PDGF-AB Reduces Myofibroblast Differentiation Without Increasing Proliferation After Myocardial Infarction

Robert D Hume; Tejas Deshmukh; Tram Doan; Woo Jun Shim; Shaan Kanagalingam; Vikram Tallapragada; Fairooj Rashid; Maria Marcuello; Daniel Blessing; Dinesh Selvakumar; Kalyan Raguram; Faraz Pathan; Dinny Graham; Samir Ounzain; Eddy Kizana; Richard P Harvey; Nathan J Palpant; James J H Chong

doi:10.1016/j.jacbts.2022.11.006

PDGF-AB Reduces Myofibroblast Differentiation Without Increasing Proliferation After Myocardial Infarction

JACC Basic Transl Sci. 2023 Mar 1;8(6):658-674. doi: 10.1016/j.jacbts.2022.11.006. eCollection 2023 Jun.

Authors

Robert D Hume^{1

2}, Tejas Deshmukh^{1

2

3}, Tram Doan⁴, Woo Jun Shim⁵, Shaan Kanagalingam¹, Vikram Tallapragada⁶, Fairooj Rashid^{1

2}, Maria Marcuello⁷, Daniel Blessing⁷, Dinesh Selvakumar^{1

2

3}, Kalyan Raguram^{1

2}, Faraz Pathan^{8

9}, Dinny Graham^{4

10

11}, Samir Ounzain⁷, Eddy Kizana^{1

2

3}, Richard P Harvey^{6

12

13

14}, Nathan J Palpant⁵, James J H Chong^{1

2

3}

Affiliations

¹ Centre for Heart Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.
² Sydney Medical School, University of Sydney, New South Wales, Australia.
³ Department of Cardiology, Westmead Hospital, Westmead, New South Wales, Australia.
⁴ Centre for Cancer Research, Westmead Institute for Medical Research, Westmead, New South Wales, Australia.
⁵ Institute for Molecular Bioscience, University of Queensland, St Lucia, Queensland, Australia.
⁶ Victor Chang Cardiac Research Institute, Darlinghurst, New South Wales, Australia.
⁷ HAYA Therapeutics, Lausanne, Switzerland.
⁸ Nepean Clinical School of Medicine, Charles Perkin Centre Nepean, University of Sydney, Kingswood, New South Wales, Australia.
⁹ Department of Cardiology, Nepean Hospital, Kingswood, New South Wales, Australia.
¹⁰ Westmead Breast Cancer Institute, Westmead, New South Wales, Australia.
¹¹ Westmead Clinical School, University of Sydney, New South Wales, Australia.
¹² St Vincent's Clinical School, University of New South Wales-Sydney, Kensington, New South Wales, Australia.
¹³ Melbourne Brain Centre, University of Melbourne, Victoria, Australia.
¹⁴ School of Biotechnology and Biomolecular Science, University of New South Wales-Sydney, Kensington, New South Wales, Australia.

Abstract

After myocardial infarction (MI), fibroblasts progress from proliferative to myofibroblast states, resulting in fibrosis. Platelet-derived growth factors (PDGFs) are reported to induce fibroblast proliferation, myofibroblast differentiation, and fibrosis. However, we have previously shown that PDGFs improve heart function post-MI without increasing fibrosis. We treated human cardiac fibroblasts with PDGF isoforms then performed RNA sequencing to show that PDGFs reduced cardiac fibroblasts myofibroblast differentiation and downregulated cell cycle pathways. Using mouse/pig MI models, we reveal that PDGF-AB infusion increases cell-cell interactions, reduces myofibroblast differentiation, does not affect proliferation, and accelerates scar formation. RNA sequencing of pig hearts after MI showed that PDGF-AB reduces inflammatory cytokines and alters both transcript variants and long noncoding RNA expression in cell cycle pathways. We propose that PDGF-AB could be used therapeutically to manipulate post-MI scar maturation with subsequent beneficial effects on cardiac function.

Keywords: myocardial infarction; platelet-derived growth factor.