Regulation of extracellular matrix assembly and structure by hybrid M1/M2 macrophages
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Abstract
Aberrant extracellular matrix (ECM) assembly surrounding implanted biomaterials is the hallmark of the foreign body response, in which implants become encapsulated in thick fibrous tissue that prevents their proper function. While macrophages are known regulators of fibroblast behavior, how their phenotype influences ECM assembly and the progression of the foreign body response is poorly understood. In this study, we used in vitro models with physiologically relevant macrophage phenotypes, as well as controlled release of macrophage-modulating cytokines from gelatin hydrogels implanted subcutaneously in vivo to investigate the role of macrophages in ECM assembly. Primary human macrophages were polarized to four distinct phenotypes, which have each been associated with fibrosis, including pro-inflammatory M1, pro-healing M2, and a hybrid M1/M2, generated by exposing macrophages to M1-and M2-promoting stimuli simultaneously. Additionally, macrophages were first polarized to M1 and then to M2 (M1→M2) to generate a phenotype typically observed during normal wound healing. Human dermal fibroblasts that were cultured in macrophage-conditioned media upregulated numerous genes involved in regulation of ECM assembly, especially in M2-conditioned media. Hybrid M1/M2 macrophage-conditioned media caused fibroblasts to produce a matrix with thicker and less aligned fibers, while M2 macrophage-conditioned media caused the formation of a more aligned matrix with thinner fibers. Gelatin methacrylate hydrogels containing interleukin-4 (IL4) and IL13-loaded poly(lactic-co-glycolic acid) (PLGA) microparticles were designed to promote the M2 phenotype in a murine subcutaneous in vivo model. NanoString multiplex gene expression analysis of hydrogel explants showed that hydrogels without cytokines caused mostly M1 phenotype markers to be highly expressed at an early time point (3 days), but the release of IL4+IL13 promoted upregulation of M2 markers and genes associated with regulation of ECM assembly, such as Col5a1 and Col6a1. Biochemical analysis and second harmonic generation microscopy showed that the release of IL4+IL13 increased total sulfated glycosaminoglycan content and decreased fibril alignment, which is typically associated with less fibrotic tissue. Together, these results show that hybrid M1/M2 macrophages regulate ECM assembly, and that shifting the balance towards M2 may promote architectural and compositional changes in ECM with enhanced potential for downstream remodeling.
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Overactive M1 macrophages can activate M2 macrophages intensively, resulting in a subsequent proliferation of fibrous tissues surrounding the scaffold and aggravating the formation of foreign body granulomas.
“Besides, overactive M1 macrophages can also activate M2 macrophages intensively, resulting in a subsequent proliferation of fibrous tissues surrounding the scaffold and aggravating the formation of foreign body granulomas (Anderson et al., 2008;Witherel et al., 2021).”
From Nanosilver alleviates foreign body reaction and facilitates wound repair by regulating macrophage polarization (2023) · cites this paper as Witherel et al., 2021
The Introduction links both M1- and M2-associated signals to fibrosis, and the Results (Effects of IL4+IL13 release on fibrous capsule properties; page unavailable) report increased matrix deposition around hydrogels given M2-promoting cytokines. But the paper does not show overactive M1 macrophages activating M2 macrophages or establish that this sequence aggravates foreign body granulomas; the reported increase in capsule thickness was only a trend. (LLM, conf=0.88)
Experimental — accuracy not yet measuredIn the absence of NAg, long-term abnormal inflammation of the wound tissue may occur resulting in granulomas, infection, or necrosis, eventually leading to the failure of tissue repair.
“Hence, in the absence of NAg, long-term abnormal inflammation of the wound tissue may occur resulting in granulomas, infection, or necrosis, eventually leading to the failure of tissue repair (Chu et al., 2020;Witherel et al., 2021).”
From Nanosilver alleviates foreign body reaction and facilitates wound repair by regulating macrophage polarization (2023) · cites this paper as Witherel et al., 2021
The Introduction (page not provided) says that fibrosis can occur when wound healing fails to resolve, supporting the general link between unresolved healing and pathological tissue changes. It does not address the absence of NAg or say that prolonged inflammation causes granulomas, infection, or necrosis leading to failed repair. (LLM, conf=0.86)
Experimental — accuracy not yet measuredM2 macrophages are induced by IL-4 and IL-13 to upregulate IL-10 and FIZZ-1 and secrete less IL-12 and nitric oxide, weakening the phagocytosis of pathogenic microorganisms.
“M2 macrophages are induced by IL-4 and IL-13 to upregulate IL-10 and FIZZ-1 and secrete less IL-12 and nitric oxide, weakening the phagocytosis of pathogenic microorganisms (Locati et al., 2020;Yunna et al., 2020;Witherel et al., 2021).”
From Nanosilver alleviates foreign body reaction and facilitates wound repair by regulating macrophage polarization (2023) · cites this paper as Witherel et al., 2021
The Results (Preparation of hybrid macrophage phenotypes) and Discussion say that IL-4 and IL-13 promote M2 polarization. The paper does not report the claimed increase in IL-10 and FIZZ-1, decrease in IL-12 and nitric oxide, or weakened phagocytosis of pathogens. The Discussion instead distinguishes IL-10-stimulated M2c macrophages from the IL-4/IL-13-stimulated M2a phenotype studied here. (LLM, conf=0.88)
Experimental — accuracy not yet measuredAligned patterns with micron-level feature sizes promote M2 macrophage differentiation through forced alignment.
“Aligned patterns with feature sizes in the micron level were shown to promote M2 macrophage differentiation through forced alignment”
From Modeling mechanical activation of macrophages during pulmonary fibrogenesis for targeted anti-fibrosis therapy (2024) · cites this paper as [42]
Irregular topographies with dimensions similar to aligned patterns produce circularly spreading macrophages with M1 characteristics.
“irregular topographies with similar dimensions produce circularly spreading macrophages with M1 characteristics”
From Modeling mechanical activation of macrophages during pulmonary fibrogenesis for targeted anti-fibrosis therapy (2024) · cites this paper as [42]
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Flagged first, then by citations
Cited by
Sorted by citations
Xu, Y., Ying, L., Lang, J. K., Hinz, B., & Zhao, R. (2024) · Science Advances · doi:10.1126/sciadv.adj9559 · Cited by 67 · see citing works
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You, C., Zhu, Z., Wang, S., Wang, X., Han, C., & Shao, H. (2023) · Journal of Zhejiang University SCIENCE B · doi:10.1631/jzus.b2200447 · Cited by 20 · see citing works
- Authors
- Witherel, C. E., Sao, K., Brisson, B. K., Han, B., Volk, S. W., Petrie, R. J., Han, L., & Spiller, K. L.
- Affiliations
- Drexel University (US)
- University of Pennsylvania (US)
- Corresponding author
- Spiller, Kara L.
- ORCID
- Venue
- Biomaterials
- Publisher
- Elsevier BV
- Published
- 2021-02
- Volume
- 269
- Pages
- 120667
- ISSN
- 0142-9612 (ISSN-L)
- PMC
- PMC7870567
- OpenAlex
- W3119621790
- Cited by
- 212
- References
- 84
- Citations by year
- 2026: 29 · 2025: 41 · 2024: 43 · 2023: 45 · 2022: 37 · 2021: 14 · 2020: 1
- FWCI
- 13.44
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- www.elsevier.com/tdm/userlicense/1.0/ (tdm)
- www.elsevier.com/legal/tdmrep-license (tdm)
- www.elsevier.com/open-access/userlicense/1.0/ (am, 345 d)
- doi.org/10.15223/policy-017 (stm-asf)
- doi.org/10.15223/policy-037 (stm-asf)
- doi.org/10.15223/policy-012 (stm-asf)
- doi.org/10.15223/policy-029 (stm-asf)
- doi.org/10.15223/policy-004 (stm-asf)
- Locations
- Biomaterials (acceptedVersion)
- bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institute of General Medical Sciences
- National Heart, Lung, and Blood Institute
- National Science Foundation
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Health Sciences › Medicine › Surgery › Tissue Engineering and Regenerative Medicine
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Keywords
- extracellular matrix assembly, macrophage polarization, foreign body reaction, implant encapsulation, fibrosis, dermal fibroblasts, IL-4, IL-13, gelatin methacryloyl hydrogel, PLGA microspheres, glycosaminoglycans, fibril alignment
- MeSH terms
- Animals, Biocompatible Materials, Extracellular Matrix, Humans, Macrophages, Phenotype, Cytokines, Hydrogels, Mice
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
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