細(xì)胞療法對(duì)受損的心肌再生具有潛在作用,，心肌再生的細(xì)胞療法具有絕對(duì)安全性,，只顯示非邊緣效應(yīng),。無細(xì)胞和無生命治療物的開發(fā)具有革新心血管再生醫(yī)學(xué)的潛力,。無細(xì)胞療法可以通過旁分泌機(jī)制影響干細(xì)胞的分化,，而不需要直接注射干細(xì)胞使其分化為心肌細(xì)胞,。因此,，無細(xì)胞療法的作用機(jī)制研究顯得尤為重要,，近日，研究人員揭秘了心力衰竭患者的心臟基質(zhì)細(xì)胞來源的外泌體的再生修復(fù)作用發(fā)生障礙的具體機(jī)制,，相關(guān)研究結(jié)果發(fā)表在Journal of clinical investigation雜志上,。

外泌體作為細(xì)胞治療的功能性旁分泌單位,，可以部分復(fù)制其親代細(xì)胞的修復(fù)特性。外泌體的構(gòu)成及其生物活性在很大程度上取決于其來源細(xì)胞,。研究人員從心力衰竭患者(FEXO)或正常供體心臟(NEXO)的心臟基質(zhì)細(xì)胞中分離外泌體,，并比較它們?cè)隗w外和體內(nèi)的再生修復(fù)活性。體外研究結(jié)果顯示FEXO組患者心臟來源的外泌體內(nèi)皮細(xì)胞形成和心肌細(xì)胞增殖的能力受損,。心肌內(nèi)注射NEXO改善了小鼠急性心肌梗死模型的結(jié)構(gòu)和功能,。相反，F(xiàn)EXO療法加劇了心臟功能和左心室重構(gòu),。micoRNA序列分析和PCR分析結(jié)果顯示,，F(xiàn)EXO源外泌體中的miR-21-5p表達(dá)失調(diào)?；謴?fù)miR-21-5p表達(dá)可重塑FEXO源外泌體的修復(fù)功能,，而抑制NEXO中miR-21-5p的表達(dá)可顯著降低其外泌體的再生修復(fù)治療效果。進(jìn)一步的機(jī)理研究顯示,，miR-21-5p通過抑制磷酸酶和tensin同源物從而增強(qiáng)Akt激酶活性,。綜上，該研究結(jié)果提示心力衰竭病理狀態(tài)改變了心臟來源的外泌體的組分從而損害了其再生修復(fù)能力,，外泌體中的miR-21-5p表達(dá)可有效促進(jìn)血管生成和心肌細(xì)胞存活,，從而有助于心臟修復(fù)。

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microRNA-21-5p dysregulation in exosomes derived from heart failure patients impairs regenerative potential.

Exosomes, as functional paracrine units of therapeutic cells, can partially reproduce the reparative properties of their parental cells. The constitution of exosomes, as well as their biological activity, largely depends on the cells that secrete them. We isolated exosomes from explant-derived cardiac stromal cells from patients with heart failure (FEXO) or from normal donor hearts (NEXO) and compared their regenerative activities in vitro and in vivo. Patients in the FEXO group exhibited an impaired ability to promote endothelial tube formation and cardiomyocyte proliferation in vitro. Intramyocardial injection of NEXO resulted in structural and functional improvements in a murine model of acute myocardial infarction. In contrast, FEXO therapy exacerbated cardiac function and left ventricular remodeling. microRNA array and PCR analysis revealed dysregulation of miR-21-5p in FEXO. Restoring miR-21-5p expression rescued FEXO's reparative function, whereas blunting miR-21-5p expression in NEXO diminished its therapeutic benefits. Further mechanistic studies revealed that miR-21-5p augmented Akt kinase activity through the inhibition of phosphatase and tensin homolog. Taken together, the heart failure pathological condition altered the miR cargos of cardiac-derived exosomes and impaired their regenerative activities. miR-21-5p contributes to exosome-mediated heart repair by enhancing angiogenesis and cardiomyocyte survival through the phosphatase and tensin homolog/Akt pathway.