title: Delayed Healing of Sickle Cell Ulcers Is due to Impaired Angiogenesis and CXCL12 Secretion in Skin Wounds.
abstract: Leg ulcers are a major complication of sickle cell disease that occur in 2.5-40% of patients. Leg ulcers are responsible for frequent complications because they are often long-lasting and are highly resistant to therapy. Although their occurrence is associated with hyperhemolysis, the mechanisms underlying sickle cell ulcers remain poorly understood. In this study, we show that skin wound healing is severely altered in old SAD sickle cell mice but is normal in young animals, consistent with reports in humans. Alterations of wound healing were associated with impaired blood and lymphatic angiogenesis in the wound beds and poor endothelial progenitor cell mobilization from the bone marrow. CXCL12 secretion by keratinocytes and inflammatory cells was low in the wounds of SAD mice. Local therapy with endothelial progenitor cells or recombinant CXCL12 injections restored wound angiogenesis and rescued the healing defect together with mobilization of circulating endothelial progenitor cells. To our knowledge, this is a previously unreported study of the cellular and molecular mechanisms of sickle cell ulcers in a murine model that provides promising therapeutic perspectives for clinical trials.
authors.affiliation: Progenitors and Endothelial Cells During and After Pregnancy Laboratory, INSERM UMR_S 938, Centre de Recherche, St. Antoine, Paris, France; UPMC-Université Paris 6, Paris, France.
authors.forename: Van Tuan
authors.initials: VT
authors.lastname: Nguyen
authors.affiliation: Progenitors and Endothelial Cells During and After Pregnancy Laboratory, INSERM UMR_S 938, Centre de Recherche, St. Antoine, Paris, France; UPMC-Université Paris 6, Paris, France; Department of Dermatology, American University of Beirut Medical Centre, Beirut, Lebanon; Department of Anatomy, Cell Biology and Physiology, Faculty of Medicine, American University of Beirut, Beirut, Lebanon.
authors.forename: Dany
authors.initials: D
authors.lastname: Nassar
authors.affiliation: Faculty of Medicine, Université Paris Descartes-Paris 5, Paris, France.
authors.forename: Fréderic
authors.initials: F
authors.lastname: Batteux
authors.affiliation: Progenitors and Endothelial Cells During and After Pregnancy Laboratory, INSERM UMR_S 938, Centre de Recherche, St. Antoine, Paris, France.
authors.forename: Karine
authors.initials: K
authors.lastname: Raymond
authors.affiliation: Paris Center for Cardiovascular Research, INSERM UMRS-970, Paris, France.
authors.forename: Pierre-Louis
authors.initials: PL
authors.lastname: Tharaux
authors.affiliation: Progenitors and Endothelial Cells During and After Pregnancy Laboratory, INSERM UMR_S 938, Centre de Recherche, St. Antoine, Paris, France; Faculty of Medicine, Université Paris Descartes-Paris 5, Paris, France; Department of Dermatology, Hôpital Cochin-Tarnier, Paris, France. Electronic address: selim.aractingi@gmail.com.
authors.forename: Sélim
authors.initials: S
authors.lastname: Aractingi
mesh_terms: D000755:Anemia, Sickle Cell / Q000150:complications* / Q000473:pathology; D000818:Animals; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000378:metabolism*; D004195:Disease Models, Animal; D066026:Endothelial Progenitor Cells / Q000637:transplantation; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D012883:Skin Ulcer / Q000473:pathology* / Q000503:physiopathology / Q000601:surgery; D033581:Stem Cell Transplantation / Q000379:methods; D013997:Time Factors; D014945:Wound Healing / Q000502:physiology*
chemical_list: D054377:Chemokine CXCL12; C515256:Cxcl12 protein, mouse