The Neuron Niu Jianqin/Yi Chen Ju team discovered the coupling mechanism between oligodendroid precursor cell differentiation and astrocytes foot process formation

Editor-in-charge | Xi

In the central nervous system, oligodendrocytes form myelin sheaths to envelop neuronal axons, which play an important supporting role in rapid nerve impulse conduction [1].

Therefore, the widespread distribution of oligodendrocytes in the central nervous system is critical
.
However, oligodendroid glial precursor cells (OPCs) are formed in only a few limited regions during development (e.
g.
, MGE and LGE in the embryonic stage in the brain, SVZ after birth) [2], and need to undergo long-distance migration, eventually achieving a distribution of the whole central nervous system 【3】
。 Professor Niu Jianqin's article published in Science in 2016 revealed that OPC uses cerebral blood vessels as scaffolds for migration [4].

However, how OPC detaches from the blood vessels after migration reaches its destination, and whether the detachment of the OPC from the blood vessels is a prerequisite for its differentiation, remains unknown
.

On November 15, 2022, the team of Niu Jianqin from the Army Medical University and the team of Yi Chenju from the Seventh Affiliated Hospital of Sun Yat-sen University jointly delivered a report on Neuron Astrocyte endfoot formation controls the termination of oligodendrocyte precursor cell perivascular migration during neocortical development
.
This study revealed the coupling mechanism
by which the foot process of developing astrocytes causes OPCs to deviate from blood vessels at the migration endpoint and allow differentiation.

In order to study the mechanism of OPC detachment from blood vessels, the authors first focused on the morphological changes of glial cells in the central nervous system in the development time and space, and found that the formation of astrocyte foot processes showed a significant negative correlation with OPC-blood vessel interaction in time and space
.
Morphologically, the astrocytes foot process is between OPC and blood vessels, separating
the two.
By breeding Aldh1l1-eGFP:NG2-CreERT:LSL-tdTomato mice, labeling astrocytes (GFP) and OPC (tdTomato), respectively, and intravenously injecting Lectin-Dylight 649 to label blood vessels, the authors achieved the goal of astrocytes in mouse brains, In vivo imaging
of oligodendroid lineage cells and blood vessels.
It was found that the growth of astrocytes foot processes was closely related to the detachment of OPCs from blood vessels (Figure 1).

Figure 1.
Astrocytes foot process growth prompts OPCs to detach from blood vessels

To further validate the necessity of astrocytes foot formation to promote OPC detachment from blood vessels, the authors established two models (two-photon laser elimination of astrocytes (Figure 1), and conditional expression of DTA to eliminate astrocytes), and observed an increase
in OPC-vascular interaction in both models.
Description: Astrocytes foot prospectus has a necessary effect
on OPC detachment from blood vessels.

From the perspective of cell development, it is speculated that when OPC migrates with blood vessels as scaffolds, there should be a mechanism to inhibit its premature differentiation, which is conducive to the spread of OPC in the whole central nervous system, but there has been a lack of relevant experimental evidence
.
In this study, the authors found that the interaction between mature oligodendrocytes and blood vessels was significantly reduced compared with OPC, suggesting that blood vessels may inhibit OPC differentiation
.
Furthermore, in vitro experiments confirmed that cerebral vascular endothelial cells can inhibit the differentiation
of OPCs through contact and secretion.
In the mouse model of astrocytes eliminated, OPC differentiation and myelination decreased
due to the increase of OPC interaction with blood vessels.
Therefore, the detachment of OPCs from blood vessels is necessary for their normal differentiation
.

In order to explore the mechanism by which astrocytes promote the detachment of OPC from blood vessels, the authors analyzed the potential interaction proteins between astrocytes and OPC surfaces through proteomics, and found that the chemical rejection of Semaphorin-Plexin can participate in regulating OPC migration [5], so it is speculated that the interaction between astrocytes Semaphorin and OPC Plexin May mediate the process
by which astrocytes regulate OPC vascular detachment.
Although Sema3a/6a did not directly affect the differentiation of OPCs in in vitro experiments, knocking down the expression of astrocyte Sema3a/6a in in vivo experiments could increase OPC-vascular interaction, so that more OPCs remained in contact with blood vessels, thereby inhibiting OPC differentiation
.
Conversely, overexpression of Sema3a in astrocytes can promote the detachment of OPCs from blood vessels and increase OPC differentiation (Figure 2).

These evidence suggest that during development, astrocytes can detach OPCs from blood vessels through Sema3a/6a and enable subsequent differentiation
.

In summary, the authors reveal the coupling mechanism
between astrocytes foot process formation and oligodendrocytes migration and differentiation of oligodendrocytes precursor cells.
During the migration of OPCs with blood vessels as scaffolds, vascular endothelial cells inhibit premature differentiation of OPCs; At the end of OPC migration, the foot process formed by astrocytes on the surface of the blood vessel promotes the separation of OPC from the blood vessel, allowing OPC to differentiate into mature oligodendrocytes (Figure 3).

Figure 3: Working model

The first author of the paper is Su Yixun
, an assistant researcher at the Army Military Medical University and the Seventh Affiliated Hospital of Sun Yat-sen University.
Professor Stephen Fancy of the University of California, San Francisco (UCSF), Professor Yi Chen Ju of the Seventh Affiliated Hospital of Sun Yat-sen University, and Professor Niu Jianqin (Lead Contact) of the Army Medical University are in common communication
.