Steps towards understanding cellular therapies for Recessive Dystrophic Epidermolysis Bullosa
2022-05
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Steps towards understanding cellular therapies for Recessive Dystrophic Epidermolysis Bullosa
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2022-05
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Abstract
Chronic or recurrent cutaneous wounding is the phenotypic hallmark of the heterogeneous inherited skin disease epidermolysis bullosa (EB). In a severe generalized form of these genodermatoses, recessive dystrophic epidermolysis bullosa (RDEB), biallelic mutations in the COL7A1 gene result in absent or dysfunctional type VII collagen. In healthy individuals, secreted type VII collagen homotrimerizes to form anchoring fibrils in the basement membrane zone (BMZ) connecting the epidermal and dermal layers of the skin. Without these protein anchors to hold the two layers together, the skin easily separates into either blisters or wounds with mild mechanical trauma. There is no cure for RDEB, but improvement in clinical phenotype has been achieved with bone marrow transplant (BMT) and subsequent epidermal allografting from the BMT donor. Previous research into BMT for RDEB has shown that the bone marrow mesenchymal stem cells (BM-MSCs) can home to wounds and secrete collagen VII. Unfortunately, BMT does not fully cure RDEB and chronic wounds can persist after therapy. Therefore, epidermal allografting from the BMT donors of RDEB patients has been employed on chronic wounds. This combination therapy has decreased wound surface area for up to three years post treatment. Characterization of RDEB full-thickness skin biopsies after BMT with and without epidermal allografting with single-cell RNA sequencing uncovered that keratinocytes co-expressing collagen VII and basal stem cell marker keratin 15 might be a source of keratinocytes allowing the epidermal allograft to persist. Additionally, pro-inflammatory immune and fibroblast phenotypes were found in RDEB skin after BMT and subsequent epidermal allografting, which is potentially driven by the local environment of RDEB skin. This is further highlighted by the presence of a myofibroblast population, which has not been described in healthy control human skin. Additionally, while human bone-marrow derived MSC (BM-MSC) trials in RDEB demonstrate improvement in clinical severity, the mechanisms of MSC migration to and persistence in injured skin and their contributions to wound healing are not completely understood. A unique subset of MSCs expressing ATP-binding cassette subfamily member 5 (ABCB5) resides in the reticular dermis and exhibits similar immunomodulatory characteristics to BM-MSCs. This work aimed to test the hypothesis that skin-derived ABCB5+ dermal MSCs (DSCs) possess superior skin homing ability compared to BM-MSCs in immunodeficient NOD-scid IL2rgammanull (NSG) mice. Compared to BM-MSCs, peripherally injected ABCB5+ DSCs demonstrated superior homing and engraftment of wounds. Further, ABCB5+ DSCs versus BM-MSCs co-cultured with macrophages induced less anti-inflammatory interleukin-1 receptor antagonist (IL-1RA) production. RNA sequencing of ABCB5+ DSCs compared to BM-MSCs showed unique expression of Homeobox (Hox) genes, specifically HOXA3. Critical to inducing migration of endothelial and epithelial cells for wound repair, increased expression of HOXA3 may explain superior skin homing properties of ABCB5+ DSCs. Further discernment of the immunomodulatory mechanisms amongst MSC populations could have broader regenerative medicine implications beyond RDEB treatment. In conclusion, this thesis provides insights into the mechanisms of existing cellular treatments for RDEB and targets for future studies and treatments.
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University of Minnesota Ph.D. dissertation. May 2022. Major: Biology. Advisor: Jakub Tolar. 1 computer file (PDF); ix, 112 pages.
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Riedl, Julia. (2022). Steps towards understanding cellular therapies for Recessive Dystrophic Epidermolysis Bullosa. Retrieved from the University Digital Conservancy, https://hdl.handle.net/11299/241308.
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