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The Pro-reparative Engine: Stem Cells Aid Healing by Dampening Inflammation

  • Wound Healing and Tissue Repair (CC Yates, Section Editor)
  • Published:
Current Pathobiology Reports

Abstract

Purpose of Review

Stem cells have been proposed as sources for tissue replacement when healing does not occur. These cells could contribute directly to skin structures via differentiation, or via producing trophic factors that would ‘educate’ the microenvironment to encourage tissue repair. Studies in animals have supported both mechanisms, but translation to humans has been challenged by poor cell survival after transplantation. However, the improvement noted with even transient existence suggests another new possibility, that of suppressing the inflammatory response that limits regenerative healing. Herein, we will propose that this immunomodulatory aspect holds promise for promoting skin healing.

Recent Findings

We have found that stem cell transplantation into wounds can dampen both acute and chronic inflammation, leading to more regenerative-like healing and diminished scarring.

Summary

Wound healing could be improved by dampening inflammation both initially to allow for tissue replacement to proceed and late to reduce scarring.

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References

Recently published papers of particular interest have been highlighted as: • Of importance

  1. Yates CC, Hebda P, Wells A. Skin wound healing and scarring: fetal wounds and regenerative restitution. Birth Defects Res. 2012;96:325–33.

    Article  CAS  Google Scholar 

  2. Raveh-Amit H, Berzsenyi S, Vas V, Ye D, Dinnyes A. Tissue resident stem cells: till death do us part. Biogerontology. 2013;14(6):573–90.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Li M, Zhao Y, Hao H, Han W, Fu X. Mesenchymal stem cell-based therapy for nonhealing wounds: today and tomorrow. Wound Repair Regen. 2015;23:465–82.

    Article  PubMed  Google Scholar 

  4. Klimczak A., Kozlowska U. Mesenchymal stromal cells and tissue-specific progenitor cells: their role in tissue homeostasis. Stem Cells Int. 2016.

  5. • Yates CC, Nuschke A, Rodrigues M, Whaley D, Dechant JJ, Taylor D, et al. Improved transplanted stem cell survival in a polymer gel supplemented with tenascin-C accelerates healing and reduces scarring of murine skin wounds. Cell Transplant. 2017;26:103–13. This study demonstrates that stem cells can reduce scarring in wounds, and links the effect to suppression of inflammation.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Golebiewska EM, Poole AW. Platelet secretion: from haemostasis to wound healing and beyond. Blood Rev. 2015;29(3):153–62.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  7. Sica A, Mantovani A. Macrophage plasticity and polarization: in vivo veritas. J Clin Investig. 2012;122:787–95.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  8. Sindrilaru A, Peters T, Wieschalka S, Baican C, Baican A, Peter H, et al. An unrestrained proinflammatory M1 macrophage population induced by iron impairs wound healing in humans and mice. J Clin Investig. 2011;131:985–97.

    Article  CAS  Google Scholar 

  9. Yates CC, Whaley D, Hooda S, Hebda PA, Bodnar RJ, Wells A. Delayed re-epithelialization and basement membrane regeneration after wounding in mice lacking CXCR3. Wound Repair Regen. 2009;17:34–41.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Yates CC, Whaley D, Wells A. Transplanted fibroblasts prevent dysfunctional repair in a murine CXCR3-deficient scarring model. Cell Transplant. 2012;21:919–31.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Larson BJ, Longaker MT, Lorenz HP. Scarless fetal wound healing: a basic science review. Plast Reconstr Surg. 2012;126(4):1172–80.

    Article  CAS  Google Scholar 

  12. Dienz O, Eaton SM, Bond JP. The induction of antibody production by IL-6 is indirectly mediated by IL-21 produced by CD4+ T cells. J Exp Med. 2009;206:69–78.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  13. Yasukawa H, Ohishi M, Mori H, Murakami M, Chinen T, Aki D, et al. IL-6 induces an anti-inflammatory response in the absence of SOCS3 in macrophages. Nat Immunol. 2003;4:551–6.

    Article  PubMed  CAS  Google Scholar 

  14. Gallucci RM, Sugawara T, Yucesoy B, Berryann K, Simeonova PP, Matheson JM, et al. Interleukin-6 treatment augments cutaneous wound healing in immunosuppressed mice. J Interf Cytokine Res. 2001;21(8):603–9.

    Article  CAS  Google Scholar 

  15. Schroeder JM, Christophers E. Identification of C5a des arg and an anionic neutrophil-activating peptide (ANAP) in psoriatic scales. J Invest Dermatol. 1986;87:53–8.

    Article  CAS  Google Scholar 

  16. Yoshimura T, Matsushima K, Oppenheim JJ, Leonard EJ. Neutrophil chemotactic factor produced by lipopolysaccharide (LPS)-stimulated human blood mononuclear leukocytes: partial characterization and separation from interleukin 1 (IL 1). J Immunol. 1987;139:788–93.

    PubMed  CAS  Google Scholar 

  17. Baggiolini M, Dewald B, Moser B. Interleukin-8 and related chemotactic cytokines-CXC and CC chemokines. Adv Immunol. 1994;55:97–179.

    Article  PubMed  CAS  Google Scholar 

  18. Koch AE, Polverini PJ, Kunkel SL, Harlow LA, DiPietro LA, Elner VM, et al. Interleukin-8 as a macrophage-derived mediator of angiogenesis. Science. 1992;258:1798–801.

    Article  PubMed  CAS  Google Scholar 

  19. Strieter RM, Polverini PJ, Kunkel SL, Arenberg DA, Burdick MD, Kasper J, et al. The functional role of the ‘ELR’ motif in CXC chemokine-mediated angiogenesis. J Biol Chem. 1995;270:27348–57.

    Article  PubMed  CAS  Google Scholar 

  20. Yao M, Zhou RH, Petreaca M, Zheng L, Shyy J, Martins-Green M. Activation of sterol regulatory element-binding proteins (SREBPs) is critical in IL-8-induced angiogenesis. J Leukoc Biol. 2006;80:608–20.

    Article  PubMed  CAS  Google Scholar 

  21. Terasaki K, Kanzaki T, Aoki T, Iwata K, Saiki I. Effects of recombinant human tissue inhibitor of metalloproteinases-2 (rhTIMP-2) on migration of epidermal keratinocytes in vitro and wound healing in vivo. J Dermatol. 2003;30(3):165–72.

    Article  PubMed  CAS  Google Scholar 

  22. Deshmane SL, Kremlev S, Amini S, Sawaya BE. Monocyte chemoattractant protein (MCP-1): an overview. J Interf Cytokine Res. 2009;29(6):313–26.

    Article  CAS  Google Scholar 

  23. Yang M, Ma B, Shao H, Clark AM, Wells A. Macrophage phenotypic subtypes diametrically regulate epithelial- mesenchymal plasticity in breast cancer cells. BMC Cancer. 2016;16:419.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  24. Bosurgi L, Cao YG, Cabeza-Cabrerizo M, Tucci A, Hughes LD, Kong Y, et al. Macrophage function in tissue repair and remodeling requires IL-4 or IL-13 with apoptotic cells. Science. 2017;356(6342):1072–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  25. Bao P, Kodra A, Tomic-Canic M, Golinko MS, Ehrlich HP, Brem H. The role of vascular endothelial growth factor in wound healing. J Surg Res. 2009;152(2):347–58.

    Article  CAS  Google Scholar 

  26. Engelhardt E, Toksoy A, Goebeler M, Debus S, Bröcker EB, Gillitzer R. Chemokines IL-8, GROα, MCP-1, IP-10, and Mig are sequentially and differentially expressed during phase-specific infiltration of leukocyte subsets in human wound healing. Am J Pathol. 1998;53(6):1849–60.

    Article  Google Scholar 

  27. Bodnar RJ, Yates CC, Rodgers ME, Du X, Wells A. IP-10 induces dissociation of newly formed blood vessels. J Cell Sci. 2009;122(Pt 12):2064–77.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  28. Barrientos S, Stojadinovic O, Golinko MS, Brem H, Tomic-Canic M. Growth factors and cytokines in wound healing. Wound Repair Regen. 2008;16:585–601.

    Article  PubMed  Google Scholar 

  29. Borthwick LA, Wynn TA, Fisher AJ. Cytokine mediated tissue fibrosis. Biochem Biophys Acta. 1832;2013:1049–60.

    Google Scholar 

  30. Bootun R. Effects of immunosuppressive therapy on wound healing. Int Wound J. 2013;10(1):98–104.

    Article  PubMed  Google Scholar 

  31. Lucas T, Waisman A, Ranjan R, Roes J, Krieg T, Muller W, et al. Differential roles of macrophages in diverse phases of skin repair. J Immunol. 2010;184(7):3964–77.

    Article  PubMed  CAS  Google Scholar 

  32. Martin P, D’Souza D, Martin J, Grose R, Cooper L, Maki R, et al. Wound healing in the PU.1 null mouse—tissue repair is not dependent on inflammatory cells. Curr Biol. 2003;13(13):1122–8.

    Article  PubMed  CAS  Google Scholar 

  33. Park CW, Kim KS, Bae S, Son HK, Myung PK, Hong HJ, et al. Cytokine secretion profiling of human mesenchymal stem cells by antibody array. Int J Stem Cells. 2009;2(1):59–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  34. Madrigal M, Rao KS, Riordan NH. A review of therapeutic effects of mesenchymal stem cell secretions and induction of secretory modification by different culture methods. J Transl Med. 2014;12:260.

    Article  PubMed  PubMed Central  Google Scholar 

  35. Ong HT, Redmond SL, Marano RJ, Atlas MD, von Unge M, Aabel P, et al. Paracrine activity from adipose-derived stem cells on in vitro wound healing in human tympanic membrane keratinocytes. Stem Cells Dev. 2017;26(6):405–18.

    Article  PubMed  CAS  Google Scholar 

  36. Han KH, Kim AK, Kim MH, Kim DH, Go HN, Kim DI. Enhancement of angiogenic effects by hypoxia-preconditioned human umbilical cord-derived mesenchymal stem cells in a mouse model of hindlimb ischemia. Cell Biol Int. 2016;40(1):27–35.

    Article  PubMed  CAS  Google Scholar 

  37. • Paquet J, Deschepper M, Moya A, Logeart-Avramoglou D, Boisson-Vidal C, Petite H. Oxygen tension regulates human mesenchymal stem cell paracrine functions. Stem Cells Transl Med. 2015;4(7):809–21. This study provides for the basis of changes in stem cell functions during distinct phases of wound healing based on the availability of blood flow and oxygenation.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  38. Nör JE, Christensen J, Mooney DJ, Polverini PJ. Vascular endothelial growth factor (VEGF)-mediated angiogenesis is associated with enhanced endothelial cell survival and induction of Bcl-2 expression. Am J Path. 1999;154(2):375–84.

    Article  PubMed  PubMed Central  Google Scholar 

  39. Oyama T, Ran S, Ishida T, Nadaf S, Kerr L, Carbone DP, et al. Vascular endothelial growth factor affects dendritic cell maturation through the inhibition of nuclear factor-kappa B activation in hemopoietic progenitor cells. J Immunol. 1998;160:1224–32.

    PubMed  CAS  Google Scholar 

  40. Marti LC, Pavon L, Severino P, Sibov T, Guilhen D, Moreira-Filho CA. Vascular endothelial growth factor-A enhances indoleamine 2,3-dioxygenase expression by dendritic cells and subsequently impacts lymphocyte proliferation. Mem Inst Oswaldo Cruz. 2014;109:70–9.

    Article  PubMed  CAS  Google Scholar 

  41. • Sivanathan KN, Gronthos S, Grey ST, Rojas-Canales D, Coates PT. Immunodepletion and hypoxia preconditioning of mouse compact bone cells as a novel protocol to isolate highly immunosuppressive mesenchymal stem cells. Stem Cells Dev. 2017;26(7):512–27. This reports on the responsiveness of stem cells to the external environment alters the communication with other endogenous cells via paracrine signaling.

    Article  PubMed  CAS  Google Scholar 

  42. Ben-Ami E, Berrih-Aknin S, Miller A. Mesenchymal stem cells as an immunomodulatory therapeutic strategy for autoimmune diseases. Autoimmun Rev. 2011;10:410–5.

    Article  PubMed  CAS  Google Scholar 

  43. Ivanova-Todorova E, Bochev I, Mourdjeva M, Dimitrov R, Bukarev D, Kyurkchiev S, et al. Adipose tissue-derived mesenchymal stem cells are more potent suppressors of dendritic cells differentiation compared to bone marrow-derived mesenchymal stem cells. Immunol Lett. 2009;126:37–42.

    Article  PubMed  CAS  Google Scholar 

  44. Kyurkchiev D, Bochev I, Ivanova-Todorova E, Mourdjeva M, Oreshkova T, Belemezova K, et al. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells. 2014;6(5):552–70.

    Article  PubMed  PubMed Central  Google Scholar 

  45. Bodnar RJ, Rodgers ME, Chen W, Wells A. Pericyte regulation of vascular remodeling through the CXC receptor 3. Arterioscler Thromb Vasc Biol. 2013;33:2818–29.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  46. Lozito TP, Jackson WM, Nesti LJ, Tuan RS. Human mesenchymal stem cells generate a distinct pericellular zone of MMP activities via binding of MMPs and secretion of high levels of TIMPs. Matrix Biol. 2014;34:132–43.

    Article  PubMed  CAS  Google Scholar 

  47. Lozito TP, Tuan RS. Mesenchymal stem cells inhibit both endogenous and exogenous MMPs via secreted TIMPs. J Cell Physiol. 2011;226:385–96.

    Article  PubMed  CAS  Google Scholar 

  48. • Yates CC, Rodrigues M, Nuschke A, Johnson Z, Whaley D, Stolz D, et al. Multipotent stromal cells/mesenchymal stem cells and fibroblasts combine to minimize skin hypertrophic scarring. Stem Cell Res Ther. 2017;8:193. These finding demonstrate that stem cells can act primarily to educate other endogenous cells to drive healing, rather than being necessary as precursors to the tissue replacement.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  49. Pittenger MF, Martin BJ. Mesenchymal stem cells and their potential as cardiac therapeutics. Circ Res. 2004;95(1):9–20.

    Article  PubMed  CAS  Google Scholar 

  50. Yang M, Wei X, Li J, Heine LA, Rosenwasser R, Lacovitti L. Changes in host blood factors and brain glia accompanying the functional recovery after systemic administration of bone marrow stem cells in ischemic stroke rats. Cell Transplant. 2010;19(9):1073–84.

    Article  PubMed  Google Scholar 

  51. Sagrinati C, Ronconi E, Lazzeri E, Lasagni L, Romagnani P. Stem-cell approaches for kidney repair: choosing the right cells. Trends Mol Med. 2008;14(7):277–85.

    Article  PubMed  CAS  Google Scholar 

  52. Toma C, Pittenger MF, Cahill KS, Byrne BJ, Kessler PD. Human mesenchymal stem cells differentiate to a cardiomyocyte phenotype in the adult murine heart. Circulation. 2002;105(1):93–8.

    Article  PubMed  Google Scholar 

  53. Rodrigues M, Blair H, Stockdale L, Griffith L, Wells A. Surface tethered epidermal growth factor protects proliferating and differentiating multipotential stromal cells from FasL induced apoptosis. Stem Cells. 2013;31:104–16.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Nuschke A, Rodrigues M, Rivera J, Yates-Binder C, Whaley D, Stolz D, et al. EGF tethered to β-tricalcium phosphate bone scaffolds via a high affinity binding peptide enhances survival of human mesenchymal stem cells/multipotent stromal cells (MSC) in an immune-competent parafascial implantation assay in mice. Stem Cells Transl Med. 2016;5:1580–6.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  55. Rodrigues M, Yates C, Nuschke A, Griffith L, Wells A. The matrikine tenascin-C protects multipotential stromal cells/mesenchymal stem cells from death cytokines such as FasL. Tissue Eng A. 2013;19(17–18):1972–83.

    Article  CAS  Google Scholar 

  56. Swindle CS, Tran K, Johnson TD, Banerjee P, Mayes AM, Griffith LG, et al. Epidermal growth factor (EGF)-like repeats of human tenascin-C as ligands for EGF receptor. J Cell Biol. 2001;154(2):459–68.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  57. Schenk S, Hintermann E, Bilban M, Koshikawa N, Hojilla C, Khokha R, et al. Binding to EGF receptor of a laminin-5 EGF-like fragment liberated during MMP-dependent mammary gland involution. J Cell Biol. 2003;161:197–209.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  58. Grahovac J, Becker D, Wells A. Melanoma cell invasiveness is regulated at least in part by the epidermal growth factor-like repeats of tenascin-C. J Invest Dermatol. 2013;133:210–20.

    Article  PubMed  CAS  Google Scholar 

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Acknowledgements

We thank the members of the Wells laboratory for helpful discussions and suggestions.

Funding

This work was supported by grants from the National Institute of General Medical Sciences (NIH, USA) (GM063569 and GM069668). A.B. is supported on a NIH T32 CATER fellowship (EB001026).

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Authors and Affiliations

  1. Departments of Pathology and Bioengineering, University of Pittsburgh, and VA Pittsburgh Health System, Pittsburgh, PA, 15213, USA

    Andrew Bradshaw, Kyle Sylakowski & Alan Wells

  2. McGowan Institute for Regenerative Medicine, University of Pittsburgh, and VA Pittsburgh Health System, Pittsburgh, PA, 15213, USA

    Andrew Bradshaw, Kyle Sylakowski & Alan Wells

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  1. Andrew Bradshaw
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  2. Kyle Sylakowski
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  3. Alan Wells
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Correspondence to Alan Wells.

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Andrew Bradshaw and Kyle Sylakowski declare that they have no conflict of interest.

Dr. Wells has a patent Owned by the University of Pittsburgh, pending; this patent is not licensed.

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This article does not contain any studies with human or animal subjects performed by any of the authors.

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This article is part of the Topical Collection on Wound Healing and Tissue Repair

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Bradshaw, A., Sylakowski, K. & Wells, A. The Pro-reparative Engine: Stem Cells Aid Healing by Dampening Inflammation. Curr Pathobiol Rep 6, 109–115 (2018). https://doi.org/10.1007/s40139-018-0167-9

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  • DOI: https://doi.org/10.1007/s40139-018-0167-9

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