Human Cord Blood Derived Unrestricted Somatic Stem Cells Suppress Fibrosis and May Prevent Malignant Transformation in Dystrophic Epidermolysis Bullosa
Health Behavior and Community Health
Background: Recessive dystrophic epidermolysis bullosa (RDEB) is an inherited blistering disease caused by mutations in COL7A1, a structure protein at the dermal/epidermal junction. Patients with RDEB suffer from recurrent erosions in the skin and have a high risk for developing squamous cell carcinoma (cSCCs). Recent studies suggest a prominent role of TGFβ signaling as well as matrix metalloproteinases (MMPs) in fibrosis and cancer development. We and others previously isolated unrestricted somatic stem cells (USSCs) from human umbilical cord blood and demonstrated that it is a more primitive stem cell population than mesenchymal stem cells. We further demonstrated that USSCs significantly promote wound healing and improve the survival of the mouse model of RDEB (col7a1−/−). Objective: To determine the mechanisms for fibrosis and inflammation in the skin of col7a1−/− mice during the development to adulthood and to investigate the modulatory activity of USSCs on col7a1−/− mice and human RDEB patients-derived cells. Methods: TGFβ signaling and related gene expression were investigated by immunocytochemical staining and quantitative RT-PCR analyses between vehicle and USSC-treated, age-matched skin of RDEB mice. Transwell coculture assay was used to investigate the effects of USSCs on the fibroblasts, keratinocytes and cSCCs derived from patients with RDEB. Results: TGFβ signaling is activated via phosphorylation of Smad2/3 in the col7a1−/− mouse skin, as early as one week after birth and become more prominent at adulthood. The activation is accompanied by increased deposition of collagen fibrils, activation of fibroblasts, and elevations in MMP-9 and MMP-13 levels. Importantly administration of USSCs significantly suppressed phosphorylation of Smad2/3 and expression of MMP-9 and MMP-13 in the skin of RDEB mice meanwhile significantly increasing the expression of TGFβ3 and decorin, both of which antagonize TGFβ1 activity. Furthermore, USSC transwell coculture significantly attenuated the secretion of MMP-9, MMP-10, MMP-13 and interferon gamma (IFNγ) from keratinocytes and cSCCs derived from patients with RDEB. Conclusions: USSCs have anti-fibrotic function via suppressing TGFβ signaling. As epithelial expression of MMP-13 is a biomarker of malignant transformation and correlates with the degree of tumor invasion, these results also suggest a potential role for USSCs in mitigating keratinocyte malignant transformation.
Liao, Y., Ivanova, L., Plumer, T., & Cairo, M. S. (2018). Human Cord Blood Derived Unrestricted Somatic Stem Cells Suppress Fibrosis and May Prevent Malignant Transformation in Dystrophic Epidermolysis Bullosa. Cytotherapy, 20 (5 Suppl.), S46. https://doi.org/10.1016/j.jcyt.2018.02.119