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bioRxiv · 10.1101/2025.10.21.683816

Astrocytic PIEZO activation by heartbeat sound promotes extracellular matrix and maturation in human brain organoids

Ferreira-Oliveira, A.·Rambow, F.·Rambow-Makhzami, S.·Nikolaev, Y. A.·Novak, A.·Shevchuk, O.·Voss, H. L.·Engel, D. R.·Schult, P. A.·Pillath-Eilers, M.·Kaltwasser, B.·Brockmeier, U.·Kleinschnitz, C.·Hermann, D. M.·Dzyubenko, E.
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Abstract

Heartbeat sound is one of the first rhythmic stimuli encountered by the developing human brain, yet its biological role has remained unexplored. Here we show that heartbeat sound promotes structural and functional maturation of human cortical organoids with a physiological astrocyte-to-neuron ratio. Continuous stimulation with heartbeat expanded the extracellular space (ECS), visualized by super-resolution 3D STED and 2-photon shadow imaging, and increased extracellular matrix (ECM) synthesis, detected by LC-MS/MS proteomics. Heartbeat sound promoted neuronal and astrocytic differentiation, synaptogenesis, and organoid maturation, as shown by single-cell RNA sequencing, synaptic marker immunohistochemistry, and high-density multielectrode electrophysiology. Transcriptomic analyses demonstrated astrocyte-specific expression of mechanosensitive PIEZO channels. Using Ca2+ imaging, we confirmed that low-frequency sound stimulation, including heartbeat, activates PIEZO-mediated Ca2+ responses, which in turn upregulate astrocytic ECM synthesis. Experiments with biomimetic hydrogels demonstrated that physiological matrix stiffness attenuates PIEZO activation, suggesting a mechanoprotective mechanism. Our findings demonstrate a fundamental mechanism for inducing ECM synthesis and neural differentiation through astrocytic PIEZO activation by heartbeat sound, suggesting that interoception of the internal acoustic environment is an underappreciated driver of human brain development. HighlightsO_LIHeartbeat sound activates PIEZO ion channels C_LIO_LIAstrocytic PIEZO activation promotes extracellular matrix synthesis C_LIO_LIHeartbeat sound stimulates neural differentiation and brain organoid maturation C_LI Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=103 SRC="FIGDIR/small/683816v2_ufig1.gif" ALT="Figure 1"> View larger version (38K): org.highwire.dtl.DTLVardef@1ba3159org.highwire.dtl.DTLVardef@fdd741org.highwire.dtl.DTLVardef@13ef417org.highwire.dtl.DTLVardef@b3064_HPS_FORMAT_FIGEXP M_FIG C_FIG

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Ferreira-Oliveira, A., Rambow, F., Rambow-Makhzami, S., Nikolaev, Y. A., Novak, A., Shevchuk, O., Voss, H. L., Engel, D. R., Schult, P. A., Pillath-Eilers, M., Kaltwasser, B., Brockmeier, U., Kleinschnitz, C., Hermann, D. M., Dzyubenko, E.. 2025-10-22. Astrocytic PIEZO activation by heartbeat sound promotes extracellular matrix and maturation in human brain organoids. https://doi.org/10.1101/2025.10.21.683816

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