With Miniature Organs: Human Pain Circuit Reconstructed in Lab for First Time

Scientists have managed to recreate in the laboratory, using miniature organs made from stem cells, the pathway that pain and touch take from the body to the brain. This model helps to better understand how we feel pain and why some people feel no pain or too much pain. The discovery could speed up the development of new treatments for sensory disorders.

Our bodies are full of sensors that detect things like pain, heat, pressure and movement. This information leaves the skin and other organs and goes up to the brain through a “pathway” formed by nerve cells. This path is called the ascending somatosensory pathway.

These signals start in special nerve cells located near the spinal cord (in regions called dorsal root ganglia and trigeminal ganglia). These cells pick up stimuli from the body and send them to the spinal cord and a part of the brain called the hindbrain.

From there, the information travels to the thalamus, a relay center in the brain, and finally reaches the cerebral cortex, where it becomes conscious perception (such as feeling pain or touch).

Genetic or environmental problems in these pathways can cause neurological disorders, such as chronic pain or sensory changes common in autism. Despite their importance, we still know little about how these pathways form in human development, and why they sometimes fail.

Diagram illustrating the route of the ascending transmission pathway

A major obstacle to studying this is that laboratory models, such as mice, are not very similar to humans in this regard. Furthermore, we have not yet been able to observe all the components of these pathways working at the same time in any animal.

But there is good news. As science advances, researchers are now using organoids, structures made from stem cells that mimic miniature body parts, to assemble these pathways in the laboratory, without needing a complete body.

When multiple types of organoids are connected together to simulate more complex circuits, they are called assembloids.

Diagram courtesy of Dr. Sergiu Paşca, Stanford University

A group of scientists had already managed to assemble an assembloid that simulates signals from the brain to the muscle (descending pathway). Now, they have gone further and created an even more complex structure: a four-part assembloid, called hASA (human ascending somatosensory assembloid), that simulates the pain and touch pathway to the brain.

They did this by connecting:

• Sensory organoids (hSeO), which sense stimuli;

• Spinal cord organoids (hdSpO), which receive sensory signals;

• Thalamus organoids (hDiO), which relay signals;

• Cerebral cortex organoids (hCO), where information is perceived.

Generation and functional characterization of hASA.

When these organoids were stimulated with pain-like chemicals, the signals actually traveled the full path, as they do in the human body. What’s more, the scientists were able to observe this activity with special cameras that capture calcium (an indicator of electrical activity between neurons).

They also tested the effect of genetic alterations linked to pain. When they simulated a mutation that causes congenital insensitivity to pain, the signals did not spread correctly between the organoids. A mutation that causes extreme pain, on the other hand, caused exaggerated activity in the sensory pathways, as if the nerves were overactive.

Abnormal calcium activity in assembloids with a pathogenic mutation in the SCN9A T1464I gene that causes extreme pain.

This type of experiment shows that it is possible to simulate and study human diseases accurately in the laboratory, without relying on animals or very limited tests. This technology could help us understand how we feel pain and, in the future, accelerate the development of new treatments for sensory disorders.

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Human assembloid model of the ascending neural sensory pathway 

Ji-il Kim, Kent Imaizumi, Ovidiu Jurjuț, Kevin W. Kelley, Dong Wang, Mayuri Vijay Thete, Zuzana Hudacova, Neal D. Amin, Rebecca J. Levy, Grégory Scherrer and Sergiu P. Pașca

Nature. 9 April 2025DOI: 10.1038/s41586-025-08808-3

Abstract

Somatosensory pathways convey crucial information about pain, touch, itch and body part movement from peripheral organs to the central nervous system1,2. Despite substantial needs to understand how these pathways assemble and to develop pain therapeutics, clinical translation remains challenging. This is probably related to species-specific features and the lack of in vitro models of the polysynaptic pathway. Here we established a human ascending somatosensory assembloid (hASA), a four-part assembloid generated from human pluripotent stem cells that integrates somatosensory, spinal, thalamic and cortical organoids to model the spinothalamic pathway. Transcriptomic profiling confirmed the presence of key cell types of this circuit. Rabies tracing and calcium imaging showed that sensory neurons connect to dorsal spinal cord neurons, which further connect to thalamic neurons. Following noxious chemical stimulation, calcium imaging of hASA demonstrated a coordinated response. In addition, extracellular recordings and imaging revealed synchronized activity across the assembloid. Notably, loss of the sodium channel NaV1.7, which causes pain insensitivity, disrupted synchrony across hASA. By contrast, a gain-of-function SCN9A variant associated with extreme pain disorder induced hypersynchrony. These experiments demonstrated the ability to functionally assemble the essential components of the human sensory pathway, which could accelerate our understanding of sensory circuits and facilitate therapeutic development.