Human PSC-derived sinoatrial node-cardiac plexus assembloids model innervation-associated maturation of pacemaker...

Area of Science:

• Cardiology
• Neuroscience
• Stem Cell Biology

Background:

• Heart rhythm and contraction originate from the sinoatrial node (SAN) and are influenced by intrinsic cardiac neural inputs.
• Existing human in vitro systems lack the ability to fully replicate complex neural-SAN interactions.
• Understanding these interactions is vital for studying cardiac electrophysiology and diseases.

Purpose of the Study:

• To develop a human in vitro model system that recapitulates neural-SAN interactions.
• To investigate the role of neural control in sinoatrial node automaticity and pacemaker-to-atrial conduction.
• To identify molecular mechanisms underlying neuro-cardiac communication in the heart.

Main Methods:

• Development of SAN-plexus assembloids by integrating human pluripotent stem cell-derived SAN organoids (SANOs) with cardiac ganglionated plexus organoids (CGPOs) and atrial-like cardiac organoids.
• Characterization of the assembloids' molecular, structural, and electrophysiological properties.
• Integration of spatial transcriptomics of human SAN tissue with functional analyses of the assembloids.

Main Results:

• The SAN-plexus assembloid system successfully models human pacemaker activity and pacemaker-to-atrial conduction.
• The platform allows for functional interrogation of neural control over SAN automaticity, including disease-associated conduction dysfunction.
• A novel neuron-to-pacemaker signaling program was identified, involving CGPO-derived prosaposin and the SAN-enriched receptor GPR37, which promotes pacemaker maturation.

Conclusions:

• SAN-plexus assembloids provide a robust human in vitro platform for studying intrinsic neuro-cardiac interactions.
• This model is valuable for investigating pacemaker development and cardiac diseases related to neuro-cardiac dysfunction.
• The identified prosaposin-GPR37 signaling pathway offers new insights into pacemaker maturation and neural modulation of heart rhythm.