Immunomodulatory effects of mesenchymal stromal cell secretome accelerate repair in a sickle cell disease wound model.

Abstract

Chronic leg ulcers (CLUs) are a debilitating complication of sickle cell disease (SCD), driven by persistent inflammation, immune dysregulation, and vascular dysfunction. Current therapies fail to correct the hostile immune microenvironment that impairs repair. Here, we investigated the therapeutic potential of the adipose-derived mesenchymal stromal cell (ASC) secretome as a cell-free immunomodulatory approach in a preclinical SCD wound model. Full-thickness excisional wounds were induced in Townes HbSS mice and treated topically with ASC secretome or vehicle control. Treatment accelerated wound closure, enhanced re-epithelialization, and reduced inflammatory infiltrates. Histology revealed advanced collagen deposition and matrix organization, while immunofluorescence demonstrated increased CD31, α-SMA, and SM22 expression, indicating neovascularization and perivascular maturation. Gene expression profiling showed early upregulation of IL-10, TGF-β, and ARG1 and later downregulation of TNF, IL-1β, and NOS2, reflecting a shift toward a reparative immune milieu. Increased F4/80macrophages together with elevated CD31vascular markers were consistent with immune-vascular interactions. Collectively, these findings demonstrate that ASC secretome restores immune balance, supports vascular integrity, and promotes tissue regeneration in SCD-associated chronic wounds. This study provides preclinical evidence for ASC secretome as a promising, scalable, and cell-free immunomodulatory therapy for refractory chronic wounds.