Cellular therapy for chronic heart failure: a key role for epicardial fibronectin


Type
Thesis
Change log
Authors
Ong, Lay Ping 
Abstract

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.

Description
Date
2021-02-20
Advisors
Sinha, Sanjay
Keywords
cardiac regeneration, epicardium, human embryonic stem cells-derived cardiomyocytes, heart failure
Qualification
Doctor of Philosophy (PhD)
Awarding Institution
University of Cambridge
Sponsorship
Wellcome Trust (203568/Z/16/Z)
Addenbrooke's Charitable Trust (ACT) (900247)
Wellcome Trust, Addenbrooke's Charitable Trust