Deep dermal fibroblast profibrotic characteristics are enhanced by bone marrow–derived mesenchymal stem cells

Abstract

Hypertrophic scars are a significant fibroproliferative disorder complicating deep injuries to the skin. We hypothesize that activated deep dermal fibroblasts are subject to regulation by bone marrow-derived mesenchymal stem cells (BM-MSCs), which leads to the development of excessive fibrosis following deep dermal injury. We found that the expression of fibrotic factors was higher in deep burn wounds compared with superficial burn wounds collected from burn patients with varying depth of skin injury. We characterized deep and superficial dermal fibroblasts, which were cultured from the deep and superficial dermal layers of normal uninjured skin obtained from abdominoplasty patients, and examined the paracrine effects of BM-MSCs on the fibrotic activities of the cells. In vitro, deep dermal fibroblasts were found higher in the messenger RNA (mRNA) levels of type 1 collagen, alpha smooth muscle actin, transforming growth factor beta, stromal cell-derived factor 1, and tissue inhibitor of metalloproteinase 1, an inhibitor of collagenase (matrix metalloproteinase 1). As well, deep dermal fibroblasts had low matrix metalloproteinase 1 mRNA, produced more collagen, and contracted collagen lattices significantly greater than superficial fibroblasts. By co-culturing layered fibroblasts with BM-MSCs in a transwell insert system, BM-MSCs enhanced the fibrotic behavior of deep dermal fibroblasts, which suggests a possible involvement of BM-MSCs in the pathogenesis of hypertrophic scarring.

Cellular and Molecular Mechanism of Dermal Fibrosis Following Burn Injury, and Exploration of Therapeutic Approaches

“…DF migrate slow, and express less decorin but more biglycan. Decorin up-regulates more apoptosis genes in SF, but down-regulates their expression in DF [13][14][15]. Superficial and deep dermal fibroblasts have different behaviors in wound healing and hypertrophic scarring, which is supported by the study recently published in Science [16].…”

“…Then activated fibroblasts, in turn, release chemokines such as SDF-1, which lead to the recruitment of blood-borne cells into wounds. These cells contribute to hypertrophic scarring by differentiating into fibroblasts and myofibroblasts, or regulating fibroblasts towards fibrosis by multiple growth factors such as TGFβ ( Figure 6) [15].…”

The Role of Chemokines in Fibrotic Wound Healing

“…7). 84 Blocking SDF-1/CXCR4 pathway by CTCE-9908, a CXCR4 antagonist, minimized HTS formation in vivo in a human HTS-like nude mouse model, in which split-thickness human skin is transplanted into fullthickness dorsal excisional wounds and it develops fibrotic scars that resemble human HTS. 82,85 In this study, wounds and scar formation were monitored using digital photography at multi-time points after split-thickness human skin tissue were transplanted into full-thickness dorsal excisional wounds in athymic mice, which were treated by CTCE-9908 or vehicle.…”

Growth factor pathways in hypertrophic scars: Molecular pathogenesis and therapeutic implications

“…It is known that myofibroblasts in hypertrophic scars are primarily originated from local dermis and subcutaneous tissues around the wound site [5]. Other origins include pericytes and vascular smooth muscle cells [6], bone marrow-derived peripheral blood fibrocytes [7], tubular epithelial cells through epithelial-mesenchymal transition (EMT) [8], and tissue specific stem cells [9] (Fig. 1).…”