APJ regulates the balance between self-renewal and differentiation of vascular endothelial stem cells

TL;DR

This study shows that APJ signaling helps control the balance between self-renewal and differentiation of vascular endothelial stem cells in the liver.

Contribution

The study identifies APJ as a key regulator of vascular endothelial stem cell function and liver vascular regeneration.

Findings

APJ deficiency causes VESC accumulation and delayed differentiation into mature endothelial cells.

APJ deletion impairs vascular regeneration after partial hepatectomy due to compromised VESC differentiation.

Transcriptomic changes in APJ KO VESCs suggest disrupted cell cycle regulation and extracellular matrix alterations.

Abstract

CD157 marks a population of tissue-resident vascular endothelial stem cells (VESCs) in mice known for their critical role in homeostatic endothelial cell (EC) turnover and the rapid response to vascular damage in the liver by regeneration. Nevertheless, the mechanism underlying the maintenance and differentiation of postnatal VESCs under both physiological and pathological conditions remains unclear.

APJ knockout (KO) mice were utilized to explore the role of apelin/APJ signaling in VESC functionality. Flow cytometry, colony-forming unit assays, and in vitro differentiation experiments were conducted to characterize VESC populations. Partial hepatectomy (PHx) was performed to assess vascular regeneration.

APJ deficiency led to an accumulation of VESCs in the liver of adult mice, which displayed enhanced colony-forming capacity but delayed differentiation into mature ECs. APJ KO mice exhibited impaired vascular regeneration following PHx, linked to compromised VESC differentiation. Transcriptomic analysis revealed upregulation of transcription factors EGR1 and EGR2 and downregulation of Ccnd1 in APJ KO VESCs, implicating disrupted cell cycle regulation. Additionally, APJ deletion reduced collagen IV levels, weakening the basement membrane and contributing to the maintenance of VESCs in an undifferentiated state.

APJ signaling is critical for balancing VESC self-renewal and differentiation. APJ deficiency disrupts this balance, leading to impaired vascular regeneration in the liver due to delayed VESC differentiation. This defect is associated with altered transcriptional regulation, favoring a proliferative, undifferentiated state and extracellular matrix changes that weaken structural integrity. These findings highlight the apelin/APJ pathway as a potential therapeutic target to enhance vascular regeneration in regenerative medicine.

The online version contains supplementary material available at 10.1186/s41232-025-00389-y.

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