Abstract
Sickle cell disease (SCD) is a monogenic red cell disorder associated with multiple vascular complications, microvessel injury and wound-healing deficiency. Although stem cell transplantation with bone marrow-derived mesenchymal stem cells (BMSC) can promote wound healing and tissue repair in SCD patients, therapeutic efficacy is largely dependent on the paracrine activity of the implanted BM stromal cells. Since in vitro expansion and culture conditions are known to modulate the innate characteristics of BMSCs, the present study investigated the effects of normoxic and hypoxic cell-culture preconditioning on the BMSC secretome, in addition to the expression of paracrine molecules that induce angiogenesis and skin regeneration. BMSCs derived from SCD patients were submitted to culturing under normoxic (norCM) and hypoxic (hypoCM) conditions. We found that hypoxically conditioned cells presented increased expression and secretion of several well-characterized trophic growth factors (VEGF, IL8, MCP-1, ANG) directly linked to angiogenesis and tissue repair. The hypoCM secretome presented stronger angiogenic potential than norCM, both in vitro and in vivo, as evidenced by HUVEC proliferation, survival, migration, sprouting formation and in vivo angiogenesis. After local application in a murine wound-healing model, HypoCM showed significantly improved wound closure, as well as enhanced neovascularization in comparison to untreated controls. In sum, the secretome of hypoxia-preconditioned BMSC has increased expression of trophic factors involved in angiogenesis and skin regeneration. Considering that these preconditioned media are easily obtainable, this strategy represents an alternative to stem cell transplantation and could form the basis of novel therapies for vascular regeneration and wound healing in individuals with sickle cell disease.
Highlights
Sickle cell disease (SCD), the most common inherited hemoglobinopathy worldwide, is characterized by repeated vaso-occlusion crises secondary to sickled red blood cells [1]
Immunofluorescence analysis showed similar increases in CD31+ and a-SMA expression in the norCM and hypoCM wounds as compared to controls (Fig 6B). These results indicate that norCM and hypoCM wound treatment increased the vascularization of newly formed tissue, an essential component of the wound healing process
The present study provides evidence that the secretome of bone marrow-derived mesenchymal stem cells (BMSC) from SCD patients demonstrates pro-angiogenic properties and promotes wound healing
Summary
Sickle cell disease (SCD), the most common inherited hemoglobinopathy worldwide, is characterized by repeated vaso-occlusion crises secondary to sickled red blood cells [1].
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