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The role of cluster of differentiation 163-positive macrophages in wound healing: a preliminary study and a systematic review

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Abstract

This is a literature assessment of essential information and current knowledge that pertains to the potential role for cluster of differentiation (CD) 163+ macrophages in different wound healing models, including extremely rapid tissue regeneration for regenerative medicine purposes. We intend to focus on the beneficial strategies that activate macrophage performance in order to advance the CD163+ macrophage-based therapy approaches to accelerate wound healing. We conducted an extensive literature search of peer reviewed articles obtained from the PubMed, Google Scholar, Scopus, Web of Science, and Cochrane databases by using the keywords “wound healing, CD163+ macrophages, diabetes mellitus, and burn.” There were no limitations in terms of publication date. Our search resulted in 300 papers from which 17 articles were screened according to the inclusion criteria. We divided the selected articles into four distinct groups: healthy humans (n = 5); healthy animals (n = 7); humans with diabetes (n = 2); and animals with diabetes (n = 3). CD163 is a biomarker of the M2c macrophage subtype in mammals. Functions of M2c macrophages include angiogenesis, matrix maturation, and phagocytosis, and they activate prior to wounding. M2c produces many cytokines and growth factors, and also contains receptors for numerous cytokines and growth factors. Induction of M2c macrophages from tissue-resident macrophages in the wound bed by a suitable agent, such as delivery of intracellular ATP, appears to induce rapid granulation tissue formation without hypertrophic scarring and significantly reduces the lag time of the wound healing process.

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References

  1. Chhabra S, Chhabra N, Kaur A, Gupta N (2017) Wound healing concepts in clinical practice of OMFS. J Maxillofacial Oral Surg 16:403–423

    Article  Google Scholar 

  2. Boateng J, Catanzano O (2015) Advanced therapeutic dressings for effective wound healing—a review. J Pharm Sci 104:3653–3680

    Article  CAS  PubMed  Google Scholar 

  3. Meara JG, Leather AJ, Hagander L, Alkire BC, Alonso N, Ameh EA, Bickler SW, Conteh L, Dare AJ, Davies J (2015) Global Surgery 2030: evidence and solutions for achieving health, welfare, and economic development. The Lancet 386:569–624

    Article  Google Scholar 

  4. Sen CK (2019) Human wounds and its burden: an updated compendium of estimates. In: Mary Ann Liebert, Inc., publishers 140 Huguenot Street, 3rd Floor New, pp 39–48

  5. Rodrigues M, Kosaric N, Bonham CA, Gurtner GC (2019) Wound healing: a cellular perspective. Physiol Rev 99:665–706

    Article  CAS  PubMed  Google Scholar 

  6. Rahim K, Saleha S, Zhu X, Huo L, Basit A, Franco OL (2017) Bacterial contribution in chronicity of wounds. Microb Ecol 73:710–721

    Article  PubMed  Google Scholar 

  7. Sen CK, Gordillo GM, Roy S, Kirsner R, Lambert L, Hunt TK, Gottrup F, Gurtner GC, Longaker MT (2009) Human skin wounds: a major and snowballing threat to public health and the economy. Wound Repair Regener 17:763–771

    Article  Google Scholar 

  8. Darwin E, Tomic-Canic M (2018) Healing chronic wounds: current challenges and potential solutions. Curr Dermatol Rep 7:296–302

    Article  PubMed  PubMed Central  Google Scholar 

  9. Dhivya S, Padma VV, Santhini E (2015) Wound dressings—a review. Biomedicine 5:1–5

    Article  Google Scholar 

  10. Wu Y, Chen L, Scott PG, Tredget EE (2007) Mesenchymal stem cells enhance wound healing through differentiation and angiogenesis. Stem Cells 25:2648–2659

    Article  CAS  PubMed  Google Scholar 

  11. Kirsner RS, Warriner R, Michela M, Stasik L, Freeman K (2010) Advanced biological therapies for diabetic foot ulcers. Arch Dermatol 146:857–862

    Article  PubMed  Google Scholar 

  12. Haney EF, Pletzer D, Hancock RE (2018) Impact of host defense peptides on chronic wounds and infections. In: Chronic wounds, wound dressings and wound healing. Springer, Berlin, pp 3–19

  13. Hirayama D, Iida T, Nakase H (2018) The phagocytic function of macrophage-enforcing innate immunity and tissue homeostasis. Int J Mol Sci 19:92

    Article  Google Scholar 

  14. MacLeod AS, Mansbridge JN (2016) The innate immune system in acute and chronic wounds. Adv Wound Care 5:65–78

    Article  Google Scholar 

  15. Ehrlich HP, Hunt TK (2012) Collagen organization critical role in wound contraction. Adv Wound Care 1:3–9

    Article  Google Scholar 

  16. Etzerodt A, Moestrup SK (2013) CD163 and inflammation: biological, diagnostic, and therapeutic aspects. Antioxid Redox Signal 18:2352–2363

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Du-Cheyne C, Martens A, De-Spiegelaere W (2021) High Numbers of CD163-Positive Macrophages in the Fibrotic Region of Exuberant Granulation Tissue in Horses. Animals 11:2728

    Article  PubMed  PubMed Central  Google Scholar 

  18. Rőszer T (2015) Understanding the mysterious M2 macrophage through activation markers and effector mechanisms. Mediat Inflam 2015:1

    Article  Google Scholar 

  19. Snyder RJ, Lantis J, Kirsner RS, Shah V, Molyneaux M, Carter MJ (2016) Macrophages: a review of their role in wound healing and their therapeutic use. Wound Repair Regener 24:613–629

    Article  Google Scholar 

  20. Kloc M, Ghobrial RM, Wosik J, Lewicka A, Lewicki S, Kubiak JZ (2019) Macrophage functions in wound healing. J Tissue Eng Regen Med 13:99–109

    CAS  PubMed  Google Scholar 

  21. Barman PK, Koh TJ (2020) Macrophage dysregulation and impaired skin wound healing in diabetes. Front Cell Dev Biol 8:528

    Article  PubMed  PubMed Central  Google Scholar 

  22. Howard JD, Sarojini H, Wan R, Chien S (2014) Rapid granulation tissue regeneration by intracellular ATP delivery-a comparison with regranex. PLoS ONE 9:e91787

    Article  PubMed  PubMed Central  Google Scholar 

  23. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. J Clin Epidemiol 62:e1–e34

    Article  PubMed  Google Scholar 

  24. Hooijmans CR, Rovers MM, de Vries RB, Leenaars M, Ritskes-Hoitinga M, Langendam MW (2014) SYRCLE’s risk of bias tool for animal studies. BMC Med Res Methodol 14:43

    Article  PubMed  PubMed Central  Google Scholar 

  25. Williams H, Suda S, Dervish S, Yap YT, Holland AJA, Medbury HJ (2021) Monocyte M1/M2 profile is altered in paediatric burn patients with hypertrophic scarring. Wound Repair Regener 29:996–1005

    Article  Google Scholar 

  26. Lurier EB, Dalton D, Dampier W, Raman P, Nassiri S, Ferraro NM, Rajagopalan R, Sarmady M, Spiller KL (2017) Transcriptome analysis of IL-10-stimulated (M2c) macrophages by next-generation sequencing. Immunobiology 222:847–856

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Li X, Wang Y, Yuan B, Yang H, Qiao L (2017) Status of M1 and M2 type macrophages in keloid. Int J Clin Exp Pathol 10:11098–11105

    PubMed  PubMed Central  Google Scholar 

  28. Zhu Z, Ding J, Ma Z, Iwashina T, Tredget EE (2016) Systemic depletion of macrophages in the subacute phase of wound healing reduces hypertrophic scar formation. Wound Repair Regener 24:644–656

    Article  Google Scholar 

  29. Barros MH, Hauck F, Dreyer JH, Kempkes B, Niedobitek G (2013) Macrophage polarisation: an immunohistochemical approach for identifying M1 and M2 macrophages. PLoS ONE 8:e80908

    Article  PubMed  PubMed Central  Google Scholar 

  30. Chen L, Li Z, Zheng Y, Zhou F, Zhao J, Zhai Q, Zhang Z, Liu T, Chen Y, Qi S (2022) 3D-printed dermis-specific extracellular matrix mitigates scar contraction via inducing early angiogenesis and macrophage M2 polarization. Bioactive Mater 10:236–246

    Article  Google Scholar 

  31. Ashouri F, Beyranvand F, Beigi-Boroujeni N, Tavafi M, Sheikhian A, Varzi AM, Shahrokhi S (2019) Macrophage polarization in wound healing: role of aloe vera/chitosan nanohydrogel. Drug Deliv Transl Res 9:1027–1042

    Article  CAS  PubMed  Google Scholar 

  32. Wu J, Xiao Z, Chen A, He H, He C, Shuai X, Li X, Chen S, Zhang Y, Ren B, Zheng J, Xiao J (2018) Sulfated zwitterionic poly(sulfobetaine methacrylate) hydrogels promote complete skin regeneration. Acta Biomater 71:293–305

    Article  CAS  PubMed  Google Scholar 

  33. Dong X, Chang J, Li H (2017) Bioglass promotes wound healing through modulating the paracrine effects between macrophages and repairing cells. J Mater Chem B 5:5240–5250

    Article  CAS  PubMed  Google Scholar 

  34. Dreymueller D, Denecke B, Ludwig A, Jahnen-Dechent W (2013) Embryonic stem cell-derived M2-like macrophages delay cutaneous wound healing. Wound Repair Regener 21:44–54

    Article  Google Scholar 

  35. Min D, Nube V, Tao A, Yuan X, Williams PF, Brooks BA, Wong J, Twigg SM, McLennan SV (2021) Monocyte phenotype as a predictive marker for wound healing in diabetes-related foot ulcers. J Diabetes Compl 35:107889

    Article  CAS  Google Scholar 

  36. Montanaro M, Meloni M, Anemona L, Giurato L, Scimeca M, Izzo V, Servadei F, Smirnov A, Candi E, Mauriello A, Uccioli L (2020) Macrophage activation and M2 polarization in wound bed of diabetic patients treated by dermal/epidermal substitute nevelia. Int J Lower Extrem Wounds. https://doi.org/10.1177/1534734620945559

    Article  Google Scholar 

  37. Li J, Chou H, Li L, Li H, Cui Z (2020) Wound healing activity of neferine in experimental diabetic rats through the inhibition of inflammatory cytokines and nrf-2 pathway. Artif Cells Nanomed Biotechnol 48:96–106

    Article  PubMed  Google Scholar 

  38. Shao Y, Dang M, Lin Y, Xue F (2019) Evaluation of wound healing activity of plumbagin in diabetic rats. Life Sci 231:116422

    Article  CAS  PubMed  Google Scholar 

  39. da Silva LP, Santos TC, Rodrigues DB, Pirraco RP, Cerqueira MT, Reis RL, Correlo VM, Marques AP (2017) Stem cell-containing hyaluronic acid-based spongy hydrogels for integrated diabetic wound healing. J Invest Dermatol 137:1541–1551

    Article  PubMed  Google Scholar 

  40. Schmidt JG, Andersen EW, Ersbøll BK, Nielsen M (2016) Muscle wound healing in rainbow trout (Oncorhynchus mykiss). Fish Shellfish Immunol 48:273–284

    Article  CAS  PubMed  Google Scholar 

  41. Keeler GD, Durdik JM, Stenken JA (2015) Localized delivery of dexamethasone-21-phosphate via microdialysis implants in rat induces M (GC) macrophage polarization and alters CCL2 concentrations. Acta Biomater 12:11–20

    Article  CAS  PubMed  Google Scholar 

  42. Boyle JJ (2012) CURRENT OPINION Heme and haemoglobin direct macrophage Mhem phenotype and counter foam cell formation in areas of intraplaque haemorrhage. Curr Opin Lipidol 23:000–000

    Article  Google Scholar 

  43. Reinke J, Sorg H (2012) Wound repair and regeneration. Eur Surg Res 49:35–43

    Article  CAS  PubMed  Google Scholar 

  44. Delavary BM, van der Veer WM, van Egmond M, Niessen FB, Beelen RH (2011) Macrophages in skin injury and repair. Immunobiology 216:753–762

    Article  CAS  Google Scholar 

  45. Zhao R, Liang H, Clarke E, Jackson C, Xue M (2016) Inflammation in chronic wounds. Int J Mol Sci 17:2085

    Article  PubMed  PubMed Central  Google Scholar 

  46. FrykbergRobert G (2015) Challenges in the treatment of chronic wounds. Adv Wound Care 4:560–582

    Article  CAS  Google Scholar 

  47. Landén NX, Li D, Ståhle M (2016) Transition from inflammation to proliferation: a critical step during wound healing. Cell Mol Life Sci 73:3861–3885

    Article  PubMed  PubMed Central  Google Scholar 

  48. Mounier R, Théret M, Arnold L, Cuvellier S, Bultot L, Göransson O, Sanz N, Ferry A, Sakamoto K, Foretz M (2013) AMPKα1 regulates macrophage skewing at the time of resolution of inflammation during skeletal muscle regeneration. Cell Metab 18:251–264

    Article  CAS  PubMed  Google Scholar 

  49. Huang SC-C, Smith AM, Everts B, Colonna M, Pearce EL, Schilling JD, Pearce EJ (2016) Metabolic reprogramming mediated by the mTORC2-IRF4 signaling axis is essential for macrophage alternative activation. Immunity 45:817–830

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kim SY, Nair MG (2019) Macrophages in wound healing: activation and plasticity. Immunol Cell Biol 97:258–267

    Article  PubMed  PubMed Central  Google Scholar 

  51. Wang J, Zhang Q, Wan R, Mo Y, Li M, Tseng MT, Chien S (2009) Intracellular adenosine triphosphate delivery enhanced skin wound healing in rabbits. Ann Plast Surg 62:180

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Mo Y, Sarojini H, Wan R, Zhang Q, Wang J, Eichenberger S, Kotwal GJ, Chien S (2019) Intracellular ATP delivery causes rapid tissue regeneration via upregulation of cytokines, chemokines, and stem cells. Front Pharmacol 10:1502

    Article  CAS  PubMed  Google Scholar 

  53. Sarojini H, Billeter AT, Eichenberger S, Druen D, Barnett R, Gardner SA, Galbraith NJ, Polk HC Jr, Chien S (2017) Rapid tissue regeneration induced by intracellular ATP delivery—a preliminary mechanistic study. PLoS ONE 12:e0174899

    Article  PubMed  PubMed Central  Google Scholar 

  54. Sarojini H, Bajorek A, Wan R, Wang J, Zhang Q, Billeter AT, Chien S (2021) Enhanced skin incisional wound healing with intracellular ATP delivery via macrophage proliferation and direct collagen production. Front Pharmacol 12:594586

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Wise LM, Bodaan CJ, Stuart GS, Real NC, Lateef Z, Mercer AA, Riley CB, Theoret CL (2018) Treatment of limb wounds of horses with orf virus IL-10 and VEGF-E accelerates resolution of exuberant granulation tissue, but does not prevent its development. PLoS ONE 13:e0197223

    Article  PubMed  PubMed Central  Google Scholar 

  56. Theoret CL, Wilmink JM (2013) Aberrant wound healing in the horse: naturally occurring conditions reminiscent of those observed in man. Wound Repair Regener 21:365–371

    Article  Google Scholar 

  57. Lee C-H, Choi EY (2018) Macrophages and inflammation. J Rheum Dis 25:11–18

    Article  Google Scholar 

  58. Mosser DM, Hamidzadeh K, Goncalves R (2021) Macrophages and the maintenance of homeostasis. Cell Mol Immunol 18:579–587

    Article  CAS  PubMed  Google Scholar 

  59. Lee S, Kivimäe S, Dolor A, Szoka FC (2016) Macrophage-based cell therapies: the long and winding road. J Control Release 240:527–540

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Spiller KL, Koh TJ (2017) Macrophage-based therapeutic strategies in regenerative medicine. Adv Drug Deliv Rev 122:74–83

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

None declared.

Funding

This work was partially funded by a grant from the National Institute of Health, DK105692 of the USA.

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Authors and Affiliations

  1. Price Institute of Surgical Research, University of Louisville and Noveratech LLC, Louisville, KY, USA

    Mohammad Bayat, Harshini Sarojini & Sufan Chien

  2. Department of Biology and Anatomical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran

    Mohammad Bayat

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  1. Mohammad Bayat
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"M.B. wrote the main manuscript text and S.H. performed some examinations, and S.C. scientifically edited paper. All authors reviewed the manuscript."

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Correspondence to Mohammad Bayat or Sufan Chien.

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Bayat, M., Sarojini, H. & Chien, S. The role of cluster of differentiation 163-positive macrophages in wound healing: a preliminary study and a systematic review. Arch Dermatol Res 315, 359–370 (2023). https://doi.org/10.1007/s00403-022-02407-2

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