Microglia Development and Maturation and Its Implications for Induction of Microglia-Like Cells from Human iPSCs
Johannes Wurm1, Henna Konttinen2, Christian Andressen1
1Anatomy and Cell Biology, Medical School OWL, Bielefeld University, 33615 Bielefeld, Germany.
Abstract:
Microglia are resident immune cells of the central nervous system and play critical roles during the development, homeostasis, and pathologies of the brain. Originated from yolk sac erythromyeloid progenitors, microglia immigrate into the embryonic brain parenchyma to undergo final postnatal differentiation and maturation driven by distinct chemokines, cytokines, and growth factors. Among them, TGFβ1 is an important regulator of microglial functions, mediating homeostasis, anti-inflammation, and triggering the expression of microglial homeostatic signature genes. Since microglia studies are mainly based on rodent cells and the isolation of homeostatic microglia from human tissue is challenging, human-induced pluripotent stem cells have been successfully differentiated into microglia-like cells recently. However, employed differentiation protocols strongly vary regarding used cytokines and growth factors, culture conditions, time span, and cell yield. Moreover, the incomplete differentiation of human microglia can hamper the similarity to primary human microglia and dramatically influence the outcome of follow-up studies with these differentiated cells. This review summarizes the current knowledge of the molecular mechanisms driving rodent microglia differentiation in vivo, further compares published differentiation protocols, and highlights the potential of TGFβ as an essential maturation factor.
Insights
This review explores microglia differentiation, focusing on transforming growth factor beta 1 (TGFβ1) as a key factor. Understanding these processes is crucial for studying brain development and diseases.
Area of Science:
- Neuroscience
- Immunology
- Developmental Biology
Background:
- Microglia, the brain's immune cells, are vital for neural development, homeostasis, and disease.
- Their differentiation is influenced by various signaling molecules, including TGFβ1, which regulates homeostasis and inflammation.
- Isolating human microglia is challenging, leading to the use of human-induced pluripotent stem cells (hiPSCs) for microglia-like cell generation.
Purpose of the Study:
- To review molecular mechanisms of rodent microglia differentiation in vivo.
- To compare various published protocols for differentiating human microglia-like cells from hiPSCs.
- To highlight the role of TGFβ1 as a critical maturation factor for microglia.
Main Methods:
- Literature review of in vivo rodent microglia differentiation mechanisms.
- Comparative analysis of published human microglia differentiation protocols.
- Focus on the role of TGFβ1 in microglial maturation.
Main Results:
- Established knowledge on rodent microglia differentiation pathways.
- Identified significant variability in current human microglia differentiation protocols (cytokines, growth factors, culture conditions, duration, yield).
- Highlighted incomplete differentiation of human microglia-like cells as a potential issue for research.
Conclusions:
- TGFβ1 is a crucial factor for microglial homeostasis and maturation.
- Standardized and optimized protocols are needed for reliable human microglia-like cell differentiation.
- Further research into TGFβ1's role can improve in vitro models for studying neurological conditions.
