A study of gene expression, structure, and contractility of iPSC-Derived Cardiac Myocytes from a family with heart disease due to LMNA mutation

Genetic mutations to the Lamin A/C gene (LMNA) can cause heart disease,
but the mechanisms making cardiac tissues uniquely vulnerable to the
mutations remain largely unknown. Further, patients with LMNA mutations
have highly variable presentation of heart disease progression and type.
In vitro patient-specific experiments could provide a powerful platform
for studying this phenomenon, but the use of induced pluripotent stem
cell-derived cardiomyocytes (iPSC-CM) introduces heterogeneity in maturity
and function thus complicating the interpretation of the results of any
single experiment. We hypothesized that integrating single cell RNA
sequencing (scRNA-seq) with analysis of the tissue architecture and
contractile function would elucidate some of the probable mechanisms. To
test this, we investigated five iPSC-CM lines, three controls and two
patients with a (c.357-2A>G) mutation. The patient iPSC-CM tissues
had significantly weaker stress generation potential than control iPSC-CM
tissues demonstrating the viability of our in vitro approach. Through
scRNA-seq, differentially expressed genes between control and patient
lines were identified. Some of these genes, linked to quantitative
structural and functional changes, were cardiac specific, explaining the
targeted nature of the disease progression seen in patients. The results
of this work demonstrate the utility of combining in vitro tools in
exploring heart disease mechanics.