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.

To learn more about sickle cell ulcers

“…In a recent study, we were able to mount an original murine model of SCD ulcers . In these mice, we confirmed that skin healing was delayed due to a reduced migration of marrow endothelial progenitor cells in wounds in relation with a defect in skin SDF1 production . In accordance with our study, another group has shown that autologous marrow progenitors injected into patient's ulcers were able to allow significant healing of ulcers .…”

“…Moreover, arginine butyrate IV infusions and local instillation of sodium nitrite appear helpful in the care of affected patients, possibly through enhanced angiogenesis or blood flow. In a recent study, we were able to mount an original murine model of SCD ulcers . In these mice, we confirmed that skin healing was delayed due to a reduced migration of marrow endothelial progenitor cells in wounds in relation with a defect in skin SDF1 production .…”

Low-dose methotrexate in sickle-cell disease: a pilot study with rationale borrowed from rheumatoid arthritis

“…There is mounting evidence that deregulated angiogenesis may be an important component of a complex pathophysiology, affecting the course of complications as varied as leg ulcers, proliferative retinopathy, pulmonary hypertension and moyamoya syndrome [53–58]. The CXCL12 up-regulation described in this report will likely have a context-dependent impact on the evolution of the disease.…”

“…The CXCL12 up-regulation described in this report will likely have a context-dependent impact on the evolution of the disease. Mobilization of bone marrow cells might have positive implications if they limit inflammation [51, 52] or if they promote neovascularization of ischemic areas, such as leg ulcers [58]. However, mobilized fibrocytes might contribute to interstitial lung disease and pulmonary hypertension [53, 55], and a pro-angiogenic environment might accelerate the development of certain complications, such as proliferative retinopathy [57].…”

Sickle cell disease induces resistance to cutaneous carcinogenesis

“…However, this method would not take into account in vivo vascular or inflammatory changes. We recently developed a murine model for sickle cell ulcer [41]. This could be another tool to study the response to carcinogenic triggers in these mice.…”