Whole-heart 3D reconstruction of mouse CVB3 myocarditis reveals spatial and transcriptomic heterogeneity of immune foci

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00023001%3A_____%2F25%3A00086105" target="_blank" >RIV/00023001:_____/25:00086105 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/00216208:11120/25:43929251 RIV/00064190:_____/25:10001421

Výsledek na webu

<a href="https://academic.oup.com/cardiovascres/article/121/17/2777/8380423" target="_blank" >https://academic.oup.com/cardiovascres/article/121/17/2777/8380423</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1093/cvr/cvaf209" target="_blank" >10.1093/cvr/cvaf209</a>

Jazyk výsledku

angličtina

Název v původním jazyce

Whole-heart 3D reconstruction of mouse CVB3 myocarditis reveals spatial and transcriptomic heterogeneity of immune foci

Popis výsledku v původním jazyce

Aims Myocarditis is an inflammation of the myocardium and is characterized by poor prognosis in symptomatic patients and significant correlation with dilated cardiomyopathy (DCM). We investigated spatial, morphological, immunological, and transcriptomic heterogeneity of myocarditis inflammatory foci in the 3D space.Methods and results Utilizing a novel large tissue histological reconstruction workflow, CODA (not an acronym), we generated whole-heart 3D reconstructions of acute mouse Coxsackievirus B3 (CVB3) myocarditis at the single-cell resolution. Furthermore, we integrated immunohistochemical staining and spatial RNA-sequencing into the CODA workflow. This approach allowed the simultaneous morphological, immunological and transcriptional 3D analysis of acute mouse CVB3 myocarditis. In addition, flow cytometry and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses were used to validate our 3D findings. We show that acute mouse CVB3 myocarditis foci are multi-branched, elongated, and found mostly within myocardial regions of the left ventricular wall. We further show that significant T-cell- and macrophage-specific niches exist within the same focus. At the organ level, we show that T-cell-rich foci are more likely to be found anteriorly while macrophage-rich foci are more likely to be found posteriorly. We further demonstrate that T-cell hotspots are well-vascularized spatial niches. Moreover, using spatial transcriptomics and qRT-PCR, we show that T-cell-rich regions of anterior immune foci uniquely upregulate the expression of collagen I and T-cell-specific chemokines. Conversely, surrounding homogeneous foci regions upregulate the expression of broad-target chemokines and T-cell retentive molecules. We show the translatability of our work since 3D immunological heterogeneity mouse results were similar to human DCM explanted hearts with similar immune cell heterogeneity along the sagittal axis.Conclusion Our multimodal findings highlight that acute mouse CVB3 myocarditis exhibits heterogeneous immune phenotype with distinct anterior T-cell hotspots that are well-vascularized and upregulate the expression of T-cell-specific chemokines and collagen I.

Název v anglickém jazyce

Whole-heart 3D reconstruction of mouse CVB3 myocarditis reveals spatial and transcriptomic heterogeneity of immune foci

Popis výsledku anglicky

Aims Myocarditis is an inflammation of the myocardium and is characterized by poor prognosis in symptomatic patients and significant correlation with dilated cardiomyopathy (DCM). We investigated spatial, morphological, immunological, and transcriptomic heterogeneity of myocarditis inflammatory foci in the 3D space.Methods and results Utilizing a novel large tissue histological reconstruction workflow, CODA (not an acronym), we generated whole-heart 3D reconstructions of acute mouse Coxsackievirus B3 (CVB3) myocarditis at the single-cell resolution. Furthermore, we integrated immunohistochemical staining and spatial RNA-sequencing into the CODA workflow. This approach allowed the simultaneous morphological, immunological and transcriptional 3D analysis of acute mouse CVB3 myocarditis. In addition, flow cytometry and quantitative reverse transcription polymerase chain reaction (qRT-PCR) analyses were used to validate our 3D findings. We show that acute mouse CVB3 myocarditis foci are multi-branched, elongated, and found mostly within myocardial regions of the left ventricular wall. We further show that significant T-cell- and macrophage-specific niches exist within the same focus. At the organ level, we show that T-cell-rich foci are more likely to be found anteriorly while macrophage-rich foci are more likely to be found posteriorly. We further demonstrate that T-cell hotspots are well-vascularized spatial niches. Moreover, using spatial transcriptomics and qRT-PCR, we show that T-cell-rich regions of anterior immune foci uniquely upregulate the expression of collagen I and T-cell-specific chemokines. Conversely, surrounding homogeneous foci regions upregulate the expression of broad-target chemokines and T-cell retentive molecules. We show the translatability of our work since 3D immunological heterogeneity mouse results were similar to human DCM explanted hearts with similar immune cell heterogeneity along the sagittal axis.Conclusion Our multimodal findings highlight that acute mouse CVB3 myocarditis exhibits heterogeneous immune phenotype with distinct anterior T-cell hotspots that are well-vascularized and upregulate the expression of T-cell-specific chemokines and collagen I.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

30201 - Cardiac and Cardiovascular systems

Projekt

<a href="/cs/project/LX22NPO5104" target="_blank" >LX22NPO5104: Národní institut pro výzkum metabolických a kardiovaskulárních onemocnění</a><br>

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2025

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Cardiovascular research

ISSN

0008-6363

e-ISSN

1755-3245

Svazek periodika

121

Číslo periodika v rámci svazku

17

Stát vydavatele periodika

GB - Spojené království Velké Británie a Severního Irska

Počet stran výsledku

14

Strana od-do

2777-2790

Kód UT WoS článku

001639616700001

EID výsledku v databázi Scopus

2-s2.0-105026367368