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Gosselin D, Skola D, Coufal NG, Holtman IR, Schlachetzki JC, Sajti E, Jaeger BN, O'Connor C, Fitzpatrick C, Pasillas MP, Pena M, Adair A, Gonda DD, Levy ML, Ransohoff RM, Gage FH, Glass CK. An environment-dependent transcriptional network specifies human microglia identity. Science. 2017 Jun 23;356(6344) Epub 2017 May 25 PubMed.
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University of Kentucky
This is an incredibly robust and systematic dataset from Chris Glass’ group. A few salient points regarding the manuscript stand out to me. 1.) The conservation of a transcriptional repertoire between mouse and human microglia is a key finding. Importantly, this reinforces the validity of using mouse models of brain disorders to define translatable mechanisms related to microglia function in the etiology and/or progression of those disorders. 2.) Comparison of the human microgliome with whole-tissue analyses showed that microglia significantly express multiple risk alleles associated with several progressive neurodegenerative disorders. These findings bolster the putative link between resident innate immune response in the diseased brain. 3.) The use of in vitro experiments involving primary microglia is a frustratingly futile endeavor given the loss of microglia identity and acquisition of a quasi-phenotype (similar to previous work by Butovsky et al., 2014). This is incredibly important in terms of microglia-specific therapeutic development for neurodegenerative disorders, and is unfortunate as the penultimate testbed would be to generate human iPSC-derived true microglia harboring specific risk alleles for AD, PD, MS, etc.
One of the main caveats with this paper is the use of a “catch-all” microglia FACS enrichment strategy. The authors even acknowledge this caveat in a sense with their dataset’s inability to show variations in transcripts across the multiple diseases/diagnosis/age. Additionally, cells were only taken from cortical tissue, and recent work shows that there is a regional heterogeneity of microglia gene expression (Grabert et al., 2016).
Two important questions remain in my mind: How does this gene signature change between different subsets of microglia within a diseased brain? Do the enriched motifs/genes in microglia have a functional basis in disease, as some of them do in homeostatic function (e.g., Bialas and Stevens, 2013)?
Butovsky O, Jedrychowski MP, Moore CS, Cialic R, Lanser AJ, Gabriely G, Koeglsperger T, Dake B, Wu PM, Doykan CE, Fanek Z, Liu L, Chen Z, Rothstein JD, Ransohoff RM, Gygi SP, Antel JP, Weiner HL. Identification of a unique TGF-β-dependent molecular and functional signature in microglia. Nat Neurosci. 2014 Jan;17(1):131-43. Epub 2013 Dec 8 PubMed.
Grabert K, Michoel T, Karavolos MH, Clohisey S, Baillie JK, Stevens MP, Freeman TC, Summers KM, McColl BW. Microglial brain region-dependent diversity and selective regional sensitivities to aging. Nat Neurosci. 2016 Mar;19(3):504-16. Epub 2016 Jan 18 PubMed.
Bialas AR, Stevens B. TGF-β signaling regulates neuronal C1q expression and developmental synaptic refinement. Nat Neurosci. 2013 Dec;16(12):1773-82. Epub 2013 Oct 27 PubMed.View all comments by Josh Morganti
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