{"doi":"10.1161/circulationaha.123.065005","title":"Inhalable Stem Cell Exosomes Promote Heart Repair After Myocardial Infarction","abstract":"<h4>Background</h4>Exosome therapy shows potential for cardiac repair after injury. However, intrinsic challenges such as short half-life and lack of clear targets hinder the clinical feasibility. Here, we report a noninvasive and repeatable method for exosome delivery through inhalation after myocardial infarction (MI), which we called stem cell-derived exosome nebulization therapy (SCENT).<h4>Methods</h4>Stem cell-derived exosomes were characterized for size distribution and surface markers. C57BL/6 mice with MI model received exosome inhalation treatment through a nebulizer for 7 consecutive days. Echocardiographies were performed to monitor cardiac function after SCENT, and histological analysis helped with the investigation of myocardial repair. Single-cell RNA sequencing of the whole heart was performed to explore the mechanism of action by SCENT. Last, the feasibility, efficacy, and general safety of SCENT were demonstrated in a swine model of MI, facilitated by 3-dimensional cardiac magnetic resonance imaging.<h4>Results</h4>Recruitment of exosomes to the ischemic heart after SCENT was detected by ex vivo IVIS imaging and fluorescence microscopy. In a mouse model of MI, SCENT ameliorated cardiac repair by improving left ventricular function, reducing fibrotic tissue, and promoting cardiomyocyte proliferation. Mechanistic studies using single-cell RNA sequencing of mouse heart after SCENT revealed a downregulation of <i>Cd36</i> in endothelial cells (ECs). In an EC-<i>Cd36</i><sup>fl/-</sup> conditional knockout mouse model, the inhibition of CD36, a fatty acid transporter in ECs, led to a compensatory increase in glucose utilization in the heart and higher ATP generation, which enhanced cardiac contractility. In pigs, cardiac magnetic resonance imaging showed an enhanced ejection fraction (Δ=11.66±5.12%) and fractional shortening (Δ=5.72±2.29%) at day 28 after MI by SCENT treatment compared with controls, along with reduced infarct size and thickened ventricular wall.<h4>Conclusions</h4>In both rodent and swine models, our data proved the feasibility, efficacy, and general safety of SCENT treatment against acute MI injury, laying the groundwork for clinical investigation. Moreover, the EC-<i>Cd36</i><sup>fl/-</sup> mouse model provides the first in vivo evidence showing that conditional EC-CD36 knockout can ameliorate cardiac injury. Our study introduces a noninvasive treatment option for heart disease and identifies new potential therapeutic targets.","journal":"Circulation","year":2024,"id":9590,"datarank":0.6663976884735476,"base_score":4.442651256490317,"endowment":4.442651256490317,"self_citation_contribution":0.6663976884735476,"citation_network_contribution":0.0,"self_endowment_contribution":0.6663976884735476,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":84,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.0472,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2024-08-27","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":6118,"name":"Shenghuan Sun","orcid":"0000-0002-4339-2716","position":1,"is_corresponding":false},{"id":14866,"name":"DASHUAI ZHU","orcid":"0000-0002-4645-5786","position":2,"is_corresponding":false},{"id":80208,"name":"Xuan Mei","orcid":"0000-0002-1190-0800","position":3,"is_corresponding":false},{"id":80209,"name":"Yongbo Lyu","orcid":null,"position":4,"is_corresponding":false},{"id":80210,"name":"Ke Huang","orcid":"0000-0002-9355-7224","position":5,"is_corresponding":false},{"id":80211,"name":"Yuan Li","orcid":"0000-0002-1929-5465","position":6,"is_corresponding":false},{"id":80212,"name":"Shuo Liu","orcid":"0000-0002-2969-5876","position":7,"is_corresponding":false},{"id":80213,"name":"Zhenzhen Wang","orcid":"0000-0002-5245-6726","position":8,"is_corresponding":false},{"id":80214,"name":"Shiqi Hu","orcid":"0000-0002-8570-3439","position":9,"is_corresponding":false},{"id":80215,"name":"Halle J. Lutz","orcid":"0000-0001-6364-7627","position":10,"is_corresponding":false},{"id":80216,"name":"Kristen D. Popowski","orcid":"0000-0002-6341-2251","position":11,"is_corresponding":false},{"id":80217,"name":"Phuong-Uyen C. Dinh","orcid":"0000-0002-8969-6256","position":12,"is_corresponding":false},{"id":51,"name":"Atul Janardhan Butte","orcid":"0000-0002-7433-2740","position":13,"is_corresponding":false},{"id":14867,"name":"Ke Cheng","orcid":"0000-0001-7082-6893","position":14,"is_corresponding":false},{"id":14865,"name":"Junlang Li","orcid":"0000-0001-5834-5704","position":0,"is_corresponding":true}],"reference_count":65,"raw_metadata":null,"created_at":"2026-03-01T18:20:47.508186Z","pmid":null,"pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}