Mapping the cellular and molecular landscape of cardiac non-myocytes in murine diabetic cardiomyopathy

Charles D Cohen; Miles J De Blasio; Gabriella E Farrugia; Malathi S I Dona; Ian Hsu; Darnel Prakoso; Helen Kiriazis; Crisdion Krstevski; David M Nash; Mandy Li; Taylah L Gaynor; Minh Deo; Grant R Drummond; Rebecca H Ritchie; Alexander R Pinto

doi:10.1016/j.isci.2023.107759

Mapping the cellular and molecular landscape of cardiac non-myocytes in murine diabetic cardiomyopathy

iScience. 2023 Aug 28;26(10):107759. doi: 10.1016/j.isci.2023.107759. eCollection 2023 Oct 20.

Authors

Charles D Cohen^{1

2

3

4}, Miles J De Blasio^{2

5}, Gabriella E Farrugia^{1

6}, Malathi S I Dona¹, Ian Hsu¹, Darnel Prakoso², Helen Kiriazis^{7

8}, Crisdion Krstevski^{1

3

4}, David M Nash², Mandy Li², Taylah L Gaynor^{1

3

4}, Minh Deo², Grant R Drummond⁴, Rebecca H Ritchie^{2

3

4}, Alexander R Pinto^{1

3

4

8}

Affiliations

¹ Cardiac Cellular Systems, Baker Heart and Diabetes Institute, Prahran, VIC, Australia.
² Heart Failure Pharmacology, Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Parkville, VIC, Australia.
³ Department of Microbiology, Anatomy, Physiology and Pharmacology, La Trobe University, Bundoora, VIC, Australia.
⁴ Centre for Cardiovascular Biology and Disease Research, La Trobe University, Melbourne, VIC, Australia.
⁵ Department of Pharmacology, Monash University, Clayton, VIC, Australia.
⁶ Baker Department of Cardiovascular Research and Implementation, La Trobe University, Melbourne, VIC, Australia.
⁷ Preclinical Cardiology, Microsurgery and Imaging Platform, Baker Heart and Diabetes Institute, Prahran, VIC, Australia.
⁸ Baker Department of Cardiometabolic Health, University of Melbourne, Parkville, VIC, Australia.

Abstract

Diabetes is associated with a significantly elevated risk of heart failure. However, despite extensive efforts to characterize the phenotype of the diabetic heart, the molecular and cellular protagonists that underpin cardiac pathological remodeling in diabetes remain unclear, with a notable paucity of data regarding the impact of diabetes on non-myocytes within the heart. Here we aimed to define key differences in cardiac non-myocytes between spontaneously type-2 diabetic (db/db) and healthy control (db/h) mouse hearts. Single-cell transcriptomic analysis revealed a concerted diabetes-induced cellular response contributing to cardiac remodeling. These included cell-specific activation of gene programs relating to fibroblast hyperplasia and cell migration, and dysregulation of pathways involving vascular homeostasis and protein folding. This work offers a new perspective for understanding the cellular mediators of diabetes-induced cardiac pathology, and pathways that may be targeted to address the cardiac complications associated with diabetes.

Keywords: Cell biology; Molecular biology; Omics; Transcriptomics.