{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,21]],"date-time":"2026-10-21T14:40:53Z","timestamp":1792593653838,"version":"4.5.0"},"reference-count":34,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2022,12,13]],"date-time":"2022-12-13T00:00:00Z","timestamp":1670889600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["81730039"],"award-info":[{"award-number":["81730039"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82071653"],"award-info":[{"award-number":["82071653"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["20194Y0477"],"award-info":[{"award-number":["20194Y0477"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017950","name":"Shanghai Municipal Health Commission","doi-asserted-by":"publisher","award":["81730039"],"award-info":[{"award-number":["81730039"]}],"id":[{"id":"10.13039\/100017950","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017950","name":"Shanghai Municipal Health Commission","doi-asserted-by":"publisher","award":["82071653"],"award-info":[{"award-number":["82071653"]}],"id":[{"id":"10.13039\/100017950","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100017950","name":"Shanghai Municipal Health Commission","doi-asserted-by":"publisher","award":["20194Y0477"],"award-info":[{"award-number":["20194Y0477"]}],"id":[{"id":"10.13039\/100017950","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Successful conception requires the synchrony of multiple systems and organs. Dysregulation of stromal cell\u2013immune cell interactions has been proposed to be associated with recurrent spontaneous abortion. However, the mechanism of this regulation has not been well elucidated. N6-methyladenosine is one of the most common RNA modifications, and is involved in many pathological processes. Our group has demonstrated that abnormal patterns of m6A modification inhibit trophoblast invasion and contribute to adverse pregnancy outcomes. The association between m6A regulators and stromal cell\u2013immune cell interactions is unclear. We obtained RNA-seq profiles from a GEO dataset and identified differentially expressed m6A regulators between healthy controls and patients with a recurrent spontaneous abortion history. ROC curves, functional enrichment and subclassification analysis were applied to elucidate the role of m6A regulators in pregnancy. We verified the expression of m6A regulators and constructed an overexpression cell line in a coculture system to reveal ALKBH5 function in stromal cell\u2013macrophage interactions. We identified 11 differentially expressed m6A regulators between healthy controls and patients with a recurrent spontaneous abortion history. Then, we identified the correlation between \u201ceraser\u201d genes and \u201cwriter\u201d genes. We tested the predictive abilities of the 11 m6A regulators based on another dataset and verified their expression in primary human endometrial stromal cells. We then subclassified three distinct patterns using the 11 genes and visualized genes related to immune infiltration and macrophage function in each cluster. ALKBH5 was proven to be correlated with recurrent spontaneous abortion. To verify the role of ALKBH5 in RSA, we constructed an ALKBH5-overexpression cell line. Finally, we cocultured the overexpression cell line with THP-1 cells. A decrease in M2 differentiation was observed, and this bias could be attributed to the hyposecretion of VEGF in stromal cells. N6-methyladenosine regulators play a pivotal role in stromal cell\u2013immune cell interactions at the maternal\u2013fetal interface. Overexpression of the m6A \u201ceraser\u201d gene ALKBH5 in stromal cells resulted in the hyposecretion of VEGF. Dysregulation of VEGF might impair macrophage recruitment and M2 differentiation, which could be the potential cause of recurrent spontaneous abortion.<\/jats:p>","DOI":"10.3390\/ijms232415819","type":"journal-article","created":{"date-parts":[[2022,12,14]],"date-time":"2022-12-14T01:52:34Z","timestamp":1670982754000},"page":"15819","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["The N6-Methyladenosine Regulator ALKBH5 Mediated Stromal Cell\u2013Macrophage Interaction via VEGF Signaling to Promote Recurrent Spontaneous Abortion: A Bioinformatic and In Vitro Study"],"prefix":"10.3390","volume":"23","author":[{"given":"Yongbo","family":"Zhao","sequence":"first","affiliation":[{"name":"Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jiani","family":"Sun","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liping","family":"Jin","sequence":"additional","affiliation":[{"name":"Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai 200092, China"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,12,13]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.3389\/fimmu.2020.01032","article-title":"Endometrial Immune Profiling: A Method to Design Personalized Care in Assisted Reproductive Medicine","volume":"11","author":"Petitbarat","year":"2020","journal-title":"Front. 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