

• Review of existing literature on microglia generation protocols.
• Analysis of ontogeny data and gene expression profiles (bulk and single-cell RNAseq).
• Discussion of cell-extrinsic (culture conditions) and intrinsic factors (transcriptional machinery, epigenetics).

Main Results:

• Recent advances in understanding macrophage ontogeny and gene profiles have enabled the development of protocols for human PSC-derived microglia-like cells.
• These cells are considered promising for therapeutic applications in neurodegenerative diseases.
• Various protocols exist, differing in their approach to mimicking in vivo microglia characteristics.

Conclusions:

• Generating functional human microglia in vitro from PSCs is advancing, offering new avenues for disease modeling and therapy.
• Optimizing culture conditions and understanding intrinsic cellular mechanisms are key to enhancing differentiation protocols.
• Further research into cell-extrinsic and intrinsic factors will refine the generation of these crucial immune cells for therapeutic use.