A hypoimmunogenic cardiac patch for optimised grafting and immunosuppression-related complications in chronic myocardial ischaemia

Heart failure is a growing global pandemic and cardiac repair using human pluripotent stem cell (hPSC)-derived cardiomyocytes is a scalable technology capable of remuscularising ischaemic myocardium and restoring contractile function.

A major remaining hurdle impeding clinical translation is the rejection of allogeneic cells by the host’s immune system, driven by T-cell activation.

Calcineurin inhibitors (CNI) such as tacrolimus are paramount immunosuppressants blunting T-cell responses in heart transplant recipients but also constitute a major cause for severe nephrotoxicity.

Here we propose a hypoimmune cardiac patch using a three-pronged approach to maximise T-cell suppression while bypassing complications of systemically administered CNIs.

We hypothesise that tacrolimus-eluting microparticles and cardiomyocytes derived from a β2-microglobulin-KO (B2M-) line will abrogate a cytotoxic T-cell response while optimising cardiac engraftment.

As an integral component, the epicardium, a powerful promoter of cardiac structure and function, is capable of immune modulation via recruitment of T-regulatory cells limiting adverse cardiac remodelling.

The proposed patch will undergo rigorous characterisation in vitro before investigating the immune response in a humanised mouse model. Finally, the optimised patch will be assessed functionally in a rat model of chronic myocardial infarction (MI). These studies will prove seminal for reparative cardiology and clinical application.