The Blurton-Jones lab utilizes iPSC-Derived Human Microglia-like cells to study neurological diseases:
Microglia play critical roles in brain development, homeostasis, and neurological disorders. Here, we report that human microglial-like cells (iMGLs) can be differentiated from iPSCs to study their function in neurological diseases, like Alzheimer’s disease (AD). We find that iMGLs develop in vitro similarly to microglia in vivo, and whole-transcriptome analysis demonstrates that they are highly similar to cultured adult and fetal human microglia. Functional assessment of iMGLs reveals that they secrete cytokines in response to inflammatory stimuli, migrate and undergo calcium transients, and robustly phagocytose CNS substrates. iMGLs were used to examine the effects of Aβ fibrils and brain-derived tau oligomers on AD-related gene expression and to interrogate mechanisms involved in synaptic pruning. Furthermore, iMGLs transplanted into transgenic mice and human brain organoids resemble microglia in vivo. Together, these findings demonstrate that iMGLs can be used to study microglial function, providing important new insight into human neurological disease.
Stemformatics: iPSC-Derived Human Microglia-like Cells to Study Neurological Diseases.
The Blurton Jones Lab has Developed and Validated a Simplified Method to Generate human Microglia from Pluripotent Stem Cells:
Microglia, the principle immune cells of the brain, play important roles in neuronal development, homeostatic function, and neurodegenerative disease. Recent genetic studies have further highlighted the importance of microglia in neurodegeneration with the identification of disease risk polymorphisms in many microglial genes. To better understand the role of these genes in microglial biology and disease, we, and others, have developed methods to differentiate microglia from human-induced pluripotent stem cells (iPSCs). While the development of these methods has begun to enable important new studies of microglial biology, labs with little prior stem cell experience have sometimes found it challenging to adopt these complex protocols. Therefore, we have now developed a greatly simplified approach to generate large numbers of highly pure human microglia.
The Blurton-Jones lab Developed a Novel Chimeric Model to Study and Manipulate Microglia in vivo:
iPSC-derived microglia offer a powerful tool to study microglial homeostasis and disease-associated inflammatory responses. Yet, microglia are highly sensitive to their environment, exhibiting transcriptomic deficiencies when kept in isolation from the brain. Furthermore, species-specific genetic variations demonstrate that rodent microglia fail to fully recapitulate the human condition. To address this, we developed an approach to study human microglia within a surrogate brain environment. Transplantation of iPSC-derived hematopoietic-progenitors into the postnatal brain of humanized, immune-deficient mice results in context-dependent differentiation into microglia and other CNS macrophages, acquisition of an ex vivo human microglial gene signature, and responsiveness to both acute and chronic insults. Most notably, transplanted microglia exhibit robust transcriptional responses to Ab-plaques that only partially overlap with that of murine microglia, revealing new, human-specific Ab-responsive genes. We, therefore, have demonstrated that this chimeric model provides a powerful new system to
examine the in vivo function of patient-derived and genetically modified microglia.
Bulk RNA-seq: xMG response to different environments and LPS treatment
This dataset contains the comparisons of three xMG cell lines compared to microglia and iMGLs in multiple maintenance environments. Also included is a comparison of the effects of in vivo vs in vitro LPS treatment.
The Blurton-Jones Lab utilizes CRISPR-Gene Editing Techniques to investigate the impact of various risk factors on the role of human microglia in neurodegeneration. This includes:
APOE, BIN1, CD9, CSF1, CSF1R (G795A-iMG), ERCC1, ERCC5, INPP5D, LIPA, MS4A4A, MS4A6A, NLRP3, NPC1, ORAI1, PLCG2 (KO, P522R), PSEN, TGFBR2, TREM2 (KO, R47H), and more.
The Blurton-Jones Lab is investigating the role of T cell infiltration into the brain parenchyma in AD utilizing both immune-deficient and immune-intact 5xFAD and Tau P301S (PS19) transgenic mouse models.