by Researchers from the Chinese Academy of Sciences have made a groundbreaking discovery regarding the regulation of brain pericyte development. The study, which was published online in Cell Reports, employed a zebrafish model to observe the developmental dynamics of brain pericytes during the early embryonic stage.
Led by Du Jiulin, the team found that blood flow plays a crucial role in promoting the proliferation of pericytes after they enter the brain. This process relies on the activation of the mechanosensitive ion channel Piezo1 in vascular endothelial cells (ECs) and its downstream Notch signaling.
The brain vasculature forms the blood-brain barrier (BBB) during development to maintain the homeostasis of neural tissues and normal neural activity. Abnormalities in the BBB are closely associated with various brain diseases, including Alzheimer’s.
Pericytes, which tightly attach to the outer side of EC tubes in capillaries, play a crucial role in maintaining the integrity of the BBB. Therefore, understanding the developmental process of brain pericytes is essential for studying the formation and maintenance of BBB.
While previous research has shown that blood flow regulates the development of brain ECs, it remained unclear whether blood flow also affects the growth of brain pericytes.
To address this question, the researchers used zebrafish as a vertebrate model and established an in vivo model with specifically marked pericytes using CRISPR/Cas9 gene-editing techniques. Through long-term time-lapse imaging, they observed that brain pericytes originate early from precursor cells on pericerebral blood vessels and primarily expand their population through proliferation after entering the brain.
By altering blood flow velocities pharmacologically, the researchers discovered that blood flow up-regulates the pericyte coverage of brain vessels by promoting their proliferation.
The team also found that the mechanosensitive ion channel Piezo1, expressed on ECs, senses changes in blood flow and mediates its effect on pericyte proliferation.
To understand how the influence of blood flow transmits from ECs to pericytes, the researchers observed that the activation of Piezo1 significantly increased the activity of Notch signaling in ECs. Specific enhancement or inhibition of Notch signaling in ECs resulted in corresponding up-regulation or down-regulation of the proliferation frequency of brain pericytes.
The results suggest that EC-intrinsic Notch signaling mediates the regulation of blood flow in the development of brain pericytes as the downstream of Piezo1. Moreover, by specifically enhancing or inhibiting the outward transmission of Notch signaling in ECs, the researchers provided evidence that ECs with enhanced Notch signaling directly activated Notch signaling in pericytes, promoting their division.
This study unveils a novel regulatory mechanism for blood flow in brain vascular development and offers new perspectives for understanding brain pericyte development.
For researchers seeking methods to treat neurological disorders, these findings may provide new therapeutic strategies. For instance, up-regulating the activity of Piezo1 or the intensity of Notch signaling in ECs could promote the proliferation of brain pericytes, improving the function of brain vessels and facilitating the recovery of brain function in patients with diseases such as Alzheimer’s, vascular dementia, and stroke.
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1. Source: Coherent Market Insights, Public sources, Desk research
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