The Surprising Discovery of Peripheral Neural Stem Cells
Neural stem cells aren’t just in the brain and spinal cord. A new study in Nature Cell Biology has found that true multipotent neural stem cells (NSCs) exist in tissues well outside the central nervous system (CNS) – including the lung, tail, and dorsal root ganglia.(1)
This is a major shift. For decades, researchers assumed that NSCs were a CNS-exclusive population, while peripheral neural crest stem cells (NCSCs) handled the rest. But Dong Han and colleagues have now shown that peripheral NSCs (pNSCs) can be isolated from multiple tissues, and they function as their NSC counterparts: they self-renew, express canonical NSC markers, and differentiate into neurons and glia.
The team isolated pNSCs from embryonic and various adult mouse tissues using NSC-specific nestin-GFP reporter mice. They cultured the GFP-positive cells in NSC media and found that these cells formed clusters indistinguishable from brain-derived NSCs in morphology and marker expression. Crucially, these cells didn’t require chemical reprogramming – they were already NSCs in situ.
To confirm the origin and identity of the pNSCs, they used lineage tracing and transcriptomics. The pNSCs expressed Sox1 and other NSC-associated genes, and their transcriptomic and epigenetic profiles aligned with neuroepithelial-derived NSCs rather than NCSCs. That distinction matters. NCSCs have limited self-renewal and a distinct differentiation capacity, whereas these pNSCs showed sustained multipotency and could integrate into developing CNS tissue.
“If these cells exist in humans and can be propagated indefinitely as they can in mice, they could have enormous therapeutic potential,” said Dong Han, lead researcher of the study, in an interview with the Max Planck Institute. He continued “this is particularly exciting because accessible peripheral neural stem cells could provide a new avenue for neural repair and regeneration, bypassing many of the challenges associated with sourcing stem cells from the central nervous system.”
Neurons originating from lung-derived neural stem cells (ldNSCs) showed hallmark electrical properties of functional neurons. They exhibited voltage-gated sodium and potassium currents and responded to depolarizing current injections with evoked action potentials. While spontaneous firing wasn’t observed, the cells were clearly excitable. Importantly, the sodium currents were fully blocked by Tetrodotoxin citrate (#T-550) (TTX) (Figure 1), confirming the presence of functional voltage-gated sodium channels.
Figure 1. Multipotency and electrophysiological properties of lung-derived neural stem cells (ldNSCs). A) Adult ldNSCs (aldNSCs) and control brain-derived neural stem cells (NSCs) both differentiated into astrocytes (GFAP marker, red), oligodendrocytes (Olig2 marker, red/MBP marker, green), and neurons (Tuj1 marker, red). The nuclei were counterstained with DAPI (blue). Scale bar, 50 μm. B) Whole-cell voltage-clamp recordings from ldNSC- and control NSC-derived neurons in response to step depolarizations from −80 mV to +60 mV. Application of TTX (1 μM) selectively abolished the fast inward Na⁺ current, confirming its identity as a voltage-gated sodium current. Adapted from Han, et al. 2025 (1).
The implications are wide-reaching. It raises the possibility that reservoirs of stem cells with true neural potential exist throughout the body. That could change how we approach injury repair, neurodegeneration, and even tissue engineering. These pNSCs may offer a more accessible source of NSCs for regenerative therapy, bypassing the blood-brain barrier entirely.
For those studying peripheral neural activity, this opens new experimental doors. The functional maturation of neurons from lung- or tail-derived pNSCs could be tracked using electrophysiological tools like Alomone’s TTX – long used to block voltage-gated sodium channels in CNS neurons. With these new cells, Alomone’s TTX might now find fresh applications in entirely different tissue systems.
