title: A Neuroprotective Sericin Hydrogel As an Effective Neuronal Cell Carrier for the Repair of Ischemic Stroke.
abstract: Ischemic stroke causes extensive cellular loss that impairs brain functions, resulting in severe disabilities. No effective treatments are currently available for brain tissue regeneration. The need to develop effective therapeutic approaches for treating stroke is compelling. A tissue engineering approach employing a hydrogel carrying both cells and neurotrophic cytokines to damaged regions is an encouraging alternative for neuronal repair. However, this approach is often challenged by low in vivo cell survival rate, and low encapsulation efficiency and loss of cytokines. To address these limitations, we propose to develop a biomaterial that can form a matrix capable of improving in vivo survival of transplanted cells and reducing in vivo loss of cytokines. Here, we report that using sericin, a natural protein from silk, we have fabricated a genipin-cross-linked sericin hydrogel (GSH) with porous structure and mild swelling ratio. The GSH supports the effective attachment and growth of neurons in vitro. Strikingly, our data reveal that sericin protein is intrinsically neurotrophic and neuroprotective, promoting axon extension and branching as well as preventing primary neurons from hypoxia-induced cell death. Notably, these functions are inherited by the GSH's degradation products, which might spare a need of incorporating costly cytokines. We further demonstrate that this neurotrophic effect is dependent on the Lkb1-Nuak1 pathway, while the neuroprotective effect is realized through regulating the Bcl-2/Bax protein ratio. Importantly, when transplanted in vivo, the GSH gives a high cell survival rate and allows the cells to continuously proliferate. Together, this work unmasks the neurotrophic and neuroprotective functions for sericin and provides strong evidence justifying the GSH's suitability as a potential neuronal cell delivery vehicle for ischemic stroke repair.
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China 430022.|Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China 430022.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China 430022.
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.affiliation: Department of Respiration, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China 430022.|Medical Research Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei, China 430022.
authors.forename: Yang
authors.initials: Y
authors.lastname: Jin
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China 430022.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Luo
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China 430022.
authors.forename: Wen
authors.initials: W
authors.lastname: Yang
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China 430022.
authors.forename: Hongjian
authors.initials: H
authors.lastname: Xie
authors.affiliation: Department of Cardiology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei, China 430022.
authors.forename: Kai
authors.initials: K
authors.lastname: Huang
authors.affiliation: Research Center for Tissue Engineering and Regenerative Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, China 430022.|Medical Research Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei, China 430022.|Department of Clinical Laboratory, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology , Wuhan, Hubei, China 430022.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
mesh_terms: D000818:Animals; D001672:Biocompatible Materials / Q000737:chemistry; D012831:Bombyx; D002545:Brain Ischemia / Q000473:pathology* / Q000628:therapy; D015687:Cell Hypoxia; D002460:Cell Line; D049109:Cell Proliferation; D002470:Cell Survival; D003432:Cross-Linking Reagents / Q000737:chemistry; D016207:Cytokines / Q000378:metabolism; D005982:Glutathione Transferase / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006801:Humans; D020100:Hydrogels / Q000737:chemistry*; D039823:Iridoids / Q000737:chemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018696:Neuroprotective Agents / Q000737:chemistry; D016062:Porosity; D012038:Regeneration; D047030:Sericins / Q000737:chemistry*; D047011:Silk / Q000737:chemistry; D012844:Sincalide / Q000737:chemistry; D017550:Spectroscopy, Fourier Transform Infrared; D020521:Stroke / Q000473:pathology* / Q000628:therapy; D023822:Tissue Engineering / Q000379:methods*
chemical_list: D001672:Biocompatible Materials; D003432:Cross-Linking Reagents; D016207:Cytokines; D020100:Hydrogels; D039823:Iridoids; D018696:Neuroprotective Agents; D047030:Sericins; D047011:Silk; D049452:Green Fluorescent Proteins; C007834:genipin; D005982:Glutathione Transferase; D012844:Sincalide
keywords: hydrogel; neuronal cell carrier; neuroprotection; sericin; stroke