Activation of dendritic cells by crosslinked collagen hydrogels (artificial corneas) varies with their composition

Christine Moelzer, Sucharita P Shankar, May Griffith, Mirazul M Islam, John Forrester, Lucia Kuffova (Corresponding Author)

Research output: Contribution to journalArticle

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Abstract

Activated T cells are known to promote fibrosis, a major complication limiting the range of polymeric hydrogels as artificial corneal implants. As T cells are activated by dendritic cells (DC), minimally activating hydrogels would be optimal. In this study, we evaluated the ability of a series of engineered (manufactured/fabricated) and natural collagen matrices to either activate DC or conversely induce DC apoptosis in vitro. Bone marrow DC were cultured on a series of singly and doubly crosslinked hydrogels (made from recombinant human collagen III [RHCIII] or collagen mimetic peptide [CMP]) or on natural collagen‐containing matrices, MatrigelTM and de‐cellularised mouse corneal stroma. DC surface expression of major histocompatibility complex Class II and CD86 as well as apoptosis markers were examined. Natural matrices induced low levels of DC activation and maintained a “tolerogenic” phenotype. The same applied to singly crosslinked CMP‐PEG gels. RHCIII gels singly crosslinked using either N‐(3‐dimethylaminopropyl)‐N′‐ethylcarbodiimide with the coinitiator N‐hydroxy succinimide (EDC‐NHS) or N‐cyclohexyl‐N‐(2‐morpholinoethyl)carbodiimide metho‐p‐toulenesulfonate with NHS (CMC‐NHS) induced varying levels of DC activation. In contrast, however, RHCIII hydrogels incorporating an additional polymeric network of 2‐methacryloyloxyethyl phosphorylcholine did not activate DC but instead induced DC apoptosis, a phenomenon observed in natural matrices. This correlated with increased DC expression of leukocyte‐associated immunoglobulin‐like receptor‐1. Despite low immunogenic potential, viable tolerogenic DC migrated into and through both natural and manufactured RHCIII gels. These data show that the immunogenic potential of RHCIII gels varies with the nature and composition of the gel. Preclinical evaluation of hydrogel immunogenic/fibrogenic potential is recommended.
Original languageEnglish
Pages (from-to)1528-1543
Number of pages16
JournalJournal of Tissue Engineering and Regenerative Medicine
Volume13
Issue number9
Early online date18 Jul 2019
DOIs
Publication statusPublished - Sep 2019

Fingerprint

Hydrogels
Cornea
Dendritic Cells
Collagen
Gels
Apoptosis
T-Lymphocytes
Corneal Stroma
Carbodiimides
Phosphorylcholine
Hydrogel
Major Histocompatibility Complex
Bone Marrow Cells
Prostheses and Implants
Fibrosis

Keywords

  • activation crosslinkers
  • collagen hydrogels
  • dendritic cells
  • extracellular matrix
  • graft
  • transplantation
  • FIBROSIS
  • IMPLANTS
  • PEPTIDE
  • RECOMBINANT HUMAN COLLAGEN
  • TRANSPLANTATION
  • IMMUNE-RESPONSES
  • ALTERNATIVES
  • GENERATION
  • DRAINING LYMPH-NODE
  • EXPRESSION

Cite this

Activation of dendritic cells by crosslinked collagen hydrogels (artificial corneas) varies with their composition. / Moelzer, Christine; Shankar, Sucharita P; Griffith, May; Islam, Mirazul M; Forrester, John; Kuffova, Lucia (Corresponding Author).

In: Journal of Tissue Engineering and Regenerative Medicine, Vol. 13, No. 9, 09.2019, p. 1528-1543.

Research output: Contribution to journalArticle

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abstract = "Activated T cells are known to promote fibrosis, a major complication limiting the range of polymeric hydrogels as artificial corneal implants. As T cells are activated by dendritic cells (DC), minimally activating hydrogels would be optimal. In this study, we evaluated the ability of a series of engineered (manufactured/fabricated) and natural collagen matrices to either activate DC or conversely induce DC apoptosis in vitro. Bone marrow DC were cultured on a series of singly and doubly crosslinked hydrogels (made from recombinant human collagen III [RHCIII] or collagen mimetic peptide [CMP]) or on natural collagen‐containing matrices, MatrigelTM and de‐cellularised mouse corneal stroma. DC surface expression of major histocompatibility complex Class II and CD86 as well as apoptosis markers were examined. Natural matrices induced low levels of DC activation and maintained a “tolerogenic” phenotype. The same applied to singly crosslinked CMP‐PEG gels. RHCIII gels singly crosslinked using either N‐(3‐dimethylaminopropyl)‐N′‐ethylcarbodiimide with the coinitiator N‐hydroxy succinimide (EDC‐NHS) or N‐cyclohexyl‐N‐(2‐morpholinoethyl)carbodiimide metho‐p‐toulenesulfonate with NHS (CMC‐NHS) induced varying levels of DC activation. In contrast, however, RHCIII hydrogels incorporating an additional polymeric network of 2‐methacryloyloxyethyl phosphorylcholine did not activate DC but instead induced DC apoptosis, a phenomenon observed in natural matrices. This correlated with increased DC expression of leukocyte‐associated immunoglobulin‐like receptor‐1. Despite low immunogenic potential, viable tolerogenic DC migrated into and through both natural and manufactured RHCIII gels. These data show that the immunogenic potential of RHCIII gels varies with the nature and composition of the gel. Preclinical evaluation of hydrogel immunogenic/fibrogenic potential is recommended.",
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note = "ACKNOWLEDGEMENTS We are grateful to the Iain Fraser Flow Cytometry Centre, the Microscopy and Histology Facility, and the Medical Research Facility at the University of Aberdeen. This work was supported by the Royal College of Surgeons of Edinburgh, UK, and Saving Sight in Grampian/Development Trust of the University of Aberdeen, UK. Funding Information: Saving Sight in Grampian/Development Trust of the University of Aberdeen, UK Royal College of Surgeons of Edinburgh, UK",
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AU - Forrester, John

AU - Kuffova, Lucia

N1 - ACKNOWLEDGEMENTS We are grateful to the Iain Fraser Flow Cytometry Centre, the Microscopy and Histology Facility, and the Medical Research Facility at the University of Aberdeen. This work was supported by the Royal College of Surgeons of Edinburgh, UK, and Saving Sight in Grampian/Development Trust of the University of Aberdeen, UK. Funding Information: Saving Sight in Grampian/Development Trust of the University of Aberdeen, UK Royal College of Surgeons of Edinburgh, UK

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N2 - Activated T cells are known to promote fibrosis, a major complication limiting the range of polymeric hydrogels as artificial corneal implants. As T cells are activated by dendritic cells (DC), minimally activating hydrogels would be optimal. In this study, we evaluated the ability of a series of engineered (manufactured/fabricated) and natural collagen matrices to either activate DC or conversely induce DC apoptosis in vitro. Bone marrow DC were cultured on a series of singly and doubly crosslinked hydrogels (made from recombinant human collagen III [RHCIII] or collagen mimetic peptide [CMP]) or on natural collagen‐containing matrices, MatrigelTM and de‐cellularised mouse corneal stroma. DC surface expression of major histocompatibility complex Class II and CD86 as well as apoptosis markers were examined. Natural matrices induced low levels of DC activation and maintained a “tolerogenic” phenotype. The same applied to singly crosslinked CMP‐PEG gels. RHCIII gels singly crosslinked using either N‐(3‐dimethylaminopropyl)‐N′‐ethylcarbodiimide with the coinitiator N‐hydroxy succinimide (EDC‐NHS) or N‐cyclohexyl‐N‐(2‐morpholinoethyl)carbodiimide metho‐p‐toulenesulfonate with NHS (CMC‐NHS) induced varying levels of DC activation. In contrast, however, RHCIII hydrogels incorporating an additional polymeric network of 2‐methacryloyloxyethyl phosphorylcholine did not activate DC but instead induced DC apoptosis, a phenomenon observed in natural matrices. This correlated with increased DC expression of leukocyte‐associated immunoglobulin‐like receptor‐1. Despite low immunogenic potential, viable tolerogenic DC migrated into and through both natural and manufactured RHCIII gels. These data show that the immunogenic potential of RHCIII gels varies with the nature and composition of the gel. Preclinical evaluation of hydrogel immunogenic/fibrogenic potential is recommended.

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KW - RECOMBINANT HUMAN COLLAGEN

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