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oai:www.repository.cam.ac.uk:1810/3334902023-12-22T13:17:56Zcom_1810_219479com_1810_34581col_1810_219488

Cellular therapy for chronic heart failure: a key role for epicardial fibronectin 10.17863/CAM.80910 Ong, Lay Ping Sinha, Sanjay Myocardial infarction (MI) results in permanent cardiomyocyte loss, frequently leading to heart failure, with a 50% 5-year mortality. At subacute time points following MI, animal studies have shown ‘remuscularization’ of the damaged heart with human embryonic stem cell (hESC)-derived cardiomyocytes. Recently, outcomes were improved by co-delivering hESC-derived epicardium. Clinically, the main challenge remains chronic heart failure. However, hESC-cardiomyocytes alone, in the chronically infarcted heart, have shown no benefit. Here, we show that both species-matched cellular therapy and combination therapy with hESC-epicardium could attenuate cardiac dysfunction in the chronically failing heart, underpinned by sizeable cardiac grafts, cardiomyocyte proliferation and maturation, together with a host-derived vascular supply. Notably, hESC-epicardium’s augmentation of cardiomyocyte maturation within 3D-engineered heart tissues in vitro appeared to be underpinned by epicardial-secreted fibronectin. Thus, hESC-combination cell therapy holds clinical promise for ‘remuscularising’ chronically infarcted hearts. University of Cambridge 2021-02-20 Thesis Doctoral Doctor of Philosophy (PhD) eng Wellcome Trust, Addenbrooke's Charitable Trust https://www.repository.cam.ac.uk/handle/1810/333490 https://apollo8-f-pro.lib.cam.ac.uk/bitstreams/423f08d8-3c73-4953-a1ab-16ecb5ebc468/download 9b826801001c260867a1e2c67a38e9c9 https://www.rioxx.net/licenses/all-rights-reserved/ cardiac regeneration epicardium human embryonic stem cells-derived cardiomyocytes heart failure