Multipotent Neural Stem Cells Originating from Neuroepithelium Exist Outside the Mouse Central Nervous System

Neurology Cell Biology Life Sciences Medicine
neural stem cells peripheral nervous system neural regeneration mouse multipotency

Background Introduction

For a long time, the scientific community has generally believed that mammalian neural stem cells (NSCs) exist only in the central nervous system (CNS), particularly in specific regions of the brain, such as the dentate gyrus of the hippocampus and the subventricular zone near the lateral ventricles. NSCs in these regions can continue to generate new neurons in adulthood, a process known as neurogenesis. However, whether NSCs exist outside the CNS, especially in the peripheral nervous system (PNS), has been a subject of debate.

The peripheral nervous system is primarily derived from neural crest cells (NCCs), and neural crest stem cells (NCSCs) are considered the main stem cell type in the PNS. NCSCs differ significantly from CNS NSCs in terms of gene expression and differentiation potential, and their self-renewal capacity is limited. Therefore, the traditional view holds that NSCs exist only in the CNS, while stem cells in the PNS are mainly NCSCs.

However, this traditional view has been challenged in recent years. Some studies have suggested that certain peripheral tissues may contain cells with NSC characteristics, but these studies failed to provide sufficient evidence to prove that these cells indeed possess NSC features. To further explore this issue, a research team from the Max Planck Institute for Molecular Biomedicine, the University of Hong Kong, and other institutions conducted a groundbreaking study aimed at revealing the existence and function of peripheral neural stem cells (PNSCs).

Research Source

This study was jointly conducted by Dong Han, Wan Xu, Hyun-Woo Jeong, and other scientists from several internationally renowned research institutions, including the Max Planck Institute for Molecular Biomedicine, the University of Hong Kong, and the University of Luxembourg. The findings were published in April 2025 in the journal Nature Cell Biology, titled “Multipotent neural stem cells originating from neuroepithelium exist outside the mouse central nervous system.”

Research Process and Results

1. Discovery and Isolation of Peripheral Neural Stem Cells

The research team first attempted to induce NSC-like cells from mouse embryonic limb cells and adult lung cells through low-pH treatment. Although they initially failed to induce pluripotent stem cells, under specific culture conditions, the researchers unexpectedly obtained a population of cells with NSC characteristics. These cells were named “Embryonic Limb Low-pH NSCs” (ELLNSCs) and “Adult Lung Low-pH NSCs” (ALLNSCs).

To verify whether these cells indeed possessed NSC characteristics, the researchers conducted multiple tests, including analyses of cell morphology, self-renewal capacity, differentiation potential, gene expression profiles, and epigenetic features. The results showed that ELLNSCs and ALLNSCs were highly similar to brain-derived NSCs in multiple aspects and could differentiate into neural cell types such as neurons, astrocytes, and oligodendrocytes.

2. Isolation of Peripheral Neural Stem Cells Without Low-pH Treatment

To further confirm the existence of endogenous NSCs in peripheral tissues, the researchers isolated NSC-like cells directly from embryonic limb, adult lung, and postnatal tail tissues without low-pH treatment. By using transgenic mice expressing the NSC-specific marker nestin (nes-gfp mice), the researchers successfully isolated GFP+ NSC-like cells from adult lung and tail tissues. These cells also exhibited self-renewal capacity, differentiation potential, and gene expression patterns similar to brain NSCs.

3. Verification of the Multipotency of Peripheral Neural Stem Cells

To verify the multipotency of PNSCs, the researchers differentiated these cells into neurons, astrocytes, and oligodendrocytes in vitro and transplanted them into the brains of newborn mice. The results showed that the transplanted PNSCs could survive and differentiate into mature neurons and glial cells in the brain, with no tumor formation observed. Additionally, through genetic labeling experiments, the researchers ruled out the possibility of fusion between transplanted cells and host cells.

4. Differences Between Peripheral Neural Stem Cells and Neural Crest Stem Cells

To determine whether PNSCs originate from neural crest cells, the researchers compared PNSCs and NCSCs. The results showed that PNSCs expressed NSC-specific markers (such as Sox2 and Olig2) but did not express NCSC-specific markers (such as Sox10 and p75). Furthermore, PNSCs primarily differentiated into neurons and glial cells, while NCSCs had difficulty differentiating into neurons, and the differentiated cells still expressed p75. These results indicate significant differences in gene expression and differentiation potential between PNSCs and NCSCs.

5. Origin of Peripheral Neural Stem Cells

Through genetic tracing experiments, the researchers found that PNSCs originate from neuroepithelial cells (NECs) rather than neural crest cells. Using Sox1-cre mice for labeling experiments, the researchers discovered that PNSCs migrate out of the neural tube during early embryonic development and settle in peripheral tissues. These PNSCs can differentiate into mature neurons and limited glial cells during embryonic and postnatal development.

6. Molecular Characteristics of Peripheral Neural Stem Cells

To further reveal the molecular characteristics of PNSCs, the researchers performed single-cell RNA sequencing (scRNA-seq) on Sox1+ cells from adult brain and postnatal tail tissues. The results showed that Sox1+ cells in the tail tissue were highly similar to brain NSCs in gene expression, and these cells retained neurogenic potential postnatally. Additionally, PNSCs differed significantly in molecular characteristics from other tissue-resident stem cells (such as lung AT1 and AT2 stem cells), indicating that PNSCs are a unique group of NSCs.

Research Conclusions and Significance

This study is the first to confirm the existence of peripheral neural stem cells (PNSCs) and reveal their similarities to central neural stem cells (NSCs) in multiple aspects. PNSCs originate from neuroepithelial cells rather than neural crest cells and can differentiate into neurons and glial cells during embryonic and postnatal development. This discovery not only challenges traditional views but also provides new possibilities for neural regenerative therapy.

Scientific Value and Application Prospects

  1. Challenging Traditional Views: This study breaks the long-held belief that NSCs exist only in the CNS, revealing the existence and function of PNSCs in the peripheral nervous system.
  2. Neural Regenerative Therapy: The discovery of PNSCs provides a new cell source for the treatment of neurodegenerative diseases (such as Alzheimer’s and Parkinson’s) and spinal cord injuries. Compared to CNS NSCs, PNSCs are easier to obtain and have similar regenerative potential.
  3. Developmental Biology: This study offers a new perspective on understanding the development of the nervous system, highlighting the important role of neuroepithelial cells in the formation of the peripheral nervous system.

Research Highlights

  1. First Discovery of Peripheral Neural Stem Cells: This study is the first to confirm the existence of PNSCs and provide a detailed description of their similarities to CNS NSCs.
  2. Innovative Experimental Methods: The research team successfully isolated and verified the existence and function of PNSCs through low-pH treatment and genetic labeling experiments.
  3. Interdisciplinary Collaboration: This study combined developmental biology, molecular biology, and single-cell sequencing technologies, providing multi-layered evidence for the discovery of PNSCs.

Summary

This study not only brings new breakthroughs to the field of neuroscience but also provides new ideas for neural regenerative therapy. Future research on the existence of PNSCs in humans and their application in disease treatment will have significant scientific and clinical implications.