Journal
ACTA BIOMATERIALIA
Volume 88, Issue -, Pages 162-180Publisher
ELSEVIER SCI LTD
DOI: 10.1016/j.actbio.2019.02.004
Keywords
Material immunomodulation; Stem cell homing; In situ tissue regeneration; Drug delivery; Periodontal tissue engineering
Funding
- National Key Research and Development Program of China [2018YFC1105204]
- National Natural Science Foundation of China [81530050]
- Shaanxi Key Scientific and Technological Innovation Team [2017KCT-32]
- Changjiang Scholars Program of Ministry of Education of the People's Republic of China
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Recently, we found that although high-stiffness matrices stimulated osteogenic differentiation of bone marrow-derived stromal cells (BMSC5), the macrophages (M phi s) in high-stiffness transglutaminase cross linked gelatins (TG-gels) tended to undergo M1 polarization and hence compromised cell osteogenesis. In this study, we hypothesized that the copresentation of interleukin (IL)-4 and stromal cell-derived factor (SDF)-1 alpha in high-stiffness TG-gels may enhance periodontal regeneration by modulating M phi polarization and promoting endogenous stem cell recruitment. We found that M phi s were more likely to polarize toward an immunomodulatory M2 state in the presence of IL-4 and hence positively influence the osteogenic differentiation of BMSCs when these cells coexisted in either indirect or direct co-culture systems. In cell migration assays, BMSC5 exhibited an enhanced capability to move toward gels containing SDF-1 alpha, and more cells could be recruited into the three-dimensional matrix of TG-gels. When TG-gels containing IL-4 and/or SDF-1 alpha were used to repair periodontal defects, more new bone (MicroCT) was formed in animals that received the dual cytokine-loaded transplants at 4 weeks postsurgery. M phi s were recruited to all the transplanted gels, and after one week, more M1-phenotype cells were found in the groups without IL-4, while the presence of IL-4 was more likely to result in M2 polarization (immunofluorescence staining). When the tissue biopsies were histologically examined, the TG-gels containing both IL-4 and SDF-1 alpha led to a generally satisfactory regeneration with respect to attachment recovery (epithelial and connective tissue) and hybrid tissue regeneration (bone, periodontal ligament and cementum). Our data suggest that the incorporation of IL-4 into high-stiffness TG-gels may promote the M2 polarization of M phi s and that SDF-1 alpha can be applied to guide endogenous cell homing. Overall, building capacity for M phi modulation and cell recruitment in high-stiffness hydrogels represents a simple and effective strategy that can support high levels of periodontal tissue regeneration. Statement of significance The development of hydrogel-based regenerative therapies centered on the mobilization and stimulation of native cells for therapeutics opens a window toward realizing periodontal endogenous regeneration. In the present study, the parallel use of immunomodulatory and homing factors in high-stiffness hydrogel materials is shown to induce stem cell homing, modulate cell differentiation and indeed induce regrowth of the periodontium. We found that incorporation of interleukin (IL)-4 in high-stiffness TG-gels coaxed macrophages to polarize into M2 phenotypes, and stromal cell-derived factor (SDF)-1 alpha could be applied to direct endogenous cell homing. Hence, we present for the first time a clinically relevant strategy based on macrophage modulation and host cell recruitment that can support high levels of periodontal tissue regeneration. (C) 2019 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
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