SPARC-overexpressing mesenchymal stem cell-hydrogel system accelerates burn wound healing and improves tissue repair...

Burn injuries, especially in diabetic patients, are difficult to treat because of persistent inflammation, impaired angiogenesis, and defective remodeling of the extracellular matrix (ECM). A hydrogel based on hyaluronic acid, chitosan, and alginate was developed to deliver adipose-derived mesenchymal stem cells (MSC) overexpressing SPARC (secreted protein acidic and rich in cysteine). SPARC is an ECM glycoprotein that promotes angiogenesis, collagen deposition, and matrix remodeling and whose activity is reduced in diabetic wounds - was overexpressed to restore these regenerative functions, and the therapeutic effect of the system was evaluated in diabetic and non-diabetic mice with deep thermal burns. The animals were treated with control (CMV) MSC, SPARC‑MSC, or SPARC‑MSC embedded in the hydrogel (SPARC‑HG). Wound healing was assessed by planimetry, histopathology, immunofluorescence, immunohistochemistry, qRT-PCR, and RNA sequencing. SPARC‑HG accelerated wound healing from day 9 and achieved near-complete re-epithelialization by day 21, even in diabetic mice. Histological analysis showed accelerated granulation-tissue formation, increased collagen deposition, and a more organized skin architecture. Immunofluorescence revealed an increased density of CD31 microvessels, activation of α-SMA myofibroblasts, proliferation of PCNA keratinocytes, and the involvement of CK15 hair-follicle stem cells. Immunohistochemistry confirmed decreased expression of the pro-inflammatory cytokines IL‑6, TNF‑α and IL‑1β. qRT-PCR and RNA-seq demonstrated the upregulation of angiogenic (CD31, Cdh5), matrix (Col1a1), and anti-inflammatory (IL-10) genes, together with the downregulation of Mmp9 and IL-6. Transcriptomic profiling revealed the enrichment of pathways related to ECM organization, collagen fibrillogenesis, endothelial integrity, and PI3K‑Akt signaling. SPARC-MSC and hydrogel in combination generated a synergistic regenerative environment with restoration of angiogenesis and matrix remodeling, promotion of epithelial proliferation and re-establishment of immune balance, resulting in superior healing outcomes. This platform can be a promising approach to treat severe burns, especially in diabetic patients.