An injectable silk sericin hydrogel promotes cardiac functional recovery after ischemic myocardial infarction.
Acute myocardial infarction (MI) leads to morbidity and mortality due to cardiac dysfunction. Here we identify sericin, a silk-derived protein, as an injectable therapeutic biomaterial for the minimally invasive MI repair. For the first time, sericin prepared in the form of an injectable hydrogel has been utilized for cardiac tissue engineering and its therapeutical outcomes evaluated in a mouse MI model. The injection of this sericin hydrogel into MI area reduces scar formation and infarct size, increases wall thickness and neovascularization, and inhibits the MI-induced inflammatory responses and apoptosis, thereby leading to a significant functional improvement. The potential therapeutical mechanisms have been further analyzed in vitro. Our results indicate that sericin downregulates pro-inflammatory cytokines (TNF-α and IL-18) and chemokine (CCL2) and reduces TNF-α expression by suppressing the TLR4-MAPK/NF-κB pathways. Moreover, sericin exhibits angiogenic activity by promoting migration and tubular formation of human umbilical vessel endothelial cells (HUVECs). Also, sericin stimulates VEGFa expression via activating ERK phosphorylation. Further, sericin protects endothelial cells and cardiomyocytes from apoptosis by inhibiting the activation of caspase 3. Together, these diverse biochemical activities of sericin protein lead to a significant recovery of cardiac function. This work represents the first study reporting sericin as an effective therapeutic biomaterial for ischemic myocardial repair in vivo.



Intramyocardial biomaterial injection is thought to be a potential therapeutic approach to improve cardiac performance after ischemic myocardial infarction. In this study, we report the successful fabrication and in vivo application of an injectable sericin hydrogel for ischemic heart disease. We for the first time show that the injection of in situ forming crosslinked sericin hydrogel promotes heart functional recovery accompanied with reduced inflammatory responses, attenuated apoptosis and increased microvessel density in the infarcted hearts. Further, we reveal that the improvement in those aspects is ascribed to sericin protein's functional bioactivities that are comprehensively uncovered in this study. Thus, we identify sericin, a natural protein, as a biomaterial suitable for myocardial repair and demonstrate that the in vivo application of this injectable sericin hydrogel can be an effective strategy for treating MI.
Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
Yu
Y
Song
Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China; Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
Cheng
C
Zhang
Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
Jinxiang
J
Zhang
Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai 20032, China.
Ning
N
Sun
Institution of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
Kun
K
Huang
Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China.
Huili
H
Li
Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China; Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China. Electronic address: zhengwang@hust.edu.cn.
Zheng
Z
Wang
Institution of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China. Electronic address: huangkai1@mail.hust.edu.cn.
Kai
K
Huang
Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China; Central Medical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China; Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China. Electronic address: lin_wang@hust.edu.cn.
Lin
L
Wang
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects; D003432:Cross-Linking Reagents / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D019610:Cytoprotection / Q000187:drug effects; D005355:Fibrosis; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate / Q000494:pharmacology*; D007249:Inflammation / Q000473:pathology; D007267:Injections; D039823:Iridoids / Q000494:pharmacology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009203:Myocardial Infarction / Q000473:pathology / Q000503:physiopathology*; D032383:Myocytes, Cardiac / Q000166:cytology / Q000187:drug effects; D041681:NIH 3T3 Cells; D018919:Neovascularization, Physiologic / Q000187:drug effects; D051381:Rats; D020127:Recovery of Function / Q000187:drug effects*; D047030:Sericins / Q000302:isolation & purification / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A / Q000235:genetics / Q000378:metabolism
D003432:Cross-Linking Reagents; D016207:Cytokines; D039823:Iridoids; D047030:Sericins; D042461:Vascular Endothelial Growth Factor A; D020136:Hydrogel, Polyethylene Glycol Dimethacrylate; C007834:genipin
Functional recovery; Injectable hydrogels; Myocardial infarction; Sericin