Developing a Panel of Human Pluripotent Stem Cell-Derived Microglia to Model Neurodegenerative Diseases
View the webinar to learn about:
- New human iPSC-derived microglia with diseased backgrounds for accurately modelling
- Analysis of disease specific anti-inflammatory and inflammatory responses to specific stimuli.
- Microglia panel uses for a variety of in vitro applications, including investigation of the role of gene variants, co-culture models, among others.
Presenters:Beatriz Freitas, PhD (Product Manager, FUJIFILM Cellular Dynamics, Inc.)
Simon Hilcove, PhD (Assoc. Director, Product Development, FUJIFILM Cellular
Abstract: Microglia, the resident immune cells of the brain, are key players in neuroinflammation and manifestation of neurodegenerative diseases. Recent studies have identified genes that are highly expressed in microglia associated with an increased risk of developing Alzheimer’s disease (AD), Parkinson’s disease (PD), Frontotemporal Dementia (FTD), or Amyotrophic Lateral Sclerosis (ALS), thus propelling microglia to the forefront of neurodegenerative disease progression and emphasizing the critical need of model systems to study microglia. Since primary human microglia from living donors are not accessible for research, human induced pluripotent stem cell (iPSC)-derived microglia emerge as an authentic human preclinical tool to mimic neurodegeneration and enable drug screening applications in vitro, as well as co-culture with other neural cell types for drug candidate validation. Recent GWAS studies have shown that genetically inherited variants apolipoprotein E4 (APOE4), presenilin 1 (PSEN1), presenilin 2 (PSEN2), or amyloid precursor protein (APP), and the presence of specific Single Nucleotide Polymorphisms (SNPs) within triggering receptor expressed on myeloid cells 2 (TREM2), CD33 or Siglec 3, ATP-binding cassette transporter A7 (ABCA7), have a strong association with increased disease risk of AD. A panel of 12 human iPSCs from apparently healthy and diseased donors harboring many inherited mutations were selected and successfully differentiated into cryopreserved hematopoietic progenitor cells and microglia. In addition, microglia were also derived from engineered and non-engineered iPSCs to create isogenic pairs with mutations in TREM2, A53T and MeCP2. End stage microglia retained the presence of cell surface (CD45, CD11b and CD33) and intracellular (P2RY12, TREM-2, CX3CR1, IBA) microglia-specific antigens, gene expression patterns and exhibited phagocytic function. In addition, cryopreserved microglia retained the ability to be polarized towards an inflammatory or anti-inflammatory subtype by specific stimuli. Thus, this panel of both normal and disease associated microglia can be used to investigate the role of gene variants in human microglia, develop co-culture applications with other neural cell types to create predictive in vitro models for neurodegenerative diseases.