Rescue of the Mucocutaneous Manifestations by Human Cord Blood Derived Nonhematopoietic Stem Cells in a Mouse Model of Recessive Dystrophic Epidermolysis Bullosa

Abstract

Recessive dystrophic epidermolysis bullosa (RDEB) is a severe skin blistering disease caused by mutations in COL7A1-encoding type VII collagen (C7). Currently, there is no curative therapy for patients with RDEB. Our previous studies demonstrated that human umbilical cord blood (HUCB) derived unrestricted somatic stem cells (USSCs) express C7 and facilitate wound healing in a murine wounding model. The primary objective of this study is to investigate the therapeutic functions of USSCs in the C7 null (Col7a1 2/2 ) C57BL6/J mice, a murine model of RDEB. We demonstrated that intrahepatic administration of USSCs significantly improved the blistering phenotype and enhanced the life span in the recipients. The injected USSCs trafficked to the sites of blistering and were incorporated in short-term in the recipients' skin and gastrointestinal tract. Consistent with an overall histological improvement in the epidermal-dermal adherence following USSC treatment, the expression of C7 at the basement membrane zone was detected and the previously disorganized integrin a6 distribution was normalized. We also demonstrated that USSCs treatment induced an infiltration of macrophages with a regenerative "M2" phenotype. Our data suggest that HUCB-derived USSCs improved the RDEB phenotype through multiple mechanisms. This study has warranted future clinical investigation of USSCs as a novel and universal allogeneic stem cell donor source in selected patients with RDEB. STEM

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

“…Furthermore, compared to other sources for stem cell therapy such as bone marrow cells for CNS therapy, USSCs showed lower immunogenicity, possibly enabling them to cross an intact BBB. USSCs have the ability to migrate to the wound or injury; they express many chemokine receptors such as CXCL12 (for SDF1), PDGFR (for HMGB1), and CCR2 (for CCL7), [31] which might direct their specific migration to the site of injury. It is also important to mention that the localization of USSCs in the brain after IV injection is not randomly dispersed; it follows a trajectory path.…”

“…[29,30] In previous studies, our group engineered USSCs to express the luciferase reporter gene, confirmed a stable nonteratogenic phenotype, and then successfully tracked USSC migration in a living animal model of recessive dystrophic epidermolysis bullosa (RDEB) and in excisional wounding healing. [24,31] In the RDEB model, USSC administration migrated to the site of injury and suppressed TGFβ signalingmediated fibrosis and attenuated inflammatory cytokine expression (IL6, IFNγ, and IL17α). [32] The goal of the present pilot study was to investigate the therapeutic potential of USSCs in a premature rabbit pup model of glycerol-induced IVH.…”

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

“…We also demonstrated that following intrahepatic ( i.h. ) administration in neonatal col7a1 −/− mice, USSCs disseminated into the circulation and migrated to skin and intestines . Specifically, USSCs were identified in the dermis within a week and in the hair follicles within 2 weeks of administration.…”

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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.…”