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Reciprocal Macrophage-MSC Crosstalk Drives Immunomodulatory and Regenerative Phenotypes in a Mineralized Collagen Scaffold
   

Reciprocal Macrophage-MSC Crosstalk Drives Immunomodulatory and Regenerative Phenotypes in a Mineralized Collagen Scaffold

Vasiliki Kolliopoulos, Maxwell Polanek, Hashni E Vidana Gamage, Melisande Wong Yan Ling, Aleczandria Tiffany, Erik R Nelson, Kara L Spiller Brendan A C Harley
Journal of biomedical materials research. Part A, v 114(6), e70106
Jun 2026
: https://doi.org/10.1002/jbm.a.70106
: 42244308

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url
https://doi.org/10.1002/jbm.a.70106
Published, Version of Record (VoR)
Animals Calcification, Physiologic - drug effects Cell Communication - drug effects Coculture Techniques Collagen - chemistry Collagen - pharmacology Humans Immunomodulation - drug effects Macrophages - cytology Macrophages - drug effects Macrophages - immunology Macrophages - metabolism Mesenchymal Stem Cells - cytology Mesenchymal Stem Cells - drug effects Mesenchymal Stem Cells - immunology Osteogenesis Tissue Scaffolds - chemistry Cell Differentiation Phenotype
Critical sized craniomaxillofacial bone defects do not heal naturally and often exhibit chronic inflammatory responses that restrict regeneration. It is increasingly apparent that biomaterials must facilitate dynamic crosstalk between immune cells, such as macrophages, and osteoprogenitors to resolve inflammation and accelerate regeneration. Here, we evaluate interactions between macrophages in a neutral (M0) or pro-inflammatory (M1) state with mesenchymal stem cells (MSCs) in a basal or licensed state within a mineralized collagen scaffold. We reveal that MSC-macrophage crosstalk influences significant changes in osteoprogenitor cell differentiation and immune cell polarization. Notably, crosstalk between MSCs and macrophages drives an early-stage inflammatory response, which enhances the immunomodulatory activity of MSCs via secretion of IL-6, an effect that is heightened for already licensed MSCs. The presence of macrophages in the co-cultures upregulated osteogenic (ALPL, BMP2, COL1A2, and RUNX2) and angiogenic genes (ANGPT1) in basal MSC groups. Further, MSC-macrophage interactions subsequently drive increased M2-like macrophage polarization as early as 7 days of culture, as indicated by surface marker expression. These findings show that biomaterial scaffolds can be leveraged as mediators of MSC-mediated immunomodulation with an emphasis on achieving early-stage pro-inflammatory phenotypes that drive subsequent macrophage polarization and markers of increased regenerative potency.
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