Human sympathetic ganglion organoids support investigation of sympathetic innervation of target organs

08 January 2026

While the human central nervous system (CNS) has often been modelled with organoids, progress in constructing the peripheral nervous system (PNS) has been relatively limited. Yet, the PNS plays a crucial role in communication between different areas of the body and the brain and dysfunction in PNS has been tied to a number of chronic diseases.

The PNS has two main subsystems, one of which is the autonomic nervous system, which automatically controls physiological functions in either the sympathetic or parasympathetic state. The sympathetic nervous system is composed of sympathetic ganglia – interconnected structures made of neuronal cell bodies, glial cells and synapses. Distinct anatomically, but functionally connected, are nerves, composed of axons that carry signals to or from those ganglia. At the cellular level, the cell bodies of postganglionic sympathetic neurons reside inside the ganglion. From there, these neurons extend long axons to target organs, where they release neurotransmitters such as norepinephrine to modulate organ function. Dysfunction of sympathetic ganglia has been implicated is several human disorders, including heart failure, type 2 diabetes, peripheral neuropathies, autoimmune conditions, infections, trauma, and tumor.

In comparison to other species, human autonomic ganglia have unique neurochemical profiles, immune‑modulatory signaling patterns, ion channel expressions, and transcriptional signatures that ultimately affect organ modulation, necessitating that they are studied in human-based systems. To make it feasible to investigate how the human sympathetic ganglia affects organ function, Liu et al. have undertaken the challenging task of engineering sympathetic ganglion organoids.

By developing a method for differentiation of human pluripotent stem cell lines (hESC and hiPSC), the researchers have generated human sympathetic ganglion organoids (hSGOs) containing  both sympathetic neurons and glial cells of the sympathetic ganglia.

To recapitulate functional sympathetic innervation of the human heart, the team has subsequently fused hSGOs with human heart-forming organoids (hHFOs). Once hSGO and hHFO fused, the sympathetic neurons extended long axons into the cardiac tissue, forming functional synapse-like contacts. In this manner they have obtained human sympathetically innervated heart-forming organoids (hSHOs) that can serve as a human-relevant preclinical research platform for modelling inter-tissue cross-talk between sympathetic ganglia and target organs and assessing its effects on sympathetic and cardiac development.

The functional relevance of connections between hSGO and hHFO was tested by applying nicotine to the hSHO, which activates nicotinic acetylcholine receptors on sympathetic neurons and triggers sympathetic nervous system activity. Upon nicotine treatment, the beating rates of hHFO domains in hSHOs increased significantly, whereas nicotine treatment of hHFOs alone did not significantly alter beating rates. Through MEA recording, the authors found that the spontaneous firing rates of hSGO neurons in hSHOs were significantly higher than those in hSGOs cultured alone, suggesting that connection with cardiac tissues enhances development of the human sympathetic lineage. This effect appears to be reciprocal, since the cardiac side in hSHOs showed significantly higher beating rates compared with hHFOs cultured alone.

Of crucial important for drug development, human sympathetically innervated heart-forming organoids also enable to dissect the mechanisms by which PNS dysfunction can contribute to human diseases, identify new therapeutic targets and test the efficacy of drug candidates. This potential was evaluated by treating the hSHOs with standard and high glucose media to simulate diabetic conditions. After 1 month of high glucose exposure, the hSHOs showed significant reduction in neuronal axons and in sympathetic neurons, as well as increase in apoptotic cells, suggesting degeneration of sympathetic innervation. This glucose‑induced degeneration of sympathetic axons is mechanistically aligned with the early stages of diabetic autonomic neuropathy and reflects processes that also contribute to complications such as chronic skin wounds.

Given that in vivo the sympathetic ganglia are not directly attached to the heart, future directions will include exploring how long‑range neuro‑cardiac signaling can be established between these tissues by integrating organoids with customized microfluidic devices.

What Puts It on the Frontier

• Development of human sympathetic ganglion organoids that contain both sympathetic neurons and glial cells

• Modelling of interactions between sympathetic ganglia and their target organ using organoids

• Engineering of human sympathetically innervated heart-forming organoids through fusion of sympathetic ganglion organoids and heart organoids

Impact Snapshot

• Understanding of reciprocal influences between the development of human sympathetic and target organ lineages

• Elucidation of mechanisms by which PNS dysfunction can contribute to human diseases

• Development of new drugs for disorders that involve PNS dysfunction

Reference

Liu Y et al. Human PSC-derived organoids model sympathetic ganglion development and its functional crosstalk with the heart. Cell Stem Cells, Volume 33, Issue 1, p29-43.e7, January 08, 2026. https://doi.org/10.1016/j.stem.2025.11.003