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1. Astrocytes drive divergent metabolic gene expression in humans and chimpanzees

   https://doi.org/10.1101/2020.11.09.374835  

   Zintel, T.M.; Pizzollo, J.; Claypool, C.G.; Babbitt, C.C. (November 2020, bioRxiv)

   null (Ed.)

   The human brain utilizes ~ 20% of all of the body’s metabolic resources, while chimpanzee brains use less than 10%. Although previous work shows significant differences in metabolic gene expression between the brains of primates, we have yet to fully resolve the contribution of distinct brain cell types. To investigate cell-type specific interspecies differences in brain gene expression, we conducted RNA-Seq on neural progenitor cells (NPCs), neurons, and astrocytes generated from induced pluripotent stem cells (iPSCs) from humans and chimpanzees. Interspecies differential expression (DE) analyses revealed that twice as many genes exhibit DE in astrocytes (12.2% of all genes expressed) than neurons (5.8%). Pathway enrichment analyses determined that astrocytes, rather than neurons, diverged in expression of glucose and lactate transmembrane transport, as well as pyruvate processing and oxidative phosphorylation. These findings suggest that astrocytes may have contributed significantly to the evolution of greater brain glucose metabolism with proximity to humans. 

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2. Comparative analysis of astrocytes in the prefrontal cortex of primates: Insights into the evolution of human brain energetics

   https://doi.org/10.1002/cne.25387  

   Munger, Emily_L; Edler, Melissa_K; Hopkins, William_D; Hof, Patrick_R; Sherwood, Chet_C; Raghanti, Mary_Ann (July 2022, Journal of Comparative Neurology)

   Abstract Astrocytes are the main homeostatic cell of the brain involved in many processes related to cognition, immune response, and energy expenditure. It has been suggested that the distribution of astrocytes is associated with brain size, and that they are specialized in humans. To evaluate these, we quantified astrocyte density, soma volume, and total glia density in layer I and white matter in Brodmann's area 9 of humans, chimpanzees, baboons, and macaques. We found that layer I astrocyte density, soma volume, and ratio of astrocytes to total glia cells were highest in humans and increased with brain size. Overall glia density in layer I and white matter were relatively invariant across brain sizes, potentially due to their important metabolic functions on a per volume basis. We also quantified two transporters involved in metabolism through the astrocyte‐neuron lactate shuttle, excitatory amino acid transporter 2 (EAAT2) and glucose transporter 1 (GLUT1). We expected these transporters would be increased in human brains due to their high rate of metabolic consumption and associated gene activity. While humans have higher EAAT2 cell density, GLUT1 vessel volume, and GLUT1 area fraction compared to baboons and chimpanzees, they did not differ from macaques. Therefore, EAAT2 and GLUT1 are not related to increased energetic demands of the human brain. Taken together, these data provide evidence that astrocytes play a unique role in both brain expansion and evolution among primates, with an emphasis on layer I astrocytes having a potentially significant role in human‐specific metabolic processing and cognition. 

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3. Chimpanzee fibroblasts exhibit greater adherence and migratory phenotypes than human fibroblasts

   https://doi.org/10.1101/838755  

   Zintel, T.M.; Ducey, D.; Babbitt, C.C. (November 2019, bioRxiv)

   null (Ed.)

   Background and objectives Previous work has identified that gene expression differences in cell adhesion pathways exist between humans and chimpanzees. Here, we used a comparative cell biology approach to assay interspecies differences in cell adhesion phenotypes in order to better understand the basic biological differences between species’ epithelial cells that may underly the organism-level differences we see in wound healing and cancer. Methodology We used skin fibroblast cell lines from humans and chimpanzees to assay cell adhesion and migration. We then utilized published RNA-Seq data from the same cell lines exposed to a cancer / wound-healing mimic to determine what gene expression changes may be corresponding to altered cellular adhesion dynamics between species. Results The functional adhesion and migration assays revealed that chimpanzee fibroblasts adhered sooner and remained adherent for significantly longer and move into a “wound” at faster rate than human fibroblasts. The gene expression data suggest that the enhanced adhesive properties of chimpanzee fibroblasts may be due to chimpanzee fibroblasts exhibiting significantly higher expression of cell and focal adhesion molecule genes than human cells, both during a wound healing assay and at rest. Conclusions and implications Chimpanzee fibroblasts exhibit stronger adhesion and greater cell migration than human fibroblasts. This may be due to divergent gene expression of focal adhesion and cell adhesion molecules, such as integrins, laminins, and cadherins, as well as ECM proteins like collagens. This is one of few studies demonstrating that these divergences in gene expression between closely related species can manifest in fundamental differences in cell biology. Our results provide better insight into species-specific cell biology phenotypes and how they may influence more complex traits, such as cancer metastasis and wound healing. 

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4. Toward universal cell embeddings: integrating single-cell RNA-seq datasets across species with SATURN

   https://doi.org/10.1038/s41592-024-02191-z  

   Rosen, Yanay; Brbić, Maria; Roohani, Yusuf; Swanson, Kyle; Li, Ziang; Leskovec, Jure (February 2024, Nature Methods)

   Abstract Analysis of single-cell datasets generated from diverse organisms offers unprecedented opportunities to unravel fundamental evolutionary processes of conservation and diversification of cell types. However, interspecies genomic differences limit the joint analysis of cross-species datasets to homologous genes. Here we present SATURN, a deep learning method for learning universal cell embeddings that encodes genes’ biological properties using protein language models. By coupling protein embeddings from language models with RNA expression, SATURN integrates datasets profiled from different species regardless of their genomic similarity. SATURN can detect functionally related genes coexpressed across species, redefining differential expression for cross-species analysis. Applying SATURN to three species whole-organism atlases and frog and zebrafish embryogenesis datasets, we show that SATURN can effectively transfer annotations across species, even when they are evolutionarily remote. We also demonstrate that SATURN can be used to find potentially divergent gene functions between glaucoma-associated genes in humans and four other species. 

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5. Assembly of Human Stem Cell-Derived Cortical Spheroids and Vascular Spheroids to Model 3-D Brain-like Tissues

   https://doi.org/10.1038/s41598-019-42439-9  

   Song, Liqing; Yuan, Xuegang; Jones, Zachary; Griffin, Kyle; Zhou, Yi; Ma, Teng; Li, Yan (April 2019, Scientific Reports)

   Abstract Human cerebral organoids derived from induced pluripotent stem cells (iPSCs) provide novel tools for recapitulating the cytoarchitecture of human brain and for studying biological mechanisms of neurological disorders. However, the heterotypic interactions of neurovascular units, composed of neurons, pericytes, astrocytes, and brain microvascular endothelial cells, in brain-like tissues are less investigated. The objective of this study is to investigate the impacts of neural spheroids and vascular spheroids interactions on the regional brain-like tissue patterning in cortical spheroids derived from human iPSCs. Hybrid neurovascular spheroids were constructed by fusion of human iPSC-derived cortical neural progenitor cell (iNPC) spheroids, endothelial cell (iEC) spheroids, and the supporting human mesenchymal stem cells (MSCs). Single hybrid spheroids were constructed at different iNPC: iEC: MSC ratios of 4:2:0, 3:2:1 2:2:2, and 1:2:3 in low-attachment 96-well plates. The incorporation of MSCs upregulated the secretion levels of cytokines VEGF-A, PGE2, and TGF-β1 in hybrid spheroid system. In addition, tri-cultured spheroids had high levels of TBR1 (deep cortical layer VI) and Nkx2.1 (ventral cells), and matrix remodeling genes, MMP2 and MMP3, as well as Notch-1, indicating the crucial role of matrix remodeling and cell-cell communications on cortical spheroid and organoid patterning. Moreover, tri-culture system elevated blood-brain barrier gene expression (e.g., GLUT-1), CD31, and tight junction protein ZO1 expression. Treatment with AMD3100, a CXCR4 antagonist, showed the immobilization of MSCs during spheroid fusion, indicating a CXCR4-dependent manner of hMSC migration and homing. This forebrain-like model has potential applications in understanding heterotypic cell-cell interactions and novel drug screening in diseased human brain. 

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