NIH SenNet Consortium: Mapping Senescent Cells in the Human Body to Understand Health and Disease

Preprint

2022 Jul 12

Lee, P;Blood, P;Börner, K;Campisi, J;Chen, F;Daldrup-Link, H;De Jager, P;Ding, L;Duncan, F;Eickelberg, O;Fan, R;Finkel, T;Garovic, V;Gehlenborg, N;Glass, C;Bar-Joseph, Z;Katiyar, P;Kim, S;Königshoff, M;Kuchel, G;Lee, H;Lee, J;Ma, J;Ma, Q;Melov, S;Metis, K;Mora, A;Musi, N;Neretti, N;Passos, J;Rahman, I;Rivera-Mulia, J;Robson, P;Rojas, M;Roy, A;Schilling, B;Shi, P;Silverstein, J;Suryadevera, V;Xie, J;Wang, J;Wong, A;Niedernhofer, L;
| DOI: 10.20944/preprints202207.0160.v1

Cells respond to a myriad of stressors by senescing, acquiring stable growth arrest, morphologic and metabolic changes, and a senescence-associated-secretory-phenotype (SASP). The heterogeneity of senescent cells (SnCs) and their SASP is vast, yet poorly characterized. SnCs have diverse roles in health and disease and are therapeutically targetable, making characterization of SnCs and harmonization of their nomenclature a priority. The Cellular Senescence Network (SenNet), a NIH Common Fund initiative, will leverage emerging single cell and spatial-omics to identify and map SnCs in numerous organs across the lifespan of humans and mice. A common coordinate framework will integrate the data, using validated, standardized methods, creating public 4-dimensional SnC atlases. Key SenNet deliverables include development of innovative tools/technologies to detect SnCs, biomarker discovery, common annotations to describe SnCs and extensive public data sets. The goal is to comprehensively understand and map SnCs for diagnostic and therapeutic purposes to improve human health.

Recombinant Human Collagen Hydrogel Rapidly Reduces Methylglyoxal Adducts within Cardiomyocytes and Improves Borderzone Contractility after Myocardial Infarction in Mice

Advanced Functional Materials

2022 May 24

McLaughlin, S;Sedlakova, V;Zhang, Q;McNeill, B;Smyth, D;Seymour, R;Davis, D;Ruel, M;Brand, M;Alarcon, E;Suuronen, E;
| DOI: 10.1002/adfm.202204076

Methylglyoxal (MG) production after myocardial infarction (MI) leads to advanced glycation end-product formation, adverse remodeling, and loss of cardiac function. The extracellular matrix (ECM) is a main target for MG glycation. This suggests that ECM-mimicking biomaterial therapies may protect the post-MI environment by removing MG. In this study, mechanisms by which a recombinant human collagen type I hydrogel therapy confers cardioprotection are investigated. One-week post-MI, mice receive intramyocardial injection of hydrogel or PBS. The hydrogel improves border zone contractility after 2 days, which is maintained for 28 days. RNA sequencing shows that hydrogel treatment decreases the expression of erythroid differentiation regulator 1, a factor associated with apoptosis. Hydrogel treatment reduces cardiomyocyte apoptosis and oxidative stress at 2 days with greater myocardial salvage seen at 28 days. The hydrogel located at the epicardial surface is modified by MG, and less MG-modified proteins are observed in the underlying myocardium of hydrogel-treated mice. Biomaterials that can be a target for MG glycation may act as a sponge to remove MG from the myocardium post-MI. This leads to less oxidative stress, greater survival and contractility of cardiomyocytes, which altogether suggests a novel mechanism by which biomaterials improve function of the infarcted heart.

Human and mouse trigeminal ganglia cell atlas implicates multiple cell types in migraine

Neuron

2022 Mar 25

Yang, L;Xu, M;Bhuiyan, SA;Li, J;Zhao, J;Cohrs, RJ;Susterich, JT;Signorelli, S;Green, U;Stone, JR;Levy, D;Lennerz, JK;Renthal, W;
PMID: 35349784 | DOI: 10.1016/j.neuron.2022.03.003

Sensitization of trigeminal ganglion neurons contributes to primary headache disorders such as migraine, but the specific neuronal and non-neuronal trigeminal subtypes that are involved remain unclear. We thus developed a cell atlas in which human and mouse trigeminal ganglia are transcriptionally and epigenomically profiled at single-cell resolution. These data describe evolutionarily conserved and human-specific gene expression patterns within each trigeminal ganglion cell type, as well as the transcription factors and gene regulatory elements that contribute to cell-type-specific gene expression. We then leveraged these data to identify trigeminal ganglion cell types that are implicated both by human genetic variation associated with migraine and two mouse models of headache. This trigeminal ganglion cell atlas improves our understanding of the cell types, genes, and epigenomic features involved in headache pathophysiology and establishes a rich resource of cell-type-specific molecular features to guide the development of more selective treatments for headache and facial pain.

Excitatory SST Neurons in the Medial Paralemniscal Nucleus Control Repetitive Self-Grooming and Encode Reward

SSRN Electronic Journal

2022 Jan 22

Sun, J;Yuan, Y;Wu, X;Liu, A;Wang, J;Yang, S;Liu, B;Kong, Y;Wang, L;Li, Q;Zhang, S;Yuan, T;Xu, T;Huang, J;
| DOI: 10.2139/ssrn.4013919

The use of body-focused repetitive behaviors (BFRBs) is conceptualized as a means for emotion regulation upon stress exposure. However, it is unclear about the neurological mechanism on how repetitive behaviors affect emotion regulation to cope with stress. Here, we identify that excitatory somatostatin-positive neurons in the medial paralemniscal nucleus (MPLSST neurons) control self-grooming and encode reward. MPLSST neuronal activity is responsible for self-grooming initiation and maintenance. Loss-of-function of MPLSST neurons attenuates both self-grooming motor actions and anxiety alleviation upon stress exposure. Activating MPLSST neurons generate reward and drive reinforcement through eliciting dopamine release in the downstream target of the ventral tegmental area (VTA), and neuropeptide SST facilitates the rewarding impact of MPLSST neurons. MPLSST neuron-mediated self-grooming is triggered by inputs from the central amygdala (CeA). Our study validates a CeA-MPLSST-VTADA circuit mediating the impact of self-grooming on emotion regulation to cope with stress through generating reward and pleasurable feelings.

DMD-TREATMENT: EP. 147 2.5-years of vamorolone treatment in Duchenne muscular dystrophy: Results of an open label long-term extension

Neuromuscular Disorder

2021 Jan 01

Hoffman, E;Dang, U;Clemens, P;
| DOI: Genotypes were determined by PCR using commercial vendors (Transnetyx, Cordova, TN, USA).

Vamorolone is a first-in-class steroidal anti-inflammatory drug with novel structure/activity relationships with glucocorticoid and mineralocorticoid receptor targets compared to deflazacort or prednisone. Published open-label dose-finding studies (0.25-6.0 mg/kg/day) in DMD showed significant motor function improvement over 24 weeks for 2.0 and 6.0 mg/kg/day dose groups (n=48; age 4 to 6-month delay and maintained a higher dose through the remaining study period. Analyses of disease trajectories showed a strong effect of age at initiation of treatment. Subjects initiating treatment at 4-5 years showed highest clinical outcome performance levels as well as a delayed decline of motor function compared to subjects initially treated with low doses (0.25 or 0.75 mg/kg/day). Stratification of participants by treatment period at high doses (2.5 years; or delayed start 2.0 years), and/or by age showed data consistent with a disease modifying effect for many outcome measures. Vamorolone treatment was not associated with typical safety concerns of corticosteroid treatment (slowing of linear growth, insulin resistance, decreases in osteocalcin).

Harnessing the Potential of Multiomics Studies for Precision Medicine in Infectious Disease

Open Forum Infectious Diseases

2021 Sep 25

Ward, R;Aghaeepour, N;Bhattacharyya, R;Clish, C;Gaudillière, B;Hacohen, N;Mansour, M;Mudd, P;Pasupneti, S;Presti, R;Rhee, E;Sen, P;Spec, A;Tam, J;Villani, A;Woolley, A;Hsu, J;Vyas, J;
| DOI: 10.1093/ofid/ofab483

The field of infectious diseases currently takes a reactive approach, treating infections as they present in patients. Although certain populations are known to be at greater risk of developing infection (e.g., immunocompromised), we lack a systems approach to define the true risk of future infection for a patient. Guided by impressive gains in -omics technologies, future strategies to infectious diseases should take a precision approach to infection through identification of patients at intermediate and high-risk of infection and deploy targeted preventative measures (i.e., prophylaxis). The advances of high-throughput immune profiling by multiomics approaches (i.e., transcriptomics, epigenomics, metabolomics, proteomics) holds the promise to identify patients at increased risk of infection and enable risk-stratifying approaches to be applied in the clinic. Integration of patient-specific data using machine learning improves the effectiveness of prediction, providing the necessary technologies needed to propel the field of infectious diseases medicine into the era of personalized medicine.

Immunological mechanisms of vaccine-induced protection against COVID-19 in humans

Nature reviews. Immunology

2021 Aug 01

Sadarangani, M;Marchant, A;Kollmann, TR;
PMID: 34211186 | DOI: 10.1038/s41577-021-00578-z

Most COVID-19 vaccines are designed to elicit immune responses, ideally neutralizing antibodies (NAbs), against the SARS-CoV-2 spike protein. Several vaccines, including mRNA, adenoviral-vectored, protein subunit and whole-cell inactivated virus vaccines, have now reported efficacy in phase III trials and have received emergency approval in many countries. The two mRNA vaccines approved to date show efficacy even after only one dose, when non-NAbs and moderate T helper 1 cell responses are detectable, but almost no NAbs. After a single dose, the adenovirus vaccines elicit polyfunctional antibodies that are capable of mediating virus neutralization and of driving other antibody-dependent effector functions, as well as potent T cell responses. These data suggest that protection may require low levels of NAbs and might involve other immune effector mechanisms including non-NAbs, T cells and innate immune mechanisms. Identifying the mechanisms of protection as well as correlates of protection is crucially important to inform further vaccine development and guide the use of licensed COVID-19 vaccines worldwide.

Alpha oscillations and event-related potentials reflect distinct dynamics of attribute construction and evidence accumulation in dietary decision making

eLife

2021 Jul 15

HajiHosseini, A;Hutcherson, CA;
PMID: 34263723 | DOI: 10.7554/eLife.60874

How does regulatory focus alter attribute value construction (AVC) and evidence accumulation (EA)? We recorded electroencephalogram during food choices while participants responded naturally or regulated their choices by attending to health attributes or decreasing attention to taste attributes. Using a drift diffusion model, we predicted the time course of neural signals associated with AVC and EA. Results suggested that event-related potentials (ERPs) correlated with the time course of model-predicted taste-attribute signals, with no modulation by regulation. By contrast, suppression of frontal and occipital alpha power correlated with the time course of EA, tracked tastiness according to its goal relevance, and predicted individual variation in successful down-regulation of tastiness. Additionally, an earlier rise in frontal and occipital theta power represented food tastiness more strongly during regulation and predicted a weaker influence of food tastiness on behaviour. Our findings illuminate how regulation modifies the representation of attributes during the process of EA.

mRNA distribution in skeletal muscle is associated with mRNA size

Journal of cell science

2021 Jun 24

Pinheiro, H;Pimentel, MR;Sequeira, C;Oliveira, LM;Pezzarossa, A;Roman, W;Gomes, ER;
PMID: 34164679 | DOI: 10.1242/jcs.256388

Skeletal muscle myofibers are large and elongated cells with multiple and evenly distributed nuclei. Nuclear distribution suggests that each nucleus influences a specific compartment within the myofiber and implies a functional role for nuclear positioning. Compartmentalization of specific mRNAs and proteins has been reported at the neuromuscular and myotendinous junctions, but mRNA distribution in non-specialized regions of the myofibers remains largely unexplored. We report that the bulk of mRNAs is enriched around the nucleus of origin and that this perinuclear accumulation depends on recently transcribed mRNAs. Surprisingly, mRNAs encoding large proteins - giant mRNAs - are spread throughout the cell and do not exhibit perinuclear accumulation. Furthermore, by expressing exogenous transcripts with different sizes we found that size contributes to mRNA spreading independently of mRNA sequence. Both these mRNA distribution patterns depend on microtubules and are independent of nuclear dispersion, mRNA expression level and stability, and the characteristics of the encoded protein. Thus, we propose that mRNA distribution in non-specialized regions of skeletal muscle is size selective to ensure cellular compartmentalization and simultaneous long-range distribution of giant mRNAs.

IL-1R1-dependent signaling coordinates epithelial regeneration in response to intestinal damage

Science immunology

2021 May 07

Cox, CB;Storm, EE;Kapoor, VN;Chavarria-Smith, J;Lin, DL;Wang, L;Li, Y;Kljavin, N;Ota, N;Bainbridge, TW;Anderson, K;Roose-Girma, M;Warming, S;Arron, JR;Turley, SJ;de Sauvage, FJ;van Lookeren Campagne, M;
PMID: 33963061 | DOI: 10.1126/sciimmunol.abe8856

Repair of the intestinal epithelium is tightly regulated to maintain homeostasis. The response after epithelial damage needs to be local and proportional to the insult. How different types of damage are coupled to repair remains incompletely understood. We report that after distinct types of intestinal epithelial damage, IL-1R1 signaling in GREM1+ mesenchymal cells increases production of R-spondin 3 (RSPO3), a Wnt agonist required for intestinal stem cell self-renewal. In parallel, IL-1R1 signaling regulates IL-22 production by innate lymphoid cells and promotes epithelial hyperplasia and regeneration. Although the regulation of both RSPO3 and IL-22 is critical for epithelial recovery from Citrobacter rodentium infection, IL-1R1-dependent RSPO3 production by GREM1+ mesenchymal cells alone is sufficient and required for recovery after dextran sulfate sodium-induced colitis. These data demonstrate how IL-1R1-dependent signaling orchestrates distinct repair programs tailored to the type of injury sustained that are required to restore intestinal epithelial barrier function.

Single-cell dissection of cellular components and interactions shaping the tumor immune phenotypes in ovarian cancer

Cancer cell

2021 Apr 27

Hornburg, M;Desbois, M;Lu, S;Guan, Y;Lo, AA;Kaufman, S;Elrod, A;Lotstein, A;DesRochers, TM;Munoz-Rodriguez, JL;Wang, X;Giltnane, J;Mayba, O;Turley, SJ;Bourgon, R;Daemen, A;Wang, Y;
PMID: 33961783 | DOI: 10.1016/j.ccell.2021.04.004

Distinct T cell infiltration patterns, i.e., immune infiltrated, excluded, and desert, result in different responses to cancer immunotherapies. However, the key determinants and biology underpinning these tumor immune phenotypes remain elusive. Here, we provide a high-resolution dissection of the entire tumor ecosystem through single-cell RNA-sequencing analysis of 15 ovarian tumors. Immune-desert tumors are characterized by unique tumor cell-intrinsic features, including metabolic pathways and low antigen presentation, and an enrichment of monocytes and immature macrophages. Immune-infiltrated and -excluded tumors differ markedly in their T cell composition and fibroblast subsets. Furthermore, our study reveals chemokine receptor-ligand interactions within and across compartments as potential mechanisms mediating immune cell infiltration, exemplified by the tumor cell-T cell cross talk via CXCL16-CXCR6 and stromal-immune cell cross talk via CXCL12/14-CXCR4. Our data highlight potential molecular mechanisms that shape the tumor immune phenotypes and may inform therapeutic strategies to improve clinical benefit from cancer immunotherapies.

The role of EBV in hematolymphoid proliferations: Emerging concepts relevant to diagnosis and treatment

Histopathology

2021 Apr 07

Ababneh, E;Saad, AM;Crane, GM;
PMID: 33829526 | DOI: 10.1111/his.14379

Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus with >90% of the adult population worldwide harboring latent infection. A small subset of those infected develop EBV-associated neoplasms including a range of lymphoproliferative disorders (LPD). The diagnostic distinction of these entities appears increasingly relevant as our understanding of EBV-host interactions and mechanisms of EBV-driven lymphomagenesis improves. EBV may lower the mutational threshold for malignant transformation, create potential vulnerabilities related to viral alteration of cell metabolism and allow for improved immune targeting. However, these tumors may escape immune surveillance by affecting their immune microenvironment, limiting viral gene expression or potential loss of the viral episome. Methods to manipulate the latency state of the virus to enhance immunogenicity are emerging as well as the potential to detect so-called "hit and run" cases where EBV has been lost. Finally, measurement of EBV DNA remains an important biomarker for screening and monitoring of LPD. Methods to distinguish EBV DNA derived from virions during lytic activation from latent, methylated EBV DNA present in EBV-associated neoplasms may broaden the utility of this testing, particularly in patients with compromised immune function. We will highlight some of these emerging areas relevant to the diagnosis and treatment of EBV-associated LPD with potential applicability to other EBV-associated neoplasms. This article is protected by

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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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