Diverging Phenotypes and Regional Accumulation of Human Microglia in Engrafted hCSF1 - and hll-34-expressing Mice

Document Type

Article

Publication Date

8-7-2024

Keywords

JMG

JAX Location

In: Student Reports, Summer 2024, The Jackson Laboratory

Abstract

Microglia are the resident macrophages of the central nervous system (CNS) and perform diverse functions during embryonic and adult development of the brain.1 Activation of microglia surrounding beta-amyloid (Aβ) plaques is a hallmark of Alzheimer’s Disease (AD).2 Human colony stimulating factor 1 (CSF1) and interluekin- 34 (IL-34) are cytokines that stimulate CSF1 receptor (CSF1R), a tyrosine kinase receptor important for the growth and proliferation of microglia.3 While transgenic human CSF1 (h-CSF1) expression has been used to support human microglia (hMG) engraftment by stimulating cell surface CSF1R, human IL-34 (h-IL34) has been underutilized despite its significant role in microglia survival in the hippocampus and cortex.4 This study examines the differences of hMG engraftment in h-CSF1Tg and h- IL34KI mice. Through fluorescent imaging, engrafted hMG were found to largely localize to the cortex region in h-IL34KI expressing mice. In contrast, hMG in h-CSF1Tg mice largely accumulated within the fimbria. Flow cytometry analysis of brain and spinal cord tissue revealed a greater proportion of human cells in h-IL34KI expressing mice in both tissues. The human cells in each strain could be grouped into high, low, and negative expressors of P2RY12 and CX3CR1. The P2RY12hiCX3CR1hi cells were most similar to mouse microglia in regards to expression of classical microglia markers, while P2RY12- CX3CR1- cells more closely resembled the phenotype seen in peripheral myeloid cells. The P2RY12lowCX3CR1low cells were most different between h-CSF1Tg and h-IL34KI mice. HLA-DR expression in this group was higher in h-IL34KI as compared to h-CSF1Tg expressing mice. However, the low CD44 expression observed in this population in h- CSF1Tg hMG more closely resembled CD44 profiles of mouse microglia. In conclusion while h-IL34KI mice support a larger population of human microglia, expression profiles suggest that there may be differences between phenotype of human microglia supported by h-IL34 and homeostatic microglia

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