Human monocyte-derived microglia-like cell models for neurodegenerative diseases

Abstract

Microglia are the macrophages and innate immune cells of the central nervous system (CNS). They differ from peripheral macrophages ontogenetically as microglia originate from the progenitors in the yolk sac supporting the early embryo whereas macrophages derive from hematopoietic stem cells in the bone marrow. Microglia maintain homeostasis within the CNS by regulating neuronal functions and phagocytosing cell debris. They can also modulate inflammatory responses when becoming activated by outside stimuli. Microglia activation can be associated with neurotoxic or neuroprotective functions. Neuroprotective microglia secrete anti-inflammatory cytokines, and they try to suppress the inflammatory response. Neurotoxic microglia secrete pro-inflammatory cytokines which enhance the inflammatory response. If the activation of microglia becomes chronic, it can lead to neuroinflammation and eventually to neurodegeneration.

The pivotal role of microglia in the progression of various neurodegenerative diseases has become clear in recent decades. Therefore, the need for cell models that could recapitulate the disease mechanisms of microglia has increased. Monocyte-derived microglia-like (MDMi) cells are a recently developed efficient in vitro cell model system. The protocol for MDMi cells includes extraction of peripheral blood mononuclear cells from the blood, monocyte isolation, and monocyte differentiation into microglia-like cells. MDMi cells can be characterized for the expression of microglia-specific markers using immunocytochemistry.

As MDMi cells closely resemble primary microglia, they can be employed as a model system to study dysfunctional microglia in various neurodegenerative diseases, such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis. MDMi cells retain the patient- and disease specificity which enables the comparison between MDMi cells derived from patients and healthy controls. The disease mechanisms studied with MDMi cells include immune responses and pathological functions such as dysfunctional phagocytosis. In the studies selected for this thesis, MDMi cells were utilized successfully to mimic pathological microglia functions. MDMi cells provided a suitable tool for therapeutic target identification and understanding the pathological role of microglia.

MDMi cells overcome some challenges of other microglia models, including efficient differentiation protocol. However, an authentic culture system resembling the CNS environment remains challenging to attain, and there is not yet a standardized protocol for inducing MDMi cells. MDMi cells are also ontogenetically different from primary microglia, which might explain some discrepancies between previous microglia studies and the ones utilizing this cell model. Nevertheless, MDMi cells hold great future potential for understanding the role of microglia in neurodegenerative diseases, and potential for personalized treatment