LMNA Haploinsufficiency in Human iPSC-Derived Cardiac Organoids Reveals Early Fibrotic Signaling as a Therapeutically Targetable Process
Year: 2026
Type: preprint
Abstract: ABSTRACT LMNA mutations are a major cause of dilated cardiomyopathy (DCM), with haploinsufficiency representing a common pathogenic mechanism. Yet the earliest disease-initiating events remain poorly defined. Here, we identify a novel intronic splice-site variant, c.937-1G>A, that disrupts pre-mRNA splicing, induces nonsense-mediated mRNA decay, and results in LMNA haploinsufficiency. We differentiated induced pluripotent stem cells (iPSCs) generated from a patient’s peripheral blood mononuclear cells (PBMCs) carrying this mutation into self-patterning human cardiac organoids to define the early consequences of reduced LMNA dosage in a multicellular human context. Single-nucleus transcriptomics revealed broad multicellular remodeling beyond the previously implicated fibroblast and cardiomyocyte populations. Functionally, LMNA -mutant organoids exhibited altered calcium handling and impaired contractility. These changes were accompanied by increased reactive oxygen species (ROS) and early pro-fibrotic signaling characterized by increased periostin (POSTN) secretion, CTGF expression, and increased p38 MAPK phosphorylation. Treatment with the antifibrotic drug nintedanib attenuated this response, partially rescued rhythmic beating, reduced POSTN secretion and CTGF expression, and broadly suppressed fibrosis-associated transcriptional programs. Together, these findings show that LMNA haploinsufficiency initiates multicellular cardiac remodeling and early targetable profibrotic signaling during human cardiac development, providing mechanistic insight into the earliest stages of LMNA -associated cardiomyopathy and establishing a human cardiac organoid platform for therapeutic discovery.
Institutions: University of Miami, Sylvester Comprehensive Cancer Center
Language: English
Subfield: Cardiology and Cardiovascular Medicine
Field: Medicine
Domain: Health Sciences
Open Access status: green
OpenAlex ID: W7142986987