In vivo bioreactor matures iPSC-CMs for MLP disease modeling.

Area of Science:

• Cardiovascular Biology
• Stem Cell Biology
• Genetic Disease Modeling

Background:

• Muscle LIM protein (MLP) is crucial for cardiomyocyte (CM) structure.
• MLP deficiency leads to dilated cardiomyopathy (DCM) in mice and humans.
• Modeling DCM using induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) is challenging due to immaturity.

Purpose of the Study:

• To generate MLP knockout (MLP-KO) iPSCs and differentiate them into CMs.
• To compare in vitro and in vivo maturation environments for modeling DCM.
• To investigate the role of the in vivo maturation environment in iPSC-CM development.

Main Methods:

• Generated MLP-KO mouse iPSCs and differentiated them into cardiomyocytes.
• Utilized in vitro maturation techniques.
• Employed in vivo transplantation into immunocompromised rat hearts for maturation.

Main Results:

• In vitro-matured MLP-KO iPSC-CMs did not exhibit DCM phenotypes.
• In vivo-matured MLP-KO iPSC-CMs showed disrupted sarcomeric architecture and ANP upregulation, mirroring DCM.
• The in vivo environment is essential for recapitulating DCM hallmarks in iPSC-CMs.

Conclusions:

• In vivo maturation is critical for iPSC-CMs to accurately model genetic cardiac diseases like DCM.
• This study highlights the limitations of in vitro maturation for complex disease modeling.
• Findings provide insights for developing novel therapeutic strategies for DCM.