Cord Blood-Derived Stem Cells Suppress Fibrosis and May Prevent Malignant Progression in Recessive Dystrophic Epidermolysis Bullosa

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin fragility disorder caused by mutations in the Col7a1 gene. Patients with RDEB suffer from recurrent erosions in skin and mucous membranes and have a high risk for developing cutaneous squamous cell carcinoma (cSCCs). TGFβ signaling has been associated with fibrosis and malignancy in RDEB. In this study, the activation of TGFβ signaling was demonstrated in col7a1−/− mice as early as a week after birth starting in the interdigital folds of the paws, accompanied by increased deposition of collagen fibrils and elevated dermal expression of matrix metalloproteinase (MMP)‐9 and MMP‐13. Furthermore, human cord blood‐derived unrestricted somatic stem cells (USSCs) that we previously demonstrated to significantly improve wound healing and prolong the survival of col7a1−/− mice showed the ability to suppress TGFβ signaling and MMP‐9 and MMP‐13 expression meanwhile upregulating anti‐fibrotic TGFβ3 and decorin. In parallel, we cocultured USSCs in a transwell with RDEB patient‐derived fibroblasts, keratinocytes, and cSCC, respectively. The patient‐derived cells were constitutively active for STAT, but not TGFβ signaling. Moreover, the levels of MMP‐9 and MMP‐13 were significantly elevated in the patient derived‐keratinocytes and cSCCs. Although USSC coculture did not inhibit STAT signaling, it significantly suppressed the secretion of MMP‐9 and MMP‐13, and interferon (IFN)‐γ from RDEB patient‐derived cells. Since epithelial expression of these MMPs is a biomarker of malignant transformation and correlates with the degree of tumor invasion, these results suggest a potential role for USSCs in mitigating epithelial malignancy, in addition to their anti‐inflammatory and anti‐fibrotic functions. Stem Cells 2018;36:1839–12

Human Cord Blood-Derived Unrestricted Somatic Stem Cell Infusion Improves Neurobehavioral Outcome in a Rabbit Model of Intraventricular Hemorrhage

“…USSCs also demonstrated the ability to migrate to the site of injury and antagonize TGFβ signaling‐induced fibrosis and decrease deposition of ECM components and expression of multiple MMPs in an inherited skin blistering disease (RDEB). The results from this study demonstrate that USSCs are also an effective stem cell type for the treatment of IVH. Moreover, USSCs are attractive for clinical‐translational potential as they can be purified and expanded without ethical concerns using good manufacturing practice (GMP)—grade procedures.…”

Tissue engineering strategies combining molecular targets against inflammation and fibrosis, and umbilical cord blood stem cells to improve hampered muscle and skin regeneration following cleft repair

“…MSCs can differentiate into several types of cells including endothelial cells, myocytes, keratinocytes, and fibroblasts . Moreover, stem cells produce several anti‐inflammatory and antifibrotic mediators, and secrete factors that create a regenerative microenvironment . Cord blood stem cells embedded in a scaffold secrete for example MMP‐9, mediating collagen degradation in uterine scars, which improves the regeneration of the endometrium, myometrium and blood vessels .…”

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“…Previous studies from the research team of Govindaiah Vinukonda (New York Medical College, Valhalla, New York, USA) explored engineered human cord blood USSCs as a therapy for recessive dystrophic epidermolysis bullosa, an inherited disease majorly affecting the skin . In their new Stem Cells Translational Medicine article, Vinukonda et al sought to extend this approach to the treatment of IVH, a severe complication of preterm birth that leads to hydrocephalus, cerebral palsy, and mental retardation through assessments in a rabbit disease model.…”