The DOI matches its Crossref record; 14 of the 14 references it cites were found in a registry or an index.
Differential Roles of Macrophages in Diverse Phases of Skin Repair
Abstract
Influx of macrophages plays a crucial role in tissue repair. However, the precise function of macrophages during the healing response has remained a subject of debate due to their functional dichotomy as effectors of both tissue injury and repair. We tested the hypothesis that macrophages recruited during the diverse phases of skin repair after mechanical injury exert specific functions to restore tissue integrity. For this purpose, we developed a mouse model that allows conditional depletion of macrophages during the sequential stages of the repair response. Depletion of macrophages restricted to the early stage of the repair response (inflammatory phase) significantly reduced the formation of vascularized granulation tissue, impaired epithelialization, and resulted in minimized scar formation. In contrast, depletion of macrophages restricted to the consecutive mid-stage of the repair response (phase of tissue formation) resulted in severe hemorrhage in the wound tissue. Under these conditions, transition into the subsequent phase of tissue maturation and wound closure did not occur. Finally, macrophage depletion restricted to the late stage of repair (phase of tissue maturation) did not significantly impact the outcome of the repair response. These results demonstrate that macrophages exert distinct functions during the diverse phases of skin repair, which are crucial to control the natural sequence of repair events.
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In the citing paper
“In both conditions, progression to the following phases of wound repair fails [83].”
From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [83]
In the citing paper
“Their study shows that when macrophages are absent in the inflammatory phase, re-epithelialization and granulation tissue formation are reduced; whereas depletion of macrophages in the proliferative phase results in haemorrhage [83].”
From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [83]
In the citing paper
“Their study shows that when macrophages are absent in the inflammatory phase, re-epithelialization and granulation tissue formation are reduced; whereas depletion of macrophages in the proliferative phase results in haemorrhage [83].”
From Transition from inflammation to proliferation: a critical step during wound healing (2016) · cites this paper as [83]
In the citing paper
“A recent study showed that depletion of macrophages during the proliferative phase of wound healing resulted in a defective transition to the remodeling phase and impaired healing [106,107].”
From Macrophage polarization: an opportunity for improved outcomes in biomaterials and regenerative medicine (2012) · cites this paper as [106]
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Cited by
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Items 401–500 of 1,005
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Allogeneic mesenchymal stem cells, but not culture modified monocytes, improve burn wound healing
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“Myeloid cells play a central role in wound healing [32], with depletion of these cells resulting in delayed wound healing due to decreased angiogenesis and decreased epithelialisation [33].”
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ResultOrchestration of Mesenchymal Stem/Stromal Cells and Inflammation During Wound Healing
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“At later stages of the inflammatory phase, their profile is switched to a more resolutive phenotype with the secretion of anti-inflammatory and angiogenic factors for progression to tissue repair (8).”
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The NF-κB Pathway: a Focus on Inflammatory Responses in Spinal Cord Injury
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“With the completion of remodeling, macrophages adopt an inactivated phenotype to reduce inflammation, prevent scar formation, and promote wound healing [78, 79].”
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“In addition, it was demonstrated that depletion of macrophages in early inflammatory phase of the healing, significantly reduced GT formation [35].”
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“23,24 Charting the progression of gene expression in single cells over space and time in the wound would yield information on the coordinated behaviors of myriad cell types in an unbiased manner, and how they drive transitions between healing phases.”
BackgroundImpaired wound healing in type 1 diabetes is dependent on 5-lipoxygenase products
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“Depletion of macrophages restricted to the early stage of the repair response (inflammatory phase) significantly reduced the formation of vascularized granulation tissue, impaired epithelialization, and resulted in minimal scar formation [13].”
BackgroundCutaneous Wound Healing in Diabetic Mice Is Improved by Topical Mineralocorticoid Receptor Blockade
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“Finally, macrophage depletion restricted to the late stage of repair did not affect the outcome of the repair response.(34) Therefore, the spontaneous liver injury in the NEMO Ccr2 mice can very likely be explained by the reduction in CCR2þ macrophages that also function in wound healing and tissue regeneration, and a…”
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“Slides were then incubated with 1% monoclonal rat anti-F4/80 (BM8, eBioscience) for labeling of all macrophage types [52,53], and 1% polyclonal goat anti-cluster of differentiation 206 (CD206, R&D Systems) for labeling of alternatively activated “M2” macrophages [9,54] in PBS supplemented with 5% Donkey serum and 0.”
MethodMesenchymal Stem Cell-Macrophage Choreography Supporting Spinal Cord Repair
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“It has also been shown previously in other mouse models that inhibition of angiogenesis and granulation tissue formation during the early stage of repair does not necessarily lead to delayed epithelial closure [29].”
BackgroundMethodInfluentialSelf-citationImplications of pH and Ionic Environment in Chronic Diabetic Wounds: An Overlooked Perspective
Guo, J., Cao, Y., Wu, Q., Zhou, Y.-M., Cao, Y.-H., & Cen, L.-S. (2024) · Clinical Cosmetic and Investigational Dermatology · doi:10.2147/ccid.s485138 · Cited by 50
“69,70”
Macrophage Motility in Wound Healing Is Regulated by HIF-1α via S1P Signaling
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“Some macrophages are long-term tissue residents and play an important role in controlling the repair [27, 28] and regeneration of skin tissue [29].”
BackgroundÖhnstedt, E., Vågesjö, E., Fasth, A., Lofton-Tomenius, H., Dahg, P., Jönsson, S., Tyagi, N., Åström, M., Myktybekova, Z., Ringstad, L., et al. (2023) · EClinicalMedicine · doi:10.1016/j.eclinm.2023.102014 · Cited by 41
Mitochondrial dysfunction and mitophagy: crucial players in burn trauma and wound healing
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Broad-Spectrum Inhibition of the CC-Chemokine Class Improves Wound Healing and Wound Angiogenesis
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“The regulation of these phenotypes has been shown to affect wound functionality and the extent of scar tissue [4].”
BackgroundResultTrypsin, Tryptase, and Thrombin Polarize Macrophages towards a Pro-Fibrotic M2a Phenotype
White, M. J. V., & Gomer, R. H. (2015) · PLoS ONE · doi:10.1371/journal.pone.0138748 · Cited by 48
“Removal of macrophages from a mouse wound by depletion or conditional knockout lowers the amount of scar tissue deposited in the wounds [34], indicating that macrophages play a major role in wound healing [35].”
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Endothelial Heterogeneity in Development and Wound Healing
Gurevich, D., David, D. T., Sundararaman, A., & Patel, J. (2021) · Cells · doi:10.3390/cells10092338 · Cited by 40
Immunological response triggered by metallic 3D printing powders
Tang, J.-C., Luo, J.-P., Huang, Y.-J., Sun, J.-F., Zhu, Z.-Y., Xu, J.-Y., Dargusch, M., & Yan, M. (2020) · Additive manufacturing · doi:10.1016/j.addma.2020.101392 · Cited by 40
Collagen-silica nanocomposites as dermal dressings preventing infection in vivo.
Mebert, A., Alvarez, G., Peroni, R. N., Illoul, C., Hélary, C., Coradin, T., & Desimone, M. (2018) · Materials Science and Engineering C: Materials for Biological Applications · doi:10.1016/j.msec.2018.07.078 · Cited by 40
The Vitamin D Receptor Regulates Tissue Resident Macrophage Response to Injury.
Song, L.-G., Papaioannou, G., Zhao, H., Luderer, H. F., Miller, C. M., Dall’Osso, C., Nazarian, R., Wagers, A., & Demay, M. (2016) · Endocrinology · doi:10.1210/en.2016-1474 · Cited by 40
Schiavinato, A., Keene, D., Wohl, A. P., Corallo, D., Colombatti, A., Wagener, R., Paulsson, M., Bonaldo, P., & Sengle, G. (2016) · Journal of Investigative Dermatology · doi:10.1016/j.jid.2016.02.021 · Cited by 40
“Wounding and harvesting of wound tissue aft r 4 days from injury was performed as previously described (Lucas et al., 2010; Lettmann et al., 2014).”
MethodGassen, N. V., Staels, W., Overmeire, E. V., Groef, S. D., Sojoodi, M., Heremans, Y., Leuckx, G., de Casteele, M. V., Ginderachter, J. A. V., Heimberg, H., et al. (2015) · Stem Cells Translational Medicine · doi:10.5966/sctm.2014-0272 · Cited by 43
Ibrahim, M. M., Bond, J., Bergeron, A., Miller, K. J., Ehanire, T., Quiles, C., Lorden, E. R., Medina, M. A., Fisher, M., Klitzman, B., et al. (2014) · Wound Repair and Regeneration · doi:10.1111/wrr.12238 · Cited by 40
“Macrophages have a large influence on scarring by removing debris and pathogens, and secreting pro-healing cytokines and growth factors.(9) By the third postoperative day, blood flow is established through these anastomotic connections, and fibroblasts have begun to migrate in from the surrounding tissue, first into t…”
Orf virus IL‐10 accelerates wound healing while limiting inflammation and scarring
Wise, L. M., Stuart, G. S., Real, N. C., Fleming, S., & Mercer, A. (2014) · Wound Repair and Regeneration · doi:10.1111/wrr.12169 · Cited by 40
“One study that utilized a mouse model, in which macrophages were depleted at distinct phases of the repair process, showed an early infiltration of macrophages into the wound site results in a vascularized granulation tissue associated with myofibroblast differentiation and wound contraction, leading to accelerated wo…”
BackgroundSherrill, J. D., Finlay, D., Binder, R. L., Robinson, M., Wei, X., Tiesman, J., Flagler, M., Zhao, W.-Z., Miller, C. M., Loftus, J. M., et al. (2021) · bioRxiv · doi:10.1371/journal.pone.0260095 · Cited by 39
“For instance, in mouse models of acute wound healing, macrophages have been shown to have critical roles in the early and midphase inflammation and tissue repair responses, respectively, but are dispensable for tissue maturation in the late phase [69].”
BackgroundMitochondrial dysfunction and potential mitochondrial protectant treatments in tendinopathy
Zhang, X.-Y., Eliasberg, C. D., & Rodeo, S. (2021) · Annals of the New York Academy of Sciences · doi:10.1111/nyas.14599 · Cited by 39
Trophic Factors in Inflammation and Regeneration: The Role of MANF and CDNF
Sousa‐Victor, P., Jasper, H., & Neves, J. (2018) · Frontiers in Physiology · doi:10.3389/fphys.2018.01629 · Cited by 38
“In multiple systems, deregulation of this timely transition from pro-inflammatory to pro-repair cytokine production compromises regenerative success (Arnold et al., 2007; Lucas et al., 2010; Perdiguero et al., 2011).”
BackgroundMacrophage‐derived GPNMB accelerates skin healing
da Silva, W. N., Prazeres, P. H. D. M., Paiva, A. E., Lousado, L., Turquetti, A. D. O. M., Barreto, R. D. S. N., de Alvarenga, É. C., Miglino, M. A., Gonçalves, R., Mintz, A., et al. (2018) · Experimental Dermatology · doi:10.1111/exd.13524 · Cited by 41
The potential role of platelets in the consensus molecular subtypes of colorectal cancer
Lam, M. S., Roszik, J., Marie, P. K., Davis, J. S., Morris, J. S., Kopetz, S., & Menter, D. G. (2017) · Cancer and Metastasis Reviews · doi:10.1007/s10555-017-9678-9 · Cited by 41
Scar‐free cutaneous wound healing in the leopard gecko, Eublepharis macularius
Peacock, H. M., Gilbert, E. A. B., & Vickaryous, M. K. (2015) · Journal of Anatomy · doi:10.1111/joa.12368 · Cited by 36
“By comparison, similarly-sized scarring wounds require 1–2 weeks to develop a complete wound epithelium (Coulombe, 1997; Galiano et al. 2004; Lucas et al. 2010; Chen et al. 2014).”
BackgroundExploiting genomics and natural genetic variation to decode macrophage enhancers
Romanoski, C. E., Link, V. M., Heinz, S., & Glass, C. K. (2015) · Trends in Immunology · doi:10.1016/j.it.2015.07.006 · Cited by 35
“Macrophages are phagocytic cells of the innate immune system that reside in all tissues of the body and play key roles in responding to infection and injury through signaling downstream of pattern recognition receptors [1, 2] [3].”
BackgroundKlose, A., Zigrino, P., & Mauch, C. (2013) · The American Journal of Pathology · doi:10.1016/j.ajpath.2012.11.028 · Cited by 38
Homeostasis, regeneration and tumour formation in the mammalian epidermis
Belokhvostova, D., Berzanskyte, I., Cujba, A.-M., Jowett, G. M., Marshall, L., Prüller, J., & Watt, F. M. (2018) · The International Journal of Developmental Biology · doi:10.1387/ijdb.170341fw · Cited by 46
“Whilst macrophages in the early stages of healing control the level of scar formation, and depletion of this population results in improved healing and reduced scar formation, depletion of mid stage macrophages causes impaired tissue maturation and wound closure (Lucas et al., 2010).”
InfluentialThe Communication from Immune Cells to the Fibroblasts in Keloids: Implications for Immunotherapy
Zhang, X., Wu, X., & Li, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms242015475 · Cited by 39
“M1 could promote inflammation, eradicate invasive microbes, and promote type I immune responses [24].”
BackgroundRisser, G. E., Machour, M., Hernaez‐Estrada, B., Li, D., Levenberg, S., & Spiller, K. L. (2023) · Biomaterials · doi:10.1016/j.biomaterials.2023.122095 · Cited by 37
Jiang, L., Yang, X.-F., Zhang, Y., He, D., Gao, Y.-J., Lü, K., Hao, Y., Gao, Y., Lu, D., Jin, X., et al. (2022) · Biomaterials Advances · doi:10.1016/j.bioadv.2022.213226 · Cited by 43
Belvedere, R., Bizzarro, V., Parente, L., Petrella, F., & Petrella, A. (2017) · International Journal of Molecular Sciences · doi:10.3390/ijms18081614 · Cited by 37
“Prisma® Skin and sodium mesoglycan showed a strong reduction of macrophage activation, in term of TNF-α production and NO secretion, probably enhancing the switch to an anti-inflammatory phenotype as promoter of angiogenesis and, generally, wound healing closure [52].”
BackgroundRuscitti, P., Cipriani, P., Ciccia, F., Benedetto, P. D., Liakouli, V., Berardicurti, O., Carubbi, F., Guggino, G., Bartolomeo, S. D., Triolo, G., et al. (2016) · Clinical & Experimental Immunology · doi:10.1111/cei.12826 · Cited by 42
Contribution of Invariant Natural Killer T Cells to Skin Wound Healing
Tanno, H., Kawakami, K., Ritsu, M., Kanno, E., Suzuki, A., Kamimatsuno, R., Takagi, N., Miyasaka, T., Ishii, K., Imai, Y., et al. (2015) · American Journal Of Pathology · doi:10.1016/j.ajpath.2015.08.012 · Cited by 39
“During the wound healing, macrophages and fibroblasts are the main source of TGFb and VEGF production.(4,21) These results suggest that iNKT cells may promote collagen deposition, myofibroblast differentiation, and angiogenesis by induction of the production of these cytokines by macrophages and fibroblasts.”
BackgroundDumont, N. A., & Frenette, J. (2012) · American Journal Of Pathology · doi:10.1016/j.ajpath.2012.10.010 · Cited by 38
Collagen Turnover in Wound Repair––A Macrophage Connection
Nissinen, L. M., & Kähäri, V.-M. (2015) · Journal of Investigative Dermatology · doi:10.1038/jid.2015.246 · Cited by 37
“In general, macrophages have a role in all phases of wound healing, and depletion of macrophages results in delayed wound repair, reduced granulation tissue formation, and delayed re-epithelialization and scar deposition (Lucas et al., 2010).”
BackgroundChan, M. W. Y., & Viswanathan, S. (2019) · Cytotherapy · doi:10.1016/j.jcyt.2019.02.002 · Cited by 34
Cellular senescence in tissue repair: every cloud has a silver lining
Yun, M. H. (2018) · The International Journal of Developmental Biology · doi:10.1387/ijdb.180081my · Cited by 44
“In particular the macrophage, an essential cell type recruited to senescent cells, plays critical functions in wound healing (Lucas et al., 2010), muscle regeneration (Ruffell et al., 2009), neurogenesis (Kyritsis et al., 2012) and regeneration of structures such as the salamander limb (Godwin et…”
BackgroundAnti-inflammatory and burn injury wound healing properties of the shell of Haliotis diversicolor
Chen, Z.-C., Wu, S.-Y. S., Su, W.-Y., Lin, Y.-C., Lee, Y.-H., Wu, W., Chen, C., & Wen, Z. (2016) · BMC Complementary and Alternative Medicine · doi:10.1186/s12906-016-1473-6 · Cited by 41
Finley, P. J., DeClue, C. E., Sell, S. A., DeBartolo, J. M., & Shornick, L. P. (2015) · Advances in Wound Care · doi:10.1089/wound.2015.0676 · Cited by 36
“Depletion of macrophages during mid-phase healing resulted in hemorrhage in the wound tissue.(2) In addition to the phase of wound healing, the role of the macrophage may depend on the subtype of macrophage that is present in each wound.”
BackgroundCD44 signaling in skin wound healing and regeneration
Guan, A. Y., Chen, Y., Tseng, S. C. G., & Lin, Q. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-06913-5 · Cited by 39
Investigating local and systemic intestinal signalling in health and disease with Drosophila
Medina, A. B., Bellec, K., Polcowñuk, S., & Cordero, J. B. (2022) · Disease Models & Mechanisms · doi:10.1242/dmm.049332 · Cited by 38
Cifuentes, A., Gómez‐Gil, V., Ortega, M. A., Asúnsolo, Á., Coca, S., Román, J. S., Álvarez‐Mon, M., Buján, J., & García‐Honduvilla, N. (2020) · Biomedicine & Pharmacotherapy · doi:10.1016/j.biopha.2020.110498 · Cited by 44
Emerging role of dermal compartment in skin pigmentation: comprehensive review
Kapoor, R., Dhatwalia, S., Kumar, R., Rani, S., & Parsad, D. (2020) · Journal of the European Academy of Dermatology and Venereology · doi:10.1111/jdv.16404 · Cited by 36
The regenerative potential of skin and the immune system
Tsepkolenko, A., Цепколенко, В. О., Dash, S., Mishra, A., Bader, A., Melerzanov, A., & Giri, S. (2019) · Clinical Cosmetic and Investigational Dermatology · doi:10.2147/ccid.s196364 · Cited by 47
β2-Adrenoceptor Activation Modulates Skin Wound Healing Processes to Reduce Scarring
Provost, G. S. L., & Pullar, C. E. (2014) · Journal of Investigative Dermatology · doi:10.1038/jid.2014.312 · Cited by 33
“M2 macrophages promote wound angiogenesis (Lucas et al. , 2010) and macrophages are necessary to stimulate and fuse tip cells at the leading edge of angiogenic sprouts (Fantin et al. , 2010).”
EGCG modified small intestine submucosa promotes wound healing through immunomodulation
Nie, R., Zhang, Q., Tan, J., Feng, Z.-Y., Huang, K., Sheng, N., Jiang, Y., Song, Y., Zou, C., Zhao, L.-M., et al. (2023) · Composites Part B Engineering · doi:10.1016/j.compositesb.2023.111005 · Cited by 39
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Microparticles Decorated with Cell‐Instructive Surface Chemistries Actively Promote Wound Healing
Latif, A., Fisher, L. E., Dundas, A. A., Crucitti, V. C., Imir‐Tekneci, Z., Lawler, K., Pappalardo, F., Muir, B. W., Wildman, R. D., Irvine, D. J., et al. (2022) · Advanced Materials · doi:10.1002/adma.202208364 · Cited by 40
Tavakoli, S., Kisiel, M. A., Biedermann, T., & Klar, A. S. (2022) · Biomedicines · doi:10.3390/biomedicines10010118 · Cited by 42
“Both M1 and M2 cells exert specific functions in this process [9,240].”
BackgroundWelcker, D., Stein, C., Feitosa, N. M., Armistead, J., Zhang, J.-L., Lütke, S., Kleinridders, A., Brüning, J., Eming, S., Sengle, G., et al. (2021) · Scientific Reports · doi:10.1038/s41598-021-96824-4 · Cited by 35
Self-citationSipka, T., Peroceschi, R., Hassan-Abdi, R., Groß, M., Ellett, F. E., Begon‐Pescia, C., Gonzalez, C., Lutfalla, G., & Chi, M. N. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.636585 · Cited by 47
Gawriluk, T. R., Simkin, J., Hacker, C. K., Kimani, J. M., Kiama, S. G., Ezenwa, V. O., & Seifert, A. W. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.01695 · Cited by 51
“Macrophages are required for normal wound healing (26, 28, 78) and similarly required for complex tissue regeneration (11, 13, 16, 79).”
BackgroundChen, Z.-C., Ceballos-Francisco, D., Guardiola, F., & Esteban, M. (2020) · Scientific Reports · doi:10.1038/s41598-020-68024-z · Cited by 35
Ferreira, D. W., Ulecia-Morón, C., Alvarado-Vazquez, P. A., Cunnane, K., Moracho-Vilrriales, C., Grosick, R. L., Cunha, T. M., & Romero-Sandoval, E. A. (2019) · Immunobiology · doi:10.1016/j.imbio.2019.10.011 · Cited by 40
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“Accumulating evidence has demonstrated that macrophages could promote tissue fibrosis, and depletion of macrophages lowers the amount of scar tissue deposited in the wounds, indicating that macrophages play a major role in wound healing, and in the progression of fibrosis (Leibovich and Ross, 1975; Duffield et al., 20…”
BackgroundFractional Factorial Design to Investigate Stromal Cell Regulation of Macrophage Plasticity
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“While the M1 macrophage stage is an essential component of normal wound healing (Lucas et al., 2010; Nemeth et al., 2009), most observed macrophage pathologies manifest in an inappropriate transition of M1 to M2 phenotypes.”
Background
Metadata
- Authors
- Lucas, T., Waisman, A., Ranjan, R., Roes, J., Krieg, T., Müller, W., Roers, A., & Eming, S. A.
- Affiliations
- Department of Dermatology
- Johannes Gutenberg University Mainz (DE)
- University College London (GB)
- University of Cologne (DE)
- University of Manchester (GB)
- Technische Universität Dresden (DE)
- Venue
- The Journal of Immunology
- Publisher
- Oxford University Press (OUP)
- Published
- 2010-04-01
- Volume
- 184
- Issue
- 7
- Pages
- 3964-3977
- ISSN
- 0022-1767 (ISSN-L)
- 1550-6606
- OpenAlex
- W2118654016
- Cited by
- 1,205
- References
- 0
- Citations by year
- 2026: 47 · 2025: 71 · 2024: 84 · 2023: 86 · 2022: 110 · 2021: 102 · 2020: 90 · 2019: 76 · 2018: 87 · 2017: 83 · 2016: 73 · 2015: 78 · 2014: 73 · 2013: 66 · 2012: 41
- FWCI
- 47.25
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- The Journal of Immunology (publishedVersion)
- PubMed (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Research Explorer (The University of Manchester) (submittedVersion)
- Funders
- University College London
- Deutsche Forschungsgemeinschaft (SFB829)
- Topics
- Health Sciences › Medicine › Surgery › Wound Healing and Treatments
- Life Sciences › Immunology and Microbiology › Immunology › Immune cells in cancer
- Health Sciences › Medicine › Hepatology › Liver physiology and pathology
- Keywords
- macrophages, skin repair, wound healing, mechanical damage, granulation tissue, re-epithelialization, scar formation, hemorrhage, tissue maturation, wound closure, tissue formation
- MeSH terms
- Animals, Cell Separation, Flow Cytometry, Immunohistochemistry, Macrophages, Mice, Inbred C57BL, Mice, Transgenic, Skin, Skin Physiological Phenomena, Wound Healing, Reverse Transcriptase Polymerase Chain Reaction, Mice
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