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

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

Research output: Contribution to journal › Article › Research › peer-review

11 Citations (Scopus)

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.

Original language	English
Article number	107759
Number of pages	21
Journal	iScience
Volume	26
Issue number	10
DOIs	https://doi.org/10.1016/j.isci.2023.107759
Publication status	Published - 20 Oct 2023

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

Cell biology
Molecular biology
Omics
Transcriptomics

Access to Document

10.1016/j.isci.2023.107759Licence: CC BY-NC-ND

Cite this

Cohen, C. D., De Blasio, M. J., Farrugia, G. E., Dona, M. S. I., Hsu, I., Prakoso, D., Kiriazis, H., Krstevski, C., Nash, D. M., Li, M., Gaynor, T. L., Deo, M., Drummond, G. R., Ritchie, R. H., & Pinto, A. R. (2023). Mapping the cellular and molecular landscape of cardiac non-myocytes in murine diabetic cardiomyopathy. iScience, 26(10), Article 107759. https://doi.org/10.1016/j.isci.2023.107759

@article{791e466665564504bd2d64aca68d60d3,

title = "Mapping the cellular and molecular landscape of cardiac non-myocytes in murine diabetic cardiomyopathy",

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",

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

note = "Funding Information: ARP and RHR received supported from the National Health and Medical Research Council (NHMRC) of Australia, including Ideas Grant GNT1188503 to ARP, Project Grant GNT 1158013 to RHR and MJD, and Senior Research Fellowship GNT1059960 to RHR. CDC, CK and TLG are supported by the La Trobe University Postgraduate Research Scholarship (LTUPRS), Research Training Program Fees Off-set (RTP-Fo) Scholarship. CDC is also supported by a Baker Institute “Bright Sparks” Scholarship and Harold Mitchell Foundation Scholarship. TLG is also supported by a Defence Science Institute RhD Grant. The work was also supported in part by an infrastructure grant from the Victorian Government of Australia. CDC, MJD, RHR, and ARP conceived the study. RHR, MJD and ARP obtained funding for, and oversaw, the study. CDC and ARP drafted the article. CDC, MJD, MD, and DP performed animal monitoring. CDC and MJD assisted with in vivo echocardiography. Echocardiographic imaging was acquired by HK. CDC analyzed echocardiography data. MJD and HK reviewed echocardiography analyses. CDC, MJD, GEF, DP, CK, DMN, ML, TLG, MD, and ARP performed endpoint cull experiments. CDC, IH, MSID, and ARP analyzed in silico transcriptomic data. CDC, MJD, GRD, RHR, and ARP regularly reviewed and interpreted the results obtained as they were acquired. All authors read, edited and agreed to submission of the final version of the article. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Funding Information: ARP and RHR received supported from the National Health and Medical Research Council (NHMRC) of Australia, including Ideas Grant GNT1188503 to ARP, Project Grant GNT 1158013 to RHR and MJD, and Senior Research Fellowship GNT1059960 to RHR. CDC, CK and TLG are supported by the La Trobe University Postgraduate Research Scholarship (LTUPRS), Research Training Program Fees Off-set (RTP-Fo) Scholarship . CDC is also supported by a Baker Institute “Bright Sparks” Scholarship and Harold Mitchell Foundation Scholarship . TLG is also supported by a Defence Science Institute RhD Grant. The work was also supported in part by an infrastructure grant from the Victorian Government of Australia . Publisher Copyright: {\textcopyright} 2023 The Authors",

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doi = "10.1016/j.isci.2023.107759",

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T1 - Mapping the cellular and molecular landscape of cardiac non-myocytes in murine diabetic cardiomyopathy

AU - Cohen, Charles D.

AU - De Blasio, Miles J.

AU - Farrugia, Gabriella E.

AU - Dona, Malathi S.I.

AU - Hsu, Ian

AU - Prakoso, Darnel

AU - Kiriazis, Helen

AU - Krstevski, Crisdion

AU - Nash, David M.

AU - Li, Mandy

AU - Gaynor, Taylah L.

AU - Deo, Minh

AU - Drummond, Grant R.

AU - Ritchie, Rebecca H.

AU - Pinto, Alexander R.

N1 - Funding Information: ARP and RHR received supported from the National Health and Medical Research Council (NHMRC) of Australia, including Ideas Grant GNT1188503 to ARP, Project Grant GNT 1158013 to RHR and MJD, and Senior Research Fellowship GNT1059960 to RHR. CDC, CK and TLG are supported by the La Trobe University Postgraduate Research Scholarship (LTUPRS), Research Training Program Fees Off-set (RTP-Fo) Scholarship. CDC is also supported by a Baker Institute “Bright Sparks” Scholarship and Harold Mitchell Foundation Scholarship. TLG is also supported by a Defence Science Institute RhD Grant. The work was also supported in part by an infrastructure grant from the Victorian Government of Australia. CDC, MJD, RHR, and ARP conceived the study. RHR, MJD and ARP obtained funding for, and oversaw, the study. CDC and ARP drafted the article. CDC, MJD, MD, and DP performed animal monitoring. CDC and MJD assisted with in vivo echocardiography. Echocardiographic imaging was acquired by HK. CDC analyzed echocardiography data. MJD and HK reviewed echocardiography analyses. CDC, MJD, GEF, DP, CK, DMN, ML, TLG, MD, and ARP performed endpoint cull experiments. CDC, IH, MSID, and ARP analyzed in silico transcriptomic data. CDC, MJD, GRD, RHR, and ARP regularly reviewed and interpreted the results obtained as they were acquired. All authors read, edited and agreed to submission of the final version of the article. The authors declare no competing interests. We support inclusive, diverse, and equitable conduct of research. Funding Information: ARP and RHR received supported from the National Health and Medical Research Council (NHMRC) of Australia, including Ideas Grant GNT1188503 to ARP, Project Grant GNT 1158013 to RHR and MJD, and Senior Research Fellowship GNT1059960 to RHR. CDC, CK and TLG are supported by the La Trobe University Postgraduate Research Scholarship (LTUPRS), Research Training Program Fees Off-set (RTP-Fo) Scholarship . CDC is also supported by a Baker Institute “Bright Sparks” Scholarship and Harold Mitchell Foundation Scholarship . TLG is also supported by a Defence Science Institute RhD Grant. The work was also supported in part by an infrastructure grant from the Victorian Government of Australia . Publisher Copyright: © 2023 The Authors

PY - 2023/10/20

Y1 - 2023/10/20

N2 - 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.

AB - 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.

KW - Cell biology

KW - Molecular biology

KW - Omics

KW - Transcriptomics

UR - https://www.scopus.com/pages/publications/85171185328

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DO - 10.1016/j.isci.2023.107759

M3 - Article

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SN - 2589-0042

VL - 26

JO - iScience

JF - iScience

IS - 10

M1 - 107759

ER -

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

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Therapeutic Targeting to Protect the Diabetic Heart

Research Fellowship: Protecting how the heart functions in health and disease

Cite this

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

Abstract

UN SDGs

Keywords

Access to Document

Other files and links

Projects

Therapeutic Targeting to Protect the Diabetic Heart

Research Fellowship: Protecting how the heart functions in health and disease

Cite this