CD47型
间充质干细胞
川地68
细胞生物学
医学
免疫系统
巨噬细胞
干细胞
免疫学
癌症研究
生物
免疫组织化学
体外
生物化学
作者
Muthukumar Gunasekaran,Rachana Mishra,Sudhish Sharma,Progyaparamita Saha,Swetha T. Krishnan,Ling Chen,Sameer Ahmad Guru,Artur Stefanowicz,Agata Bilewska,Anshuman Sinha,Emily Ciolak,Zhi‐Dong Ge,Sunjay Kaushal
出处
期刊:Circulation
[Ovid Technologies (Wolters Kluwer)]
日期:2022-11-08
卷期号:146 (Suppl_1)
被引量:1
标识
DOI:10.1161/circ.146.suppl_1.15107
摘要
Introduction: Successful cell therapy should be able to resist the hostile ischemic myocardium, should be retained for longer duration to continue secreting cardioprotective growth factors/exosomes and should not elicited immunological host response. Hypothesis: Analysis of 5 clinically relevant human stem/progenitor cells in a rodent model of acute myocardial infarction demonstrated that neonatal cardiac mesenchymal stromal cells (nMSCs) provide the strongest cardiac functional recovery. Methods: Cardiac functional outcome following nMSCs/aMSCs in rat MI model was measured by echocardiography. Transplanted cell retention, in vivo phagocytosis and CD68 + cells was assessed by immunohistochemistry. In vitro phagocytosis analysis for aMSCs/nMSCs were performed with THP-1 derived macrophages. THP-1 differentiated macrophages were validated for the expression of CD68 and absence of CD31. Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for proteomic analysis of nMSCs and aMSCs. CD47 expression in nMSCs was blocked by anti-CD47/ siRNA transections/lenti-virus expressing CD47 shRNAs approaches. CD47 knock down efficiency by siRNA and lenti-virus were validated by immunoblot. Isotype antibody, scrambled siRNA and lentivirus expressing empty vector served as control. Results: Transplanted nMSCs significantly increased the number of tissue reparative macrophages and regulatory T cells and significantly decreased monocyte-derived inflammatory macrophages and neutrophils. nMSCs also showed immune evasion in the host myocardium. mRNA microarray and single-cell analyses combined with targeted depletion studies established CD47 in nMSCs as a key molecule responsible for stem cell retention in the myocardium through an antiphagocytic mechanism regulated by miR34a-5p. Gain- and loss-of-function studies demonstrated that mir34a-5p regulated the production of exosomes and cardioprotective paracrine factors in the nMSC secretome. Conclusions: We conclude that the functional benefits of nMSCs are governed by a novel miR34a-5p pathway regulating immunomodulation, cell retention, exosome production, and cytokine secretion.
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