Molecular Diversity and Specializations among the Cells of the Adult Mouse Brain

Cell.

2018 Aug 09

Saunders A, Macosko EZ, Wysoker A, Goldman M, Krienen FM, de Rivera H, Bien E, Baum M, Bortolin L, Wang S, Goeva A, Nemesh J, Kamitaki N, Brumbaugh S, Kulp D, McCarroll SA.
PMID: 30096299 | DOI: 10.1016/j.cell.2018.07.028

The mammalian brain is composed of diverse, specialized cell populations. To systematically ascertain and learn from these cellular specializations, we used Drop-seq to profile RNA expression in 690,000 individual cells sampled from 9 regions of the adult mouse brain. We identified 565 transcriptionally distinct groups of cells using computational approaches developed to distinguish biological from technical signals. Cross-region analysis of these 565 cell populations revealed features of brain organization, including a gene-expression module for synthesizing axonal and presynaptic components, patterns in the co-deployment of voltage-gated ion channels, functional distinctions among the cells of the vasculature and specialization of glutamatergic neurons across cortical regions. Systematic neuronal classifications for two complex basal ganglia nuclei and the striatum revealed a rare population of spiny projection neurons. This adult mouse brain cell atlas, accessible through interactive online software (DropViz), serves as a reference for development, disease, and evolution.

Single-cell transcriptomics of human embryos identifies multiple sympathoblast lineages with potential implications for neuroblastoma origin

Nature genetics

2021 Apr 08

Kameneva, P;Artemov, AV;Kastriti, ME;Faure, L;Olsen, TK;Otte, J;Erickson, A;Semsch, B;Andersson, ER;Ratz, M;Frisén, J;Tischler, AS;de Krijger, RR;Bouderlique, T;Akkuratova, N;Vorontsova, M;Gusev, O;Fried, K;Sundström, E;Mei, S;Kogner, P;Baryawno, N;Kharchenko, PV;Adameyko, I;
PMID: 33833454 | DOI: 10.1038/s41588-021-00818-x

Characterization of the progression of cellular states during human embryogenesis can provide insights into the origin of pediatric diseases. We examined the transcriptional states of neural crest- and mesoderm-derived lineages differentiating into adrenal glands, kidneys, endothelium and hematopoietic tissue between post-conception weeks 6 and 14 of human development. Our results reveal transitions connecting the intermediate mesoderm and progenitors of organ primordia, the hematopoietic system and endothelial subtypes. Unexpectedly, by using a combination of single-cell transcriptomics and lineage tracing, we found that intra-adrenal sympathoblasts at that stage are directly derived from nerve-associated Schwann cell precursors, similarly to local chromaffin cells, whereas the majority of extra-adrenal sympathoblasts arise from the migratory neural crest. In humans, this process persists during several weeks of development within the large intra-adrenal ganglia-like structures, which may also serve as reservoirs of originating cells in neuroblastoma.

T-cell infiltration correlates with CXCL10 expression in ganglia of cynomolgus macaques with reactivated simian varicella virus.

Journal of virology, 87(5), 2979–2982.

Ouwendijk WJ, Abendroth A, Traina-Dorge V, Getu S, Steain M, Wellish M, Andeweg AC, Osterhaus AD, Gilden D, Verjans GM, Mahalingam R (2013).
PMID: 23269790 | DOI: 10.1128/JVI.03181-12.

Ganglia of monkeys with reactivated simian varicella virus (SVV) contained more CD8 than CD4 T cells around neurons. The abundance of CD8 T cells was greater less than 2 months after reactivation than that at later times and correlated with that of CXCL10 RNA but not with those of SVV protein or open reading frame 61 (ORF61) antisense RNA. CXCL10 RNA colocalized with T-cell clusters. After SVV reactivation, transient T-cell infiltration, possibly mediated by CXCL10, parallels varicella zoster virus (VZV) reactivation in humans.

Single-cell transcriptomic analyses provide insights into the developmental origins of neuroblastoma

Nature genetics

2021 Mar 25

Jansky, S;Sharma, AK;Körber, V;Quintero, A;Toprak, UH;Wecht, EM;Gartlgruber, M;Greco, A;Chomsky, E;Grünewald, TGP;Henrich, KO;Tanay, A;Herrmann, C;Höfer, T;Westermann, F;
PMID: 33767450 | DOI: 10.1038/s41588-021-00806-1

Neuroblastoma is a pediatric tumor of the developing sympathetic nervous system. However, the cellular origin of neuroblastoma has yet to be defined. Here we studied the single-cell transcriptomes of neuroblastomas and normal human developing adrenal glands at various stages of embryonic and fetal development. We defined normal differentiation trajectories from Schwann cell precursors over intermediate states to neuroblasts or chromaffin cells and showed that neuroblastomas transcriptionally resemble normal fetal adrenal neuroblasts. Importantly, neuroblastomas with varying clinical phenotypes matched different temporal states along normal neuroblast differentiation trajectories, with the degree of differentiation corresponding to clinical prognosis. Our work highlights the roles of oncogenic MYCN and loss of TFAP2B in blocking differentiation and may provide the basis for designing therapeutic interventions to overcome differentiation blocks.

Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma

Cancer cell

2023 Apr 08

Gaglia, G;Burger, ML;Ritch, CC;Rammos, D;Dai, Y;Crossland, GE;Tavana, SZ;Warchol, S;Jaeger, AM;Naranjo, S;Coy, S;Nirmal, AJ;Krueger, R;Lin, JR;Pfister, H;Sorger, PK;Jacks, T;Santagata, S;
PMID: 37059105 | DOI: 10.1016/j.ccell.2023.03.015

Lymphocytes are key for immune surveillance of tumors, but our understanding of the spatial organization and physical interactions that facilitate lymphocyte anti-cancer functions is limited. We used multiplexed imaging, quantitative spatial analysis, and machine learning to create high-definition maps of lung tumors from a Kras/Trp53-mutant mouse model and human resections. Networks of interacting lymphocytes ("lymphonets") emerged as a distinctive feature of the anti-cancer immune response. Lymphonets nucleated from small T cell clusters and incorporated B cells with increasing size. CXCR3-mediated trafficking modulated lymphonet size and number, but T cell antigen expression directed intratumoral localization. Lymphonets preferentially harbored TCF1+ PD-1+ progenitor CD8+ T cells involved in responses to immune checkpoint blockade (ICB) therapy. Upon treatment of mice with ICB or an antigen-targeted vaccine, lymphonets retained progenitor and gained cytotoxic CD8+ T cell populations, likely via progenitor differentiation. These data show that lymphonets create a spatial environment supportive of CD8+ T cell anti-tumor responses.

Positional influence on cellular transcriptional identity revealed through spatially segmented single-cell transcriptomics

Cell systems

2023 Jun 21

Morse, DB;Michalowski, AM;Ceribelli, M;De Jonghe, J;Vias, M;Riley, D;Davies-Hill, T;Voss, T;Pittaluga, S;Muus, C;Liu, J;Boyle, S;Weitz, DA;Brenton, JD;Buenrostro, JD;Knowles, TPJ;Thomas, CJ;
PMID: 37348462 | DOI: 10.1016/j.cels.2023.05.003

Single-cell RNA sequencing (scRNA-seq) is a powerful technique for describing cell states. Identifying the spatial arrangement of these states in tissues remains challenging, with the existing methods requiring niche methodologies and expertise. Here, we describe segmentation by exogenous perfusion (SEEP), a rapid and integrated method to link surface proximity and environment accessibility to transcriptional identity within three-dimensional (3D) disease models. The method utilizes the steady-state diffusion kinetics of a fluorescent dye to establish a gradient along the radial axis of disease models. Classification of sample layers based on dye accessibility enables dissociated and sorted cells to be characterized by transcriptomic and regional identities. Using SEEP, we analyze spheroid, organoid, and in vivo tumor models of high-grade serous ovarian cancer (HGSOC). The results validate long-standing beliefs about the relationship between cell state and position while revealing new concepts regarding how spatially unique microenvironments influence the identity of individual cells within tumors.

Spatially organized multicellular immune hubs in human colorectal cancer

Cell

2021 Aug 24

Pelka, K;Hofree, M;Chen, JH;Sarkizova, S;Pirl, JD;Jorgji, V;Bejnood, A;Dionne, D;Ge, WH;Xu, KH;Chao, SX;Zollinger, DR;Lieb, DJ;Reeves, JW;Fuhrman, CA;Hoang, ML;Delorey, T;Nguyen, LT;Waldman, J;Klapholz, M;Wakiro, I;Cohen, O;Albers, J;Smillie, CS;Cuoco, MS;Wu, J;Su, MJ;Yeung, J;Vijaykumar, B;Magnuson, AM;Asinovski, N;Moll, T;Goder-Reiser, MN;Applebaum, AS;Brais, LK;DelloStritto, LK;Denning, SL;Phillips, ST;Hill, EK;Meehan, JK;Frederick, DT;Sharova, T;Kanodia, A;Todres, EZ;Jané-Valbuena, J;Biton, M;Izar, B;Lambden, CD;Clancy, TE;Bleday, R;Melnitchouk, N;Irani, J;Kunitake, H;Berger, DL;Srivastava, A;Hornick, JL;Ogino, S;Rotem, A;Vigneau, S;Johnson, BE;Corcoran, RB;Sharpe, AH;Kuchroo, VK;Ng, K;Giannakis, M;Nieman, LT;Boland, GM;Aguirre, AJ;Anderson, AC;Rozenblatt-Rosen, O;Regev, A;Hacohen, N;
PMID: 34450029 | DOI: 10.1016/j.cell.2021.08.003

Immune responses to cancer are highly variable, with mismatch repair-deficient (MMRd) tumors exhibiting more anti-tumor immunity than mismatch repair-proficient (MMRp) tumors. To understand the rules governing these varied responses, we transcriptionally profiled 371,223 cells from colorectal tumors and adjacent normal tissues of 28 MMRp and 34 MMRd individuals. Analysis of 88 cell subsets and their 204 associated gene expression programs revealed extensive transcriptional and spatial remodeling across tumors. To discover hubs of interacting malignant and immune cells, we identified expression programs in different cell types that co-varied across tumors from affected individuals and used spatial profiling to localize coordinated programs. We discovered a myeloid cell-attracting hub at the tumor-luminal interface associated with tissue damage and an MMRd-enriched immune hub within the tumor, with activated T cells together with malignant and myeloid cells expressing T cell-attracting chemokines. By identifying interacting cellular programs, we reveal the logic underlying spatially organized immune-malignant cell networks.

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	Description
sense Example: Hs-LAG3-sense	Standard probes for RNA detection are in antisense. Sense probe is reverse complent to the corresponding antisense probe.
Intron# Example: Mm-Htt-intron2	Probe targets the indicated intron in the target gene, commonly used for pre-mRNA detection
Pool/Pan Example: Hs-CD3-pool (Hs-CD3D, Hs-CD3E, Hs-CD3G)	A mixture of multiple probe sets targeting multiple genes or transcripts
No-XSp Example: Hs-PDGFB-No-XMm	Does not cross detect with the species (Sp)
XSp Example: Rn-Pde9a-XMm	designed to cross detect with the species (Sp)
O# Example: Mm-Islr-O1	Alternative design targeting different regions of the same transcript or isoforms
CDS Example: Hs-SLC31A-CDS	Probe targets the protein-coding sequence only
EnEm	Probe targets exons n and m
En-Em	Probe targets region from exon n to exon m
Retired Nomenclature
tvn Example: Hs-LEPR-tv1	Designed to target transcript variant n
ORF Example: Hs-ACVRL1-ORF	Probe targets open reading frame
UTR Example: Hs-HTT-UTR-C3	Probe targets the untranslated region (non-protein-coding region) only
5UTR Example: Hs-GNRHR-5UTR	Probe targets the 5' untranslated region only
3UTR Example: Rn-Npy1r-3UTR	Probe targets the 3' untranslated region only
Pan Example: Pool	A mixture of multiple probe sets targeting multiple genes or transcripts

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