Wound Administration of M2-Polarized Macrophages Does Not Improve Murine Cutaneous Healing Responses
Open accessAbstract
Macrophages play a crucial role in all stages of cutaneous wound healing responses and dysregulation of macrophage function can result in derailed wound repair. The phenotype of macrophages is influenced by the wound microenvironment and evolves during healing from a more pro-inflammatory (M1) profile in early stages, to a less inflammatory pro-healing (M2) phenotype in later stages of repair. The aim of the current study was to investigate the potential of exogenous administration of M2 macrophages to promote wound healing in an experimental mouse model of cutaneous injury. Bone marrow derived macrophages were stimulated in-vitro with IL-4 or IL-10 to obtain two different subsets of M2-polarized cells, M2a or M2c respectively. Polarized macrophages were injected into full-thickness excisional skin wounds of either C57BL/6 or diabetic db/db mice. Control groups were injected with non-polarized (M0) macrophages or saline. Our data indicate that despite M2 macrophages exhibit an anti-inflammatory phenotype in-vitro, they do not improve wound closure in wild type mice while they delay healing in diabetic mice. Examination of wounds on day 15 post-injury indicated delayed re-epithelialization and persistence of neutrophils in M2 macrophage treated diabetic wounds. Therefore, topical application of ex-vivo generated M2 macrophages is not beneficial and contraindicated for cell therapy of skin wounds.
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Timing of release is crucial where, especially in older organisms, the balance between M1 and M2 polarization may be dysregulated and impairs wound healing.
“Timing of release is crucial where, especially in older organisms, the balance between M1 and M2 polarization may be dysregulated and impairs wound healing.[ 223 ]”
From Unraveling and Harnessing the Immune Response at the Cell–Biomaterial Interface for Tissue Engineering Purposes (2024) · cites this paper as [223]
The Introduction (page unavailable) links an incomplete M1-to-M2 switch to chronic non-healing wounds, and the Discussion (page unavailable) suggests that administering M2 macrophages during the early inflammatory phase may disrupt a balance needed for healing. The paper does not establish this specifically in older organisms or test the timing of a controlled release. (LLM, conf=0.86)
Experimental — accuracy not yet measuredAddition of macrophages induced with IL-4 or IL-10 delays wound healing in db/db mice.
“It is also consistent with the observation that the addition of macrophages induced with IL-4 or IL-10 delays wound healing in db/db mice.107”
From The Innate Immune System in Acute and Chronic Wounds (2016) · cites this paper as [107]
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- Authors
- Jetten, N., Roumans, N., Gijbels, M. J., Romano, A., Post, M. J., de Winther, M. P. J., van der Hulst, R. R. W. J., & Xanthoulea, S.
- Affiliations
- Maastricht University (NL)
- Maastricht University Medical Centre (NL)
- Corresponding author
- Xanthoulea, Sofia
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2014-07-28
- Volume
- 9
- Issue
- 7
- Pages
- e102994
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC4113363
- OpenAlex
- W2036736332
- Cited by
- 162
- References
- 40
- Citations by year
- 2026: 5 · 2025: 15 · 2024: 20 · 2023: 16 · 2022: 24 · 2021: 10 · 2020: 13 · 2019: 18 · 2018: 11 · 2017: 14 · 2016: 10 · 2015: 4 · 2014: 2
- FWCI
- 9.68
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Research Publications (Maastricht University) (publishedVersion, cc-by)
- Pure Amsterdam UMC (publishedVersion, other-oa)
- Data Archiving and Networked Services (DANS) (submittedVersion, other-oa)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Research Publications (Maastricht University) (submittedVersion, other-oa)
- Funders
- Universiteit Maastricht
- Maastricht Universitair Medisch Centrum
- Topics
- Health Sciences › Medicine › Rehabilitation › Wound Healing and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Life Sciences › Immunology and Microbiology › Immunology › Macrophage Migration Inhibitory Factor
- Keywords
- M2 macrophages, macrophage polarization, skin wound healing, diabetic wounds, IL-4, IL-10, re-epithelialization, neutrophils, db/db mice, full-thickness skin wounds
- MeSH terms
- Animals, Diabetes Mellitus, Experimental, Disease Models, Animal, Female, Immunohistochemistry, Macrophages, Skin, Wound Healing, Gene Expression, Genes, Reporter, Mice
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