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The secretome, derived from hypoxia\u2010preconditioned cardiomyocytes (SHPC), potentially mimics the IPC microenvironment and facilitates IPC clinical translation. This study aims to determine whether SHPC can be a feasible alternative to IPC for attenuating MI\/R injury, and to identify the functional factor of SHPC. The ultrafiltration technique is applied to generate an SHPC formulation that is intramyocardially injected before reperfusion in a murine MI\/R model. The effects of SHPC on cardiomyocyte apoptosis, pyroptosis, and neutrophil polarization are evaluated. Secretomics, neutralizing antibodies, and recombinant proteins are employed to identify the functional factor in SHPC. Co\u2010immunoprecipitation assays, RNA sequencing, and site\u2010directed mutagenesis are conducted to investigate the underlying mechanism. Additionally, a recombinant functional factor\u2010encapsulated hydrogel is developed for intrapericardial injections (iPC). An intramyocardial SHPC injection in MI\/R\u2010injured mice strikingly reduces infarct size and the expression of cardiac injury biomarker while improving cardiac function. SHPC eliminated mitochondrial reactive oxygen species and triggered neutrophil polarization to reduce cardiomyocyte apoptosis\/pyroptosis upon hypoxia\/reoxygenation injury. Stanniocalcin 1 (Stc1) is identified as the functional factor in SHPC, mediating hypoxic microenvironment. Mechanistically, hypoxia\u2010preconditioned cardiomyocytes secrete Stc1 into the microenvironment and activate calcium\u2010sensing receptor (CaSR) that increases Stat3 phosphorylation at Ser727 via nitric oxide synthase 2 (NOS2)\u2010mediated S\u2010nitrosylation, thereby decreasing cardiomyocyte apoptosis\/pyroptosis in an autocrine mechanism. Simultaneously, Stc1 facilitates cardiomyocyte\u2010neutrophil crosstalk, thereby triggering neutrophil polarization to reduce inflammatory damage via the CaSR\/NOS2\/Stat3 axis in a paracrine mechanism. Pericardial delivery of a recombinant rStc1\u2010encapsulated hydrogel has extended the therapeutic time window of rStc1, improving long\u2010term cardiac function. The hypoxia microenvironment preconditioning, which mimicked by SHPC, attenuated MI\/R injury via Stc1\u2010mediated cardiomyocyte self\u2010protection and neutrophil polarization. This study suggests that SHPC, with hypoxia preconditioning factor Stc1, represents a clinically feasible alternative to IPC for attenuating MI\/R injury.<\/jats:p>","DOI":"10.1002\/advs.202411880","type":"journal-article","created":{"date-parts":[[2024,12,16]],"date-time":"2024-12-16T05:24:31Z","timestamp":1734326671000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":17,"title":["Hypoxia Microenvironment Preconditioning Attenuated Myocardial Ischemia\u2010Reperfusion Injury via Stc1\u2010Mediating Cardiomyocyte Self\u2010Protection and Neutrophil Polarization"],"prefix":"10.1002","volume":"12","author":[{"given":"Haoxiang","family":"Huang","sequence":"first","affiliation":[{"name":"Department of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University  1838 North Guangzhou Avenue Guangzhou 510515 China"},{"name":"Guangdong Provincial Key Laboratory of Cardiac Function and 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Provincial Key Laboratory of Cardiac Function and Microcirculation  Guangzhou 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guangkai","family":"Wu","sequence":"additional","affiliation":[{"name":"Department of Cardiology State Key Laboratory of Organ Failure Research Nanfang Hospital Southern Medical University  1838 North Guangzhou Avenue Guangzhou 510515 China"},{"name":"Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation  Guangzhou 510515 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zhenhua","family":"Li","sequence":"additional","affiliation":[{"name":"Guangdong Provincial Key Laboratory of Cardiac Function and Microcirculation  Guangzhou 510515 China"},{"name":"The Tenth Affiliated Hospital of Southern Medical University  Dongguan Guangdong 523059 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuegang","family":"Wang","sequence":"additional","affiliation":[{"name":"Department 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