SOX17 is a Critical Factor in Maintaining Endothelial Function in Pulmonary Hypertension by an Exosome‐Mediated Autocrine Manner

Zou, Xingfu; Liu, Ting; Huang, Zhongjie; Zhou, Wei; Yuan, Mengnan; Zhao, Hongying; Pan, Zongfu; Chen, Pengcheng; Shao, Yanfei; Hu, Xiaoping; Zhang, Su; Zheng, Shuilian; Zhang, Yiwen; Huang, Ping

doi:10.1002/advs.202206139

Cited by 8 publications

(6 citation statements)

References 72 publications

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“…Previous studies have reported that genes such as Ki67 [ 20 ] /Egfr [ 21 ] /Sox17 [ 22 ] /Cyclins [ 23 ] are actively expressed in proliferating cells, indicating that the cells are in an active state of proliferation. To investigate the role of IGFBP7 on endothelial cell growth, we first examined the role of IGFBP7 in the injured endothelial model (LPS stimulation).…”

Section: Resultsmentioning

confidence: 99%

IGFBP7 promotes endothelial cell repair in the recovery phase of acute lung injury

He,

Feng,

Zhang

et al. 2024

Clinical Science

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IGFBP7 has been found to play an important role in inflammatory diseases, such as acute lung injury (ALI). However, the role of IGFBP7 in different stages of inflammation remains unclear. Transcriptome sequencing was used to identify the regulatory genes of IGFBP7, and endothelial IGFBP7 expression was knocked down using Aplnr-Dre mice to evaluate the endothelial proliferation capacity. The expression of proliferation-related genes was detected by western blotting and RT-PCR assays. In this study, we found that knockdown of IGFBP7 in endothelial cells significantly decreases the expression of endothelial cell proliferation-related genes and cell number in the recovery phase but not in the acute phase of ALI. Mechanistically, using bulk-RNA sequencing and CO-IP, we found that IGFBP7 promotes phosphorylation of FOS and subsequently upregulates YAP1 molecules, thereby promoting endothelial cell proliferation. This study indicated that IGFBP7 has diverse roles in different stages of ALI, which extends the understanding of IGFBP7 in different stages of ALI and suggests that IGFBP7 as a potential therapeutic target in ALI needs to take into account the period specificity of ALI.

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Section: Resultsmentioning

confidence: 99%

IGFBP7 promotes endothelial cell repair in the recovery phase of acute lung injury

He,

Feng,

Zhang

et al. 2024

Clinical Science

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“…Of particular interest to us are documented instances of exosomal autocrine secretion. For instance, SOX17 has been demonstrated to maintain endothelial function inpulmonary hypertension through the process of exosomal autocrine secretion (Zou et al, 2023). Furthermore, exosomes that transport plasma gelsolin (pGSN) promote the survival of ovarian cancer cells through both autocrine and paracrine mechanisms, transforming chemosensitive cells into resistant counterparts (Asare-Werehene et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Regulation of spermatogonial stem cell differentiation by Sertoli cells‐derived exosomes through paracrine and autocrine signaling

Tian,

Wang,

et al. 2024

Journal Cellular Physiology

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In the orchestrated environment of the testicular niche, the equilibrium between self‐renewal and differentiation of spermatogonial stem cells (SSCs) is meticulously maintained, ensuring a stable stem cell reserve and robust spermatogenesis. Within this milieu, extracellular vesicles, specifically exosomes, have emerged as critical conveyors of intercellular communication. Despite their recognized significance, the implications of testicular exosomes in modulating SSC fate remain incompletely characterized. Given the fundamental support and regulatory influence of Sertoli cells (SCs) on SSCs, we were compelled to explore the role of SC‐derived exosomes (SC‐EXOs) in the SSC‐testicular niche. Our investigation hinged on the hypothesis that SC‐EXOs, secreted by SCs from the testes of 5‐day‐old mice—a developmental juncture marking the onset of SSC differentiation—participate in the regulation of this process. We discovered that exposure to SC‐EXOs resulted in an upsurge of PLZF, MVH, and STRA8 expression in SSC cultures, concomitant with a diminution of ID4 and GFRA1 levels. Intriguingly, obstructing exosomal communication in a SC‐SSC coculture system with the exosome inhibitor GW4869 attenuated SSC differentiation, suggesting that SC‐EXOs may modulate this process via paracrine signaling. Further scrutiny revealed the presence of miR‐493‐5p within SC‐EXOs, which suppresses Gdnf mRNA in SCs to indirectly restrain SSC differentiation through the modulation of GDNF expression—an indication of autocrine regulation. Collectively, our findings illuminate the complex regulatory schema by which SC‐EXOs affect SSC differentiation, offering novel perspectives and laying the groundwork for future preclinical and clinical investigations.

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“…Sangam et al 16 reported that SOX17 deficiency inhibits mitochondrial bioenergetics and induces PAH partly via HIF-2α signaling. Zou et al 32 identified SOX17-associated exosomes including microR-224-5p and microR-361-3p improve endothelial function. Taken together, these studies highlight the critical role of SOX17 in maintaining endothelial function and repressing PH development.…”

Section: Discussionmentioning

confidence: 99%

E2F1 Mediates SOX17 Deficiency–Induced Pulmonary Hypertension

Yi,

Liu,

Ding

et al. 2023

Hypertension

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Background: Rare genetic variants and genetic variation at loci in an enhancer in SOX17 (SRY-box transcription factor 17) are identified in patients with idiopathic pulmonary arterial hypertension (PAH) and PAH with congenital heart disease. However, the exact role of genetic variants or mutations in SOX17 in PAH pathogenesis has not been reported. Methods: SOX17 expression was evaluated in the lungs and pulmonary endothelial cells (ECs) of patients with idiopathic PAH. Mice with Tie2Cre-mediated Sox17 knockdown and EC-specific Sox17 deletion were generated to determine the role of SOX17 deficiency in the pathogenesis of PAH. Human pulmonary ECs were cultured to understand the role of SOX17 deficiency. Single-cell RNA sequencing, RNA-sequencing analysis, and luciferase assay were performed to understand the underlying molecular mechanisms of SOX17 deficiency–induced PAH. E2F1 (E2F transcription factor 1) inhibitor HLM006474 was used in EC-specific Sox17 mice. Results: SOX17 expression was downregulated in the lung and pulmonary ECs from patients with idiopathic PAH. Mice with Tie2Cre-mediated Sox17 knockdown and EC-specific Sox17 deletion induced spontaneously mild pulmonary hypertension. Loss of endothelial Sox17 in EC exacerbated hypoxia-induced pulmonary hypertension in mice. Loss of SOX17 in lung ECs induced endothelial dysfunctions including upregulation of cell cycle programming, proliferative and antiapoptotic phenotypes, augmentation of paracrine effect on pulmonary arterial smooth muscle cells, impaired cellular junction, and BMP (bone morphogenetic protein) signaling. E2F1 signaling was shown to mediate the SOX17 deficiency–induced EC dysfunction. Pharmacological inhibition of E2F1 in Sox17 EC-deficient mice attenuated pulmonary hypertension development. Conclusions: Our study demonstrated that endothelial SOX17 deficiency induces pulmonary hypertension through E2F1. Thus, targeting E2F1 signaling represents a promising approach in patients with PAH.

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SOX17 is a Critical Factor in Maintaining Endothelial Function in Pulmonary Hypertension by an Exosome‐Mediated Autocrine Manner

Cited by 8 publications

References 72 publications

IGFBP7 promotes endothelial cell repair in the recovery phase of acute lung injury

IGFBP7 promotes endothelial cell repair in the recovery phase of acute lung injury

Regulation of spermatogonial stem cell differentiation by Sertoli cells‐derived exosomes through paracrine and autocrine signaling

E2F1 Mediates SOX17 Deficiency–Induced Pulmonary Hypertension

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