Human induced pluripotent stem cell-derived cardiac myocytes and sympathetic neurons in disease modelling. (19th June 2023)

• Record Type: Journal Article
• Authors: Li, Ni; Edel, Michael; Liu, Kun; Denning, Chris; Betts, Jacob; Neely, Oliver C.; Li, Dan; Paterson, David J.
• Is Part Of: Philosophical transactions. Volume 378:Number 1879(2023)
• Publication Date: 2023-06-19
• Subjects: hiPSC -- cardiac myocytes -- sympathetic neurons -- neurocardiac co-culture; Biology -- Periodicals; Science -- Periodicals; 570
• DOI: 10.1098/rstb.2022.0173
• Languages: English
• ISSNs: 0962-8436

Abstract

Abstract : Human induced pluripotent stem cells (hiPSC) offer an unprecedented opportunity to generate model systems that facilitate a mechanistic understanding of human disease. Current differentiation protocols are capable of generating cardiac myocytes (hiPSC-CM) and sympathetic neurons (hiPSC-SN). However, the ability of hiPSC-derived neurocardiac co-culture systems to replicate the human phenotype in disease modelling is still in its infancy. Here, we adapted current methods for efficient and replicable induction of hiPSC-CM and hiPSC-SN. Expression of cell-type-specific proteins were confirmed by flow cytometry and immunofluorescence staining. The utility of healthy hiPSC-CM was tested with pressor agents to develop a model of cardiac hypertrophy. Treatment with angiotensin II (AngII) resulted in: (i) cell and nuclear enlargement, (ii) enhanced fetal gene expression, and (iii) FRET-activated cAMP responses to adrenergic stimulation. AngII or KCl increased intracellular calcium transients in hiPSC-SN. Immunostaining in neurocardiac co-cultures demonstrated anatomical innervation to myocytes, where myocyte cytosolic cAMP responses were enhanced by forskolin compared with monocultures. In conclusion, human iPSC-derived cardiac myocytes and sympathetic neurons replicated many features of the anatomy and (patho)physiology of these cells, where co-culture preparations behaved in a manner that mimicked key physiological responses seen in other mammalian systems. This article is part of the theme issue 'The heartbeat: its molecular basis and physiological mechanisms'.