title: Stromal Tissue Rigidity Promotes Mesenchymal Stem Cell-Mediated Corneal Wound Healing Through the Transforming Growth Factor β Signaling Pathway.
abstract: The healing of a corneal epithelial defect is essential for preventing infectious corneal ulcers and subsequent blindness. We previously demonstrated that mesenchymal stem cells (MSCs) in the corneal stroma, through a paracrine mechanism, yield a more favorable therapeutic benefit for corneal wound re-epithelialization than do MSCs in the corneal epithelium. In this study, MSCs were grown on a matrix with the rigidity of the physiological human vitreous (1 kPa), corneal epithelium (8 kPa), or corneal stroma (25 kPa) for investigating the role of corneal tissue rigidity in MSC functions regarding re-epithelialization promotion. MSC growth on a 25-kPa dish significantly promoted the wound healing of human corneal epithelial (HCE-T) cells. Among growth factors contributing to corneal epithelial wound healing, corneal stromal rigidity selectively enhanced transforming growth factor-beta (TGF-β) secretion from MSCs. Inhibitors of TGF-β pan receptor, TGF-β receptor 1, and Smad2 dose dependently abrogated MSC-mediated HCE-T wound healing. Furthermore, MSCs growth on a matrix with corneal stromal rigidity enhanced the ability of themselves to promote corneal re-epithelialization by activating matrix metalloproteinase (MMP) expression and integrin β1 production in HCE-T cells through TGF-β signaling pathway activation. Smad2 activation resulted in the upregulation of MMP-2 and -13 expression in HCE-T cells, whereas integrin β1 production favored a Smad2-independent TGF-β pathway. Altogether, we conclude that corneal stromal rigidity is a critical factor for MSC-induced promotion of corneal re-epithelialization. The activation of the TGF-β signaling pathway, which maintains the balance between integrin and MMP expression, in HCE-T cells is the major pathway responsible for MSC-mediated wound healing. Stem Cells 2016;34:2525-2535.
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan.|Department of Ophthalmology, Taipei Tzu Chi Hospital, The Buddhist Tzu Chi Medical Foundation, New Taipei City, Taiwan.
authors.forename: Yun-Hsiang
authors.initials: YH
authors.lastname: Yang
authors.affiliation: Center for Stem Cell Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Ting-Lieh
authors.initials: TL
authors.lastname: Hsieh
authors.affiliation: Center for Stem Cell Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Andrea Tung-Qian
authors.initials: AT
authors.lastname: Ji
authors.affiliation: Center for Stem Cell Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Wei-Tse
authors.initials: WT
authors.lastname: Hsu
authors.affiliation: Center for Stem Cell Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan.
authors.forename: Chia-Yu
authors.initials: CY
authors.lastname: Liu
authors.affiliation: Department of Orthopaedic Surgery, Taipei City Hospital, Taipei, Taiwan.|Institute of Clinical Medicine, National Yang-Ming University, Taipei, Taiwan.|Stem Cell Research Center, National Yang-Ming University, Taipei, Taiwan.
authors.forename: Oscar Kuang-Sheng
authors.initials: OK
authors.lastname: Lee
authors.affiliation: Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, Taiwan. wh9801@yahoo.com.tw.|Center for Stem Cell Research, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. wh9801@yahoo.com.tw.|Department of Ophthalmology, Wan Fang Hospital, Taipei Medical University, Taipei, Taiwan. wh9801@yahoo.com.tw.
authors.forename: Jennifer Hui-Chun
authors.initials: JH
authors.lastname: Ho
mesh_terms: D002460:Cell Line; D049109:Cell Proliferation; D065306:Corneal Injuries / Q000473:pathology* / Q000628:therapy*; D003319:Corneal Stroma / Q000473:pathology*; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D020782:Matrix Metalloproteinases / Q000378:metabolism; D045164:Mesenchymal Stem Cell Transplantation; D059630:Mesenchymal Stem Cells / Q000166:cytology* / Q000378:metabolism; D062326:Re-Epithelialization; D015398:Signal Transduction; D051899:Smad2 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D015854:Up-Regulation; D014945:Wound Healing
chemical_list: D019012:Integrin beta1; D051899:Smad2 Protein; D016212:Transforming Growth Factor beta; D020782:Matrix Metalloproteinases
keywords: Corneal stroma; Matrix rigidity; Mesenchymal stem cells; Transforming growth factor-β; Wound healing