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Single-cell transcriptomics following ischemic injury identifies a role for B2M in cardiac repair.

ABSTRACT: The efficiency of the repair process following ischemic cardiac injury is a crucial determinant for the progression into heart failure and is controlled by both intra- and intercellular signaling within the heart. An enhanced understanding of this complex interplay will enable better exploitation of these mechanisms for therapeutic use. We used single-cell transcriptomics to collect gene expression data of all main cardiac cell types at different time-points after ischemic injury. These data unveiled cellular and transcriptional heterogeneity and changes in cellular function during cardiac remodeling. Furthermore, we established potential intercellular communication networks after ischemic injury. Follow up experiments confirmed that cardiomyocytes express and secrete elevated levels of beta-2 microglobulin in response to ischemic damage, which can activate fibroblasts in a paracrine manner. Collectively, our data indicate phase-specific changes in cellular heterogeneity during different stages of cardiac remodeling and allow for the identification of therapeutic targets relevant for cardiac repair.

SUBMITTER: Molenaar B

PROVIDER: S-EPMC7846780 | biostudies-literature | 2021 Jan

REPOSITORIES: biostudies-literature

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Single-cell transcriptomics following ischemic injury identifies a role for B2M in cardiac repair.

Molenaar Bas B Timmer Louk T LT Droog Marjolein M Perini Ilaria I Versteeg Danielle D Kooijman Lieneke L Monshouwer-Kloots Jantine J de Ruiter Hesther H Gladka Monika M MM van Rooij Eva E

Communications biology 20210129 1

The efficiency of the repair process following ischemic cardiac injury is a crucial determinant for the progression into heart failure and is controlled by both intra- and intercellular signaling within the heart. An enhanced understanding of this complex interplay will enable better exploitation of these mechanisms for therapeutic use. We used single-cell transcriptomics to collect gene expression data of all main cardiac cell types at different time-points after ischemic injury. These data unv ...[more]

PMID: 33514846

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Project description:Fluid resuscitation in the critically ill often results in a positive fluid balance, potentially diluting the serum creatinine concentration and delaying diagnosis of acute kidney injury (AKI).Dilution during AKI was quantified by combining creatinine and volume kinetics to account for fluid type, and rates of fluid infusion and urine output. The model was refined using simulated patients receiving crystalloids or colloids under four glomerular filtration rate (GFR) change scenarios and then applied to a cohort of critically ill patients following cardiac arrest.The creatinine concentration decreased during six hours of fluid infusion at 1 litre-per-hour in simulated patients, irrespective of fluid type or extent of change in GFR (from 0% to 67% reduction). This delayed diagnosis of AKI by 2 to 9 hours. Crystalloids reduced creatinine concentration by 11 to 19% whereas colloids reduced concentration by 36 to 43%. The greatest reduction was at the end of the infusion period. Fluid dilution alone could not explain the rapid reduction of plasma creatinine concentration observed in 39 of 49 patients after cardiac arrest. Additional loss of creatinine production could account for those changes. AKI was suggested in six patients demonstrating little change in creatinine, since a 52 ± 13% reduction in GFR was required after accounting for fluid dilution and reduced creatinine production. Increased injury biomarkers within a few hours of cardiac arrest, including urinary cystatin C and plasma and urinary Neutrophil-Gelatinase-Associated-Lipocalin (biomarker-positive, creatinine-negative patients) also indicated AKI in these patients.Creatinine and volume kinetics combined to quantify GFR loss, even in the absence of an increase in creatinine. The model improved disease severity estimation, and demonstrated that diagnostic delays due to dilution are minimally affected by fluid type. Creatinine sampling should be delayed at least one hour following a large fluid bolus to avoid dilution. Unchanged plasma creatinine post cardiac arrest signifies renal injury and loss of function.Australian and New Zealand Clinical Trials Registry ACTRN12610001012066.

Dataset Information

Single-cell transcriptomics following ischemic injury identifies a role for B2M in cardiac repair.

Publications

Single-cell transcriptomics following ischemic injury identifies a role for B2M in cardiac repair.

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