Involvement of Notch Signaling in Wound Healing

The Notch signaling pathway is critically involved in cell fate decisions during development of many tissues and organs. In the present study we employed in vivo and cell culture models to elucidate the role of Notch signaling in wound healing. The healing of full-thickness dermal wounds was significantly delayed in Notch antisense transgenic mice and in normal mice treated with γ-secretase inhibitors that block proteolytic cleavage and activation of Notch. In contrast, mice treated with a Notch ligand Jagged peptide showed significantly enhanced wound healing compared to controls. Activation or inhibition of Notch signaling altered the behaviors of cultured vascular endothelial cells, keratinocytes and fibroblasts in a scratch wound healing model in ways consistent with roles for Notch signaling in wound healing functions all three cell types. These results suggest that Notch signaling plays important roles in wound healing and tissue repair, and that targeting the Notch pathway might provide a novel strategy for treatment of wounds and for modulation of angiogenesis in other pathological conditions.

[1]  M. Shibuya,et al.  Chimeric VEGF-ENZ7/PlGF Specifically Binding to VEGFR-2 Accelerates Skin Wound Healing via Enhancement of Neovascularization , 2007, Arteriosclerosis, thrombosis, and vascular biology.

[2]  J. Liao,et al.  Serveur Académique Lausannois SERVAL serval.unil.ch , 2022 .

[3]  Minhong Yan,et al.  Inhibition of Dll4 signalling inhibits tumour growth by deregulating angiogenesis , 2006, Nature.

[4]  Gavin Thurston,et al.  Blockade of Dll4 inhibits tumour growth by promoting non-productive angiogenesis , 2006, Nature.

[5]  L. Chatenoud,et al.  Jagged2-expressing hematopoietic progenitors promote regulatory T cell expansion in the periphery through notch signaling. , 2006, Immunity.

[6]  Daniel J. Hoeppner,et al.  Notch signalling regulates stem cell numbers in vitro and in vivo , 2006, Nature.

[7]  M. Mattson,et al.  Gamma secretase–mediated Notch signaling worsens brain damage and functional outcome in ischemic stroke , 2006, Nature Medicine.

[8]  E. Monsalve,et al.  Notch-1 Up-Regulation and Signaling following Macrophage Activation Modulates Gene Expression Patterns Known to Affect Antigen-Presenting Capacity and Cytotoxic Activity1 , 2006, The Journal of Immunology.

[9]  A. Ray,et al.  Treg-mediated immunosuppression involves activation of the Notch-HES1 axis by membrane-bound TGF-beta. , 2006, The Journal of clinical investigation.

[10]  P. Stanley,et al.  Evolutionary Origins of Notch Signaling in Early Development , 2006, Cell cycle.

[11]  Paul Martin,et al.  Inflammatory cells during wound repair: the good, the bad and the ugly. , 2005, Trends in cell biology.

[12]  M. Zasloff,et al.  The nervous system and innate immunity: the neuropeptide connection. , 2005, Nature immunology.

[13]  Christopher C W Hughes,et al.  Cell‐autonomous notch signaling regulates endothelial cell branching and proliferation during vascular tubulogenesis , 2005, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[14]  N. Patel,et al.  Inhibition of angiogenesis and tumor growth by and ?-secretase inhibitors , 2005 .

[15]  R. Bronson,et al.  Essential Role of Endothelial Notch1 in Angiogenesis , 2005, Circulation.

[16]  N. Patel,et al.  Inhibition of angiogenesis and tumor growth by beta and gamma-secretase inhibitors. , 2005, European journal of pharmacology.

[17]  T. Golde,et al.  Inhibitors of γ-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21 , 2005, Nature Immunology.

[18]  A. Israël,et al.  The Notch Ligand Delta1 Recruits Dlg1 at Cell-Cell Contacts and Regulates Cell Migration*[boxs] , 2004, Journal of Biological Chemistry.

[19]  S. Aho.  Soluble form of Jagged1: Unique product of epithelial keratinocytes and a regulator of keratinocyte differentiation , 2004, Journal of cellular biochemistry.

[20]  M. Mattson,et al.  Involvement of Notch signaling in hippocampal synaptic plasticity. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[21]  G. Dotto,et al.  High commitment of embryonic keratinocytes to terminal differentiation through a Notch1-caspase 3 regulatory mechanism. , 2004, Developmental cell.

[22]  T. Golde,et al.  TCR-Mediated Notch Signaling Regulates Proliferation and IFN-γ Production in Peripheral T Cells 1 , 2003, The Journal of Immunology.

[23]  Nicholas J Savill,et al.  Control of epidermal stem cell clusters by Notch-mediated lateral induction. , 2003, Developmental biology.

[24]  M. Ueno,et al.  Abnormal blood vessel development in mice lacking presenilin-1 , 2003, Mechanisms of Development.

[25]  L. Kedes,et al.  Notch Signaling in Vascular Development , 2003, Arteriosclerosis, thrombosis, and vascular biology.

[26]  T. Golde,et al.  TCR-mediated Notch signaling regulates proliferation and IFN-gamma production in peripheral T cells. , 2003, Journal of immunology.

[27]  Jie Li,et al.  Angiogenesis in wound repair: Angiogenic growth factors and the extracellular matrix , 2003, Microscopy research and technique.

[28]  Qiong Shen,et al.  Ectopic expression of Delta4 impairs hematopoietic development and leads to lymphoproliferative disease. , 2002, Blood.

[29]  J-Z Qin,et al.  Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-κB and PPARγ , 2002, Cell Death and Differentiation.

[30]  J-Z Qin,et al.  Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma. , 2002, Cell death and differentiation.

[31]  B. Osborne,et al.  Notch-1 Regulates NF-κB Activity in Hemopoietic Progenitor Cells1 , 2001, The Journal of Immunology.

[32]  L. Liaw,et al.  Members of the Jagged/Notch gene families are expressed in injured arteries and regulate cell phenotype via alterations in cell matrix and cell-cell interaction. , 2001, The American journal of pathology.

[33]  Freddy Radtke,et al.  Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation , 2001, The EMBO journal.

[34]  F. D. Miller,et al.  Functional gamma‐secretase inhibitors reduce beta‐amyloid peptide levels in brain , 2000, Journal of neurochemistry.

[35]  B. Osborne,et al.  Notch-1 regulates NF-kappaB activity in hemopoietic progenitor cells. , 2001, Journal of immunology.

[36]  S. Tsai,et al.  Jagged2 induces cell cycling in confluent fibroblasts susceptible to density‐dependent inhibition of cell division , 2000, Journal of cellular physiology.

[37]  P. Carmeliet,et al.  Angiogenesis in cancer and other diseases , 2000, Nature.

[38]  G. Weinmaster,et al.  Notch4 and Jagged-1 induce microvessel differentiation of rat brain endothelial cells. , 2000, Microvascular research.

[39]  J. Sundberg,et al.  Notch signaling is essential for vascular morphogenesis in mice. , 2000, Genes & development.

[40]  David J. Anderson,et al.  Notch signalling controls pancreatic cell differentiation , 1999, Nature.

[41]  G. Weinmaster,et al.  Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1. , 1999, Human molecular genetics.

[42]  William J. Ray,et al.  A presenilin-1-dependent γ-secretase-like protease mediates release of Notch intracellular domain , 1999, Nature.

[43]  J. Folkman,et al.  Vasculogenesis, Angiogenesis, and Growth Factors: Ephrins Enter the Fray at the Border , 1998, Cell.

[44]  Paul S. Meltzer,et al.  Mutations in the human Jagged1 gene are responsible for Alagille syndrome , 1997, Nature Genetics.

[45]  W. Risau,et al.  Mechanisms of angiogenesis , 1997, Nature.

[46]  Paul Martin,et al.  Wound Healing--Aiming for Perfect Skin Regeneration , 1997, Science.

[47]  R. Montesano,et al.  An Antisense Oligonucleotide to the Notch Ligand Jagged Enhances Fibroblast Growth Factor-induced Angiogenesis in Vitro* , 1996, The Journal of Biological Chemistry.

[48]  Kenji Matsuno,et al.  Notch signaling. , 1995, Science.

[49]  T. Shows,et al.  Cloning of a novel tumor necrosis factor-alpha-inducible primary response gene that is differentially expressed in development and capillary tube-like formation in vitro. , 1992, Journal of immunology.

[50]  C Torrance,et al.  The physiology of wound healing. , 1986, Nursing.