Mutations in LMNA gene, encoding a structural protein of the cell nucleus, cause dilated cardiomyopathy (DCM). DCM is characterised by arrhytmia, heart failure and sudden cardiac death (SCD). While the genetic basis of the disease is well characterised, a lot remains unknown about the driving mechanisms. There is currently no cure, and treatments are based on SCD symptom management/prevention, and ultimately heart transplantation.
Impact
Our work focuses on the development of in vitro stem cell-derived three-dimensional (3D) miniaturized heart tissues, called cardiac microtissues, resembling the complex structure of the heart, that can recapitulate the DCM defects observed in patient hearts. This advanced physiological human-relevant disease model provides with unprecedented possibilities to understand disease biology and assess the therapeutic impact of novel interventions.
reNEW research
We simultaneously generated a library of genetically matched stem cells carrying multiple mutations in LMNA gene, differentiated them into different cardiac cells and then combined in spheroids to create 3D cardiac microtissues. We are currently studying the contribution of each cell population to the disease pathogenesis and their crosstalk in 3D environment. Finally, we will test gene editing correction tools as proof-of-concept for gene therapy efficacy as novel therapeutic strategy.
Image description
3D cardiac microtissue. The three-dimensional sphere is composed of 5000 stem-derived cardiac cells in a defined ratio: 70% heart muscle cells (red), 15% fibroblast stromal cells (green) and blood vessel cells (grey).
Credits
Viviana Meraviglia (senior researcher), Bellin/Mummery lab, Anatomy & Embriology, reNEW Leiden, the Netherlands.
