Multi-organ single-cell analysis reveals an on/off switch system with potential for personalized treatment of immunological diseases

Lilja, Sandra; Li, Xinxiu; Smelik, Martin; Lee, Eun Jung; Loscalzo, Joseph; Marthanda, Pratheek  Bellur; Hu, Lang; Magnusson, Mattias; Sysoev, Oleg; Zhang, Huan; Zhao, Yongsheng; Sjöwall, Christopher; Gawel, Danuta R.; Wang, Hui; Benson, Mikael

doi:10.1016/j.xcrm.2023.100956

Cited by 12 publications

(14 citation statements)

References 88 publications

(107 reference statements)

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“…Although air pollution exposures are associated with multiorgan toxicity, the mechanisms by which pollutants, upon encountering the lung, trigger substantial systemic and distal effects is poorly understood. We have previously demonstrated that activation of the neuroendocrine system is critical for the systemic response (Henriquez et al, 2018(Henriquez et al, , 2021 Transcriptome analysis identi ed strongest clustering by tissue (lung, hypothalamus, adrenals, liver, adipose, and muscle) representing the highly speci c basal tissue expression re ective of homeostatic function of a given organ (Lilja et al, 2023). Assessment of ozone-induced differentially expressed genes revealed that the greatest impact of ozone was not in lung, but in skeletal muscle, with ozone-induced transcriptomic changes in order of muscle (5,102 DEG), adrenal (2,516 DEG), lung (1,640 DEG), liver (1,333 DEG), adipose (1,242 DEG), and hypothalamus (274 DEG).…”

Section: Discussionmentioning

confidence: 99%

Multi-tissue transcriptomic and serum metabolomic assessment reveals systemic implications of acute ozone-induced stress response in male Wistar Kyoto rats

Jackson¹,

House

Henriquez

et al. 2023

Preprint

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Air pollutant exposures have been linked to systemic disease; however, the underlying mechanisms between responses of the target tissue and systemic effects are poorly understood. A prototypic inducer of stress, ozone causes respiratory and systemic multiorgan effects through activation of a neuroendocrine stress response. The goal of this study was to assess transcriptomic signatures of multiple tissues and serum metabolomics to understand how neuroendocrine and adrenal-derived stress hormones contribute to multiorgan health outcomes. Male Wistar Kyoto rats (12–13 weeks old) were exposed to filtered air or 0.8 ppm ozone for 4-hours, and blood/tissues were collected immediately post-exposure. Each tissue had distinct expression profiles at baseline. Ozone changed 1,640 genes in lung, 274 in hypothalamus, 2,516 in adrenals, 1,333 in liver, 1,242 in adipose, and 5,102 in muscle (adjusted p-value < .1, absolute fold-change > 50%). Serum metabolomic analysis identified 863 metabolites, of which 447 were significantly altered in ozone-exposed rats (adjusted p-value < .1, absolute fold change > 20%). A total of 6 genes were differentially expressed in all 6 tissues. Glucocorticoid signaling, hypoxia, and GPCR signaling were commonly changed, but ozone induced tissue-specific changes in oxidative stress, immune processes, and metabolic pathways. Genes upregulated by TNF-mediated NFkB signaling were differentially expressed in all ozone-exposed tissues, but those defining inflammatory response were tissue-specific. Upstream predictor analysis identified common mediators of effects including glucocorticoids, although the specific genes responsible for these predictors varied by tissue. Metabolomic analysis showed major changes in lipids, amino acids, and metabolites linked to the gut microbiome, concordant with transcriptional changes identified through pathway analysis within liver, muscle, and adipose tissues. The distribution of receptors and transcriptional mechanisms underlying the ozone-induced stress response are tissue-specific and involve induction of unique gene networks and metabolic phenotypes, but the shared initiating triggers converge into shared pathway-level responses. This multi-tissue transcriptomic analysis, combined with circulating metabolomic assessment, allows characterization of the systemic inhaled pollutant-induced stress response.

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Section: Discussionmentioning

confidence: 99%

Multi-tissue transcriptomic and serum metabolomic assessment reveals systemic implications of acute ozone-induced stress response in male Wistar Kyoto rats

Jackson¹,

House

Henriquez

et al. 2023

Preprint

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“…In response to the aforementioned challenges, CURATE.AI used a personalized dosing approach by generating digital twins for individual patients, a concept that has demonstrated potential use for personalized treatments. [ 15 ] CURATE.AI demonstrated the potential to identify the optimal doses to enable more patients to have their TTL reach the therapeutic range in the first week (Figure 8). Additionally, CURATE.AI could achieve similar results in terms of maintaining the TTL within the therapeutic range and the number of days required to for the TTL reach the therapeutic range.…”

Section: Discussionmentioning

confidence: 99%

CURATE.AI—Artificial Intelligence‐Derived Personalized Tacrolimus Dosing for Pediatric Liver Transplant: A Retrospective Study

Tan,

Senthil Kumar,

Gan

et al. 2023

Advanced Therapeutics

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Tacrolimus is the cornerstone of immunosuppressive therapy after pediatric liver transplantation. However, reliance on the physician's experience for dose titration, coupled with tacrolimus's narrow therapeutic window and inter‐ and intrapatient variability, often results in frequent under or overdosing events with detrimental patient outcomes. Existing predictive dose personalization models are not readily feasible for clinical implementation, as they require multiple measurements each day while the standard frequency is once daily. CURATE.AI, a small‐data artificial intelligence‐derived platform, is developed as a clinical decision support system to dynamically personalize doses using the patient's own data obtained once a day. Retrospective dose personalization with CURATE.AI on 16 patients’ data demonstrates potential to enable more patients to reach therapeutic range within the first week. The findings support the testing of CURATE.AI in a prospective controlled trial as an aid for the physician's decision on tacrolimus dose personalization after pediatric liver transplantation.

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“…Lilja et al. 1 present an analysis method based on gene expression changes through single-cell RNA sequencing (scRNA-seq) in multiple organs of mice induced to develop collagen-induced arthritis (CIA) to prioritize intercellular pathways dysregulated in the joints and other organs. Based on these tissue-specific single-cell transcriptomes, the authors identify transcriptional changes at inflamed sites (e.g., paws) and sites with no histologic evidence of tissue inflammation (e.g., muscle) and relate these to upregulated functional pathways in cell types of paw origin, including fibroblasts, T cells, endothelial cells, macrophages, and epithelial cells, and downregulated functional pathways in cell types of muscle origin, including natural killer (NK) cells, endothelial cells, dendritic cells, B cells, and monocytes.…”

Section: Main Textmentioning

confidence: 99%

“… Lilja et al. 1 explore single-cell transcriptomes across multiple organs of mice with collagen-induced arthritis. They apply network analysis to prioritize functional pathways that support or suppress inflammation and integrate findings with tissue transcriptomics in human immune-mediated inflammatory diseases.…”

mentioning

confidence: 99%

Multi-organ single-cell analysis reveals an on/off switch system with potential for personalized treatment of immunological diseases

Cited by 12 publications

References 88 publications

Multi-tissue transcriptomic and serum metabolomic assessment reveals systemic implications of acute ozone-induced stress response in male Wistar Kyoto rats

Multi-tissue transcriptomic and serum metabolomic assessment reveals systemic implications of acute ozone-induced stress response in male Wistar Kyoto rats

CURATE.AI—Artificial Intelligence‐Derived Personalized Tacrolimus Dosing for Pediatric Liver Transplant: A Retrospective Study

Translating from mouse to man to better understand immune-mediated inflammatory diseases

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