Recent Advances in Microglia Modelling to Address Translational Outcomes in Neurodegenerative Diseases

Abstract

Neurodegenerative diseases are deteriorating conditions of the nervous system that are rapidly increasing in the ageing population. Increasing evidence suggests that neuroinflammation, largely mediated by microglia, the resident immune cells of the brain, contributes to the onset and progression of neurodegenerative diseases. Hence, microglia are considered a major therapeutic target that could potentially yield effective disease-modifying treatments for neurodegenerative diseases. Despite the interest in studying microglia as drug targets, the availability of cost-effective, flexible, and patient-specific microglia cellular models is limited. Importantly, the current model systems do not accurately recapitulate important pathological features or disease processes, leading to the failure of many therapeutic drugs. Here, we review the key roles of microglia in neurodegenerative diseases and provide an update on the current microglial plaforms utilised in neurodegenerative diseases, with a focus on human microglia-like cells derived from peripheral blood mononuclear cells as well as human-induced pluripotent stem cells. The described microglial platforms can serve as tools for investigating disease biomarkers and improving the clinical translatability of the drug development process in neurodegenerative diseases.

Keywords: clinical translation; microglial platforms; neuroinflammation; patient heterogeneity; patient-derived microglia cells.

Figure 1

Schematic illustration of the development of myeloid cells. Hematopoietic stem cells can commit to either a lymphoid or a myeloid fate through the generation of common lymphoid or myeloid progenitor cells. Common myeloid progenitors are located in the bone marrow of adults, and the yolk sac in embryos. When yolk sac-derived myeloid progenitors colonise the CNS, specific microenvironmental cues direct their differentiation into microglia. These embryonically derived microglia are able to proliferate and self-maintain until adulthood. In the bone marrow, common myeloid progenitors differentiate towards megakaryocytic/erythrocytic or granulocytic/monocytic phenotypes. In the blood, megakaryocyte/erythrocyte progenitors give rise to platelets and erythrocytes (red blood cells), while granulocyte/monocyte progenitors give rise to leukocytes, including granulocytes and monocytes. Circulating monocytes can then be recruited to sites of infection or injury in specific tissues and differentiate into macrophages or dendritic cells. During aging and certain inflammatory conditions, monocytes and other bone marrow-derived progenitors infiltrate the CNS and differentiate into microglia-like cells. It is not well understood whether these microglia-like cells persist or are a temporary addition to the existing microglial population. Listed in grey boxes are representative markers expressed by myeloid cell types. Common markers between microglia and macrophages are highlighted in yellow (MERTK, TREM2, CD68 and IBA1).