Single-cell atlases: shared and tissue-specific cell types across human organs

Nature reviews. Genetics

2022 Feb 25

Elmentaite, R;Domínguez Conde, C;Yang, L;Teichmann, SA;
PMID: 35217821 | DOI: 10.1038/s41576-022-00449-w

The development of single-cell and spatial transcriptomics methods was instrumental in the conception of the Human Cell Atlas initiative, which aims to generate an integrated map of all cells across the human body. These technology advances are bringing increasing depth and resolution to maps of human organs and tissues, as well as our understanding of individual human cell types. Commonalities as well as tissue-specific features of primary and supportive cell types across human organs are beginning to emerge from these human tissue maps. In this Review, we highlight key biological insights obtained from cross-tissue studies into epithelial, fibroblast, vascular and immune cells based on single-cell gene expression data in humans and contrast it with mechanisms reported in mice.

Experimental challenges to modeling prostate cancer heterogeneity

Cancer letters

2021 Oct 21

Flores-Téllez, TDNJ;Baena, E;
PMID: 34688843 | DOI: 10.1016/j.canlet.2021.10.012

Tumor heterogeneity plays a key role in prostate cancer prognosis, therapy selection, relapse, and acquisition of treatment resistance. Prostate cancer presents a heterogeneous diversity at inter- and intra-tumor and inter-patient levels which are influenced by multiple intrinsic and/or extrinsic factors. Recent studies have started to characterize the complexity of prostate tumors and these different tiers of heterogeneity. In this review, we discuss the most common factors that contribute to tumoral diversity. Moreover, we focus on the description of the in vitro and in vivo approaches, as well as high-throughput technologies, that help to model intra-tumoral diversity. Further understanding tumor heterogeneities and the challenges they present will guide enhanced patient risk stratification, aid the design of more precise therapies, and ultimately help beat this chameleon-like disease.

Macrophage/microglia-derived IL-1β induces glioblastoma growth via the STAT3/NF-κB pathway

Human cell

2021 Sep 30

Kai, K;Komohara, Y;Esumi, S;Fujiwara, Y;Yamamoto, T;Uekawa, K;Ohta, K;Takezaki, T;Kuroda, J;Shinojima, N;Hamasaki, T;Mukasa, A;
PMID: 34591282 | DOI: 10.1007/s13577-021-00619-8

Glioblastoma is a glioma characterized by highly malignant features. Numerous studies conducted on the relationship between glioblastoma and the microenvironment have indicated the significance of tumor-associated macrophages/microglia (TAMs) in glioblastoma progression. Since interleukin (IL)-1β secreted by TAMs has been suggested to promote glioblastoma growth, we attempted to elucidate the detailed mechanisms of IL-1β in glioblastoma growth in this study. A phospho-receptor tyrosine kinase array and RNA-sequencing studies indicated that IL-1β induced the activation of signal transducer and activator of transcription-3 and nuclear factor-kappa B signaling. Glioblastoma cells stimulated by IL-1β induced the production of IL-6 and CXCL8, which synergistically promoted glioblastoma growth via signal transducer and activator of transcription-3 and nuclear factor-kappa B signaling. By immunohistochemistry, IL-1β expression was seen on TAMs, especially in perinecrotic areas. These results suggest that IL-1β might be a useful target molecule for anti-glioblastoma therapy.

An mPOA-ARC AgRP Pathway Modulates Cold-Evoked Eating Behavior

SSRN Electronic Journal

2021 Feb 09

Yang, S;Tan, Y;Wu, X;Wang, J;Sun, J;Gan, L;Shen, B;Huang, J;
| DOI: 10.2139/ssrn.3780283

Behavioral thermoregulation involves enhanced appetite under decreased temperature. The neural circuitry mediating the crosstalk between behavioral thermoregulation and energy homeostasis remains to be elucidated. We find that the hypothalamic orexigenic agouti-related neuropeptide (AgRP) neurons in the arcuate nucleus (ARC) are profoundly activated by cold exposure. Inhibition of AgRP neurons attenuates the cold-evoked eating behavior. The calcium signals in AgRP neurons display an immediate-response pattern in response to cold stimulation. We find that the upstream cold-responsive neurons in the medial preoptic area (mPOA) make excitatory synaptic connections onto AgRP neurons. These findings reveal an mPOA-ARC neural pathway that modulates the cold-evoked eating behavior.

The origin of the expressed retrotransposed gene ACTBL2 and its influence on human melanoma cells\' motility and focal adhesion formation

Scientific reports

2021 Feb 08

Malek, N;Michrowska, A;Mazurkiewicz, E;Mrówczyńska, E;Mackiewicz, P;Mazur, AJ;
PMID: 33558623 | DOI: 10.1038/s41598-021-82074-x

We have recently found that β-actin-like protein 2 (actbl2) forms complexes with gelsolin in human melanoma cells and can polymerize. Phylogenetic and bioinformatic analyses showed that actbl2 has a common origin with two non-muscle actins, which share a separate history from the muscle actins. The actin groups' divergence started at the beginning of vertebrate evolution, and actbl2 actins are characterized by the largest number of non-conserved amino acid substitutions of all actins. We also discovered that ACTBL2 is expressed at a very low level in several melanoma cell lines, but a small subset of cells exhibited a high ACTBL2 expression. We found that clones with knocked-out ACTBL2 (CR-ACTBL2) or overexpressing actbl2 (OE-ACTBL2) differ from control cells in the invasion, focal adhesion formation, and actin polymerization ratio, as well as in the formation of lamellipodia and stress fibers. Thus, we postulate that actbl2 is the seventh actin isoform and is essential for cell motility.

Identification of novel neurocircuitry through which leptin targets multiple inputs to the dopamine system to reduce food reward seeking

Biological Psychiatry

2021 Jan 01

Omrani, A;de Vrind, V;Lodder, B;Stoltenborg, I;Kooij, K;Wolterink-Donselaar, I;Luijendijk-Berg, M;Garner, K;van ’t Sant, L;Rozeboom, A;Dickson, S;Meye, F;Adan, R;
| DOI: 10.1016/j.biopsych.2021.02.017

A large number of dopamine neurons projecting to the NAc are innervated by local VTA LepR-expressing gamma-aminobutyric acid (GABA) neurons. Leptin enhances the activity of these GABA neurons and thereby inhibits NAc-projecting dopamine neurons. In addition, we find that lateral hypothalamic (LH) LepR-expressing neurons projecting to the VTA are inhibited by leptin and that these neurons modulate dopamine neurons indirectly via inhibition of VTA GABA neurons. In accordance with such a disinhibitory function, optogenetically stimulating LH LepR projections to the VTA potently activates dopamine neurons in vivo. Moreover, we found that chemogenetic activation of LH LepR neurons increases the motivation to obtain a food reward only when mice are in positive energy balance.

Oxycodone withdrawal induces HDAC1/HDAC2-dependent transcriptional maladaptations in the reward pathway in a mouse model of peripheral nerve injury

Nature neuroscience

2023 Jun 08

Pryce, KD;Serafini, RA;Ramakrishnan, A;Nicolais, A;Giosan, IM;Polizu, C;Torres-Berrío, A;Vuppala, S;Kronman, H;Ruiz, A;Gaspari, S;Peña, CJ;Sakloth, F;Mitsi, V;van Duzer, J;Mazitschek, R;Jarpe, M;Shen, L;Nestler, EJ;Zachariou, V;
PMID: 37291337 | DOI: 10.1038/s41593-023-01350-3

The development of physical dependence and addiction disorders due to misuse of opioid analgesics is a major concern with pain therapeutics. We developed a mouse model of oxycodone exposure and subsequent withdrawal in the presence or absence of chronic neuropathic pain. Oxycodone withdrawal alone triggered robust gene expression adaptations in the nucleus accumbens, medial prefrontal cortex and ventral tegmental area, with numerous genes and pathways selectively affected by oxycodone withdrawal in mice with peripheral nerve injury. Pathway analysis predicted that histone deacetylase (HDAC) 1 is a top upstream regulator in opioid withdrawal in nucleus accumbens and medial prefrontal cortex. The novel HDAC1/HDAC2 inhibitor, Regenacy Brain Class I HDAC Inhibitor (RBC1HI), attenuated behavioral manifestations of oxycodone withdrawal, especially in mice with neuropathic pain. These findings suggest that inhibition of HDAC1/HDAC2 may provide an avenue for patients with chronic pain who are dependent on opioids to transition to non-opioid analgesics.

Transfer learning in a biomaterial fibrosis model identifies in vivo senescence heterogeneity and contributions to vascularization and matrix production across species and diverse pathologies

GeroScience

2023 Apr 20

Cherry, C;Andorko, JI;Krishnan, K;Mejías, JC;Nguyen, HH;Stivers, KB;Gray-Gaillard, EF;Ruta, A;Han, J;Hamada, N;Hamada, M;Sturmlechner, I;Trewartha, S;Michel, JH;Davenport Huyer, L;Wolf, MT;Tam, AJ;Peña, AN;Keerthivasan, S;Le Saux, CJ;Fertig, EJ;Baker, DJ;Housseau, F;van Deursen, JM;Pardoll, DM;Elisseeff, JH;
PMID: 37079217 | DOI: 10.1007/s11357-023-00785-7

Cellular senescence is a state of permanent growth arrest that plays an important role in wound healing, tissue fibrosis, and tumor suppression. Despite senescent cells' (SnCs) pathological role and therapeutic interest, their phenotype in vivo remains poorly defined. Here, we developed an in vivo-derived senescence signature (SenSig) using a foreign body response-driven fibrosis model in a p16-CreERT2;Ai14 reporter mouse. We identified pericytes and "cartilage-like" fibroblasts as senescent and defined cell type-specific senescence-associated secretory phenotypes (SASPs). Transfer learning and senescence scoring identified these two SnC populations along with endothelial and epithelial SnCs in new and publicly available murine and human data single-cell RNA sequencing (scRNAseq) datasets from diverse pathologies. Signaling analysis uncovered crosstalk between SnCs and myeloid cells via an IL34-CSF1R-TGFβR signaling axis, contributing to tissue balance of vascularization and matrix production. Overall, our study provides a senescence signature and a computational approach that may be broadly applied to identify SnC transcriptional profiles and SASP factors in wound healing, aging, and other pathologies.

Baseline skin cytokine profiles determined by RNA in situ hybridization correlate with response to dupilumab in patients with eczematous dermatitis

Journal of the American Academy of Dermatology

2023 Feb 11

Singh, K;Valido, K;Swallow, M;Okifo, KO;Wang, A;Cohen, JM;Damsky, W;
PMID: 36780951 | DOI: 10.1016/j.jaad.2022.12.052

Dupilumab has revolutionized the treatment of atopic dermatitis. However, not all patients respond optimally, and this may relate to underlying molecular heterogeneity. Nevertheless, clinically useful and accessible methods to assess such heterogeneity have not been developed.We assessed whether cytokine staining and/or histologic features correlate with clinical response to dupilumab in patients with eczematous dermatitis.We retrospectively analyzed biopsies from 61 patients with eczematous dermatitis treated with dupilumab (90.2% met Hanifin-Rajka criteria for atopic dermatitis). RNA in situ hybridization was used to measure markers of type 2 (interleukin [IL]4, IL13), type 1 (interferon gamma) and type 3 (IL17A, IL17F, IL22) inflammation. Histologic features were also assessed. Patterns were compared among complete (n = 16), partial (n = 37), and nonresponders (n = 8) to dupilumab.We found that increased IL13 expression was associated with optimal response to dupilumab. In contrast, nonresponders tended to express less IL13 and relatively greater levels of type 1 and 3 cytokines. In addition, certain histologic features tended to correlate with improved response to dupilumab.Retrospective approach and small size of the nonresponder group.Cytokine RNA in situ hybridization may aid in treatment selection for eczematous disorders. Moreover, personalization of treatment selection for inflammatory skin diseases may be possible.

APC7 mediates ubiquitin signaling in constitutive heterochromatin in the developing mammalian brain

Molecular cell

2021 Dec 16

Ferguson, CJ;Urso, O;Bodrug, T;Gassaway, BM;Watson, ER;Prabu, JR;Lara-Gonzalez, P;Martinez-Chacin, RC;Wu, DY;Brigatti, KW;Puffenberger, EG;Taylor, CM;Haas-Givler, B;Jinks, RN;Strauss, KA;Desai, A;Gabel, HW;Gygi, SP;Schulman, BA;Brown, NG;Bonni, A;
PMID: 34942119 | DOI: 10.1016/j.molcel.2021.11.031

Neurodevelopmental cognitive disorders provide insights into mechanisms of human brain development. Here, we report an intellectual disability syndrome caused by the loss of APC7, a core component of the E3 ubiquitin ligase anaphase promoting complex (APC). In mechanistic studies, we uncover a critical role for APC7 during the recruitment and ubiquitination of APC substrates. In proteomics analyses of the brain from mice harboring the patient-specific APC7 mutation, we identify the chromatin-associated protein Ki-67 as an APC7-dependent substrate of the APC in neurons. Conditional knockout of the APC coactivator protein Cdh1, but not Cdc20, leads to the accumulation of Ki-67 protein in neurons in vivo, suggesting that APC7 is required for the function of Cdh1-APC in the brain. Deregulated neuronal Ki-67 upon APC7 loss localizes predominantly to constitutive heterochromatin. Our findings define an essential function for APC7 and Cdh1-APC in neuronal heterochromatin regulation, with implications for understanding human brain development and disease.

Peroxisomal Multifunctional Protein 2 Deficiency Perturbs Lipid Homeostasis in the Retina and Causes Visual Dysfunction in Mice

Frontiers in cell and developmental biology

2021 Feb 02

Das, Y;Swinkels, D;Kocherlakota, S;Vinckier, S;Vaz, FM;Wever, E;van Kampen, AHC;Jun, B;Do, KV;Moons, L;Bazan, NG;Van Veldhoven, PP;Baes, M;
PMID: 33604342 | DOI: 10.3389/fcell.2021.632930

Patients lacking multifunctional protein 2 (MFP2), the central enzyme of the peroxisomal β-oxidation pathway, develop retinopathy. This pathway is involved in the metabolism of very long chain (VLCFAs) and polyunsaturated (PUFAs) fatty acids, which are enriched in the photoreceptor outer segments (POS). The molecular mechanisms underlying the retinopathy remain, however, elusive. Here, we report that mice with MFP2 inactivation display decreased retinal function already at the age of 3 weeks, which is accompanied by a profound shortening of the photoreceptor outer and inner segments, but with preserved photoreceptor ultrastructure. Furthermore, MFP2 deficient retinas exhibit severe changes in gene expression with downregulation of genes involved in the phototransduction pathway and upregulation of inflammation related genes. Lipid profiling of the mutant retinas revealed a profound reduction of DHA-containing phospholipids. This was likely due to a hampered systemic supply and retinal traffic of this PUFA, although we cannot exclude that the local defect of peroxisomal β-oxidation contributes to this DHA decrease. Moreover, very long chain PUFAs were also reduced, with the exception of those containing ≥ 34 carbons that accumulated. The latter suggests that there is an uncontrollable elongation of retinal PUFAs. In conclusion, our data reveal that intact peroxisomal β-oxidation is indispensable for retinal integrity, most likely by maintaining PUFA homeostasis.

Immune cell populations in the broiler ileum exhibit differential cytokine profiles in response to lipid source and peroxidation

2020 Iowa State University Animal Industry Report

2021 Jan 28

Kerr, B;Bobeck, E;Fries-Craft, K;
| DOI: 10.31274/air.11909

Used restaurant oil offers a sustainable and affordable energy source in broiler diets but variable lipid composition and the presence of harmful peroxidation products may alter intestinal immunity. The objective of this study was to evaluate the effects of feeding different lipid sources with variable peroxidation statuses on immune cell populations producing interleukin-6 (IL6) and interferon-γ (IFNG) in the broiler ileum. Two hundred broilers were fed diets with 5% inclusion of control or peroxidized palm, soybean, flaxseed or fish oil in a 4 × 2 factorial treatment design. At 21d, 2 birds/ treatment were euthanized for ileum collection and immune cell populations were analyzed by RNAscope- in situ hybridization (ISH). Ileal production of IL6 increased 85.8% by feeding peroxidized flaxseed oil while IFNG-producing cells were increased 55.1-59.9% by feeding either control or peroxidized soybean oil (P ≤ 0.05). Feeding peroxidized lipid generally reduced CD3+ T cells not producing either IL6 or IFNG by 14.9-39.0% (P ≤ 0.05). Overall, these results suggest that IL6 and IFNG have differential responses to lipid source and peroxidation while lipid peroxidation negatively impacts T cell presence in the broiler chicken ileum. Inflammatory outcomes observed in broilers fed peroxidized flaxseed oil suggest that yellow grease containing this type of oil may detrimentally impact broilers, while soybean oil generally contributes to intestinal inflammation regardless of heat exposure

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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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