Hemin enhances the cardioprotective effects of mesenchymal stem cell-derived exosomes against infarction via amelioration of cardiomyocyte senescence

被引：85

作者：

Zheng, Huifeng ^{[1
,2
]}

Liang, Xiaoting ^{[3
]}

Han, Qian ^{[4
]}

Shao, Zhuang ^{[2
]}

Zhang, Yuxiao ^{[2
]}

Shi, Linli ^{[2
]}

Hong, Yimei ^{[2
]}

Li, Weifeng ^{[2
]}

Mai, Cong ^{[2
]}

Mo, Qingwen ^{[5
]}

Fu, Qingling ^{[5
]}

Ma, Xiaoxue ^{[6
]}

Lin, Fang ^{[6
]}

Li, Mimi ^{[6
]}

Hu, Bei ^{[1
,2
]}

Li, Xin ^{[1
,2
]}

Zhang, Yuelin ^{[1
,2
]}

机构：

[1] Southern Med Univ, Sch Clin Med 2, Guangzhou 510515, Guangdong, Peoples R China

[2] Guangdong Acad Med Sci, Guangdong Prov Peoples Hosp, Dept Emergency Med, Guangzhou 510080, Guangdong, Peoples R China

[3] Tongji Univ, Shanghai East Hosp, Inst Regenerat Med, Sch Life Sci & Technol, Shanghai 200120, Peoples R China

[4] Guangzhou Med Univ, Affiliated Hosp 1, Dept Resp Med, State Key Lab Resp Dis,Guangzhou Inst Resp Hlth, Guangzhou 510120, Guangdong, Peoples R China

[5] Sun Yat Sen Univ, Otorhinolaryngol Hosp, Affiliated Hosp 1, Guangzhou 510080, Guangdong, Peoples R China

[6] Tongji Univ, Shanghai East Hosp, Sch Med, Res Ctr Translat Med, Shanghai 200120, Peoples R China

来源：

JOURNAL OF NANOBIOTECHNOLOGY | 2021年 / 19卷 / 01期

关键词：

Mesenchymal stem cells; Exosomes; Hemin; Cardiomyocytes; Senescence; Myocardial infarction; MECHANISMS;

D O I：

10.1186/s12951-021-01077-y

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 [微生物学]; 090105 [作物生产系统与生态工程];

摘要：

Background: Application of mesenchymal stem cell-derived exosomes (MSC-EXO) has emerged as a novel therapeutic strategy for myocardial infarction (MI). Our previous study showed that pretreatment with hemin, a potent heme oxygenase-1 (HO-1) inducer, enhanced the cardioprotective effects of MSCs in a mouse model of MI. This study aimed to investigate the therapeutic effects of EXO derived from hemin-pretreated MSCs (Hemin-MSC-EXO) in MI and explore the potential mechanisms. Methods: MSC-EXO and Hemin-MSC-EXO were collected and characterized. MSC-EXO and Hemin-MSC-EXO were intramuscularly injected into the peri-infarct region in a mouse model of MI. Heart function of mice was assessed by echocardiography. The mitochondrial morphology of neonatal mice cardiomyocytes (NMCMs) under serum deprivation and hypoxic (SD/H) conditions was examined by Mitotracker staining. The cellular senescence of NMCMs was determined by senescence-associated-beta-galactosidase assay. A loss-of-function approach was adopted to determine the role of Hemin-MSC-exosomal-miR-183-5p in the regulation of cardiomyocyte senescence Results: EXO were successfully isolated from the supernatant of MSCs and Hemin-pretreated MSCs. Compared with MSC-EXO, injection of Hemin-MSC-EXO significantly improved cardiac function and reduced fibrosis. Both MSC-EXO and Hemin-MSC-EXO ameliorated cardiomyocyte senescence and mitochondrial fission in vitro and in vivo, and the latter exhibited better protective effects. MicroRNA sequencing revealed a higher level of miR-183-5p in Hemin-MSC-EXO than in MSC-EXO. MiR-183-5p knockdown partially abrogated the protective effects of Hemin-MSC-EXO in attenuating mitochondrial fission and cellular senescence of cardiomyocytes induced by SD/H. High mobility group box-1 (HMGB1) abundance was lower in Hemin-MSC-EXO-treated than MSC-EXO-treated mouse hearts, and HMGB1 was identified as one of the potential target genes of miR-183-5p. Mechanistically, Hemin-MSC-EXO inhibited SD/H-induced cardiomyocyte senescence partially by delivering miR-183-5p into recipient cardiomyocytes via regulation of the HMGB1/ERK pathway. Furthermore, knockdown of miR-183-5p reduced the Hemin-MSC-EXO-mediated cardioprotective effects in a mouse model of MI. Conclusion: Our results reveal that Hemin-MSC-EXO are superior to MSC-EXO in treating MI. Exosomal miR-183-5p mediates, at least partially, the cardioprotective effects of Hemin-MSC-EXO by inhibiting cardiomyocyte senescence via regulation of the HMGB1/ERK pathway. This study highlights that MSC-EXO have high translational value in repairing cardiac dysfunction following infarction. Graphic abstract

引用

页数：18

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