Cell-based therapy for dystrophic epidermolysis bullosa (Igoucheva 1)Completed
|Project lead||Dr Olga Igoucheva|
|Organisation||Thomas Jefferson University, Jefferson Medical College, Philadelphia, USA|
|Project budget||EUR 85,000.00|
|Start date / Duration||01. Apr 2009 / 24 months|
|Funder(s) / Co-Funder(s)||DEBRA Austria, MSAP/EBEP Recommended|
|Research area||Cellular therapy|
Short lay summary
In the current project, we suggested to test the hypothesis that engraftment of genetically normal mesenchymal stem cells isolated from bone marrow will lead to expansion of transplanted cells in sufficient numbers in the affected skin of DEB mice and the level of collagen VII will be sufficient to reduce the pathologic phenotype. If successful, the suggested strategy may become powerful therapeutic approach for treatment of connective tissue disorders, in particular dystrophic epidermolysis bullosa, and benefit public health.
What did this project achieve?
Multiple studies demonstrated that adult stem cells such as mesenchymal stem cells (MSCs) can be utilized therapeutically for various congenital and acquired disorders. Involvement of MSCs in maintenance of skin homeostasis and their curative application for the treatment of skin wounds were also documented. However, it is not known whether adult stem cells can commit to cutaneous lineages, produce structural proteins essential for the skin integrity, and be used for hereditary skin disorders. To address these questions, we conducted comparative expression analysis between MSCs and potentially adjacent cutaneous cells, such as fibroblasts and keratinocytes, with special emphasis on extracellular matrix encoding and related genes. Our data demonstrated that MSCs share many features with cutaneous fibroblasts. We also observed that under direct influence of cutaneous fibroblasts in vitro and fibroblast-derived matrix in vivo MSCs acquire fibroblastic phenotype, suggesting that specific cell-cell interactions play a key regulatory role in differentiation of MSCs. Additionally, observed fibroblastic transition of MSCs was underlined by the significant up-regulation of several cutaneous-specific genes encoding lumican, decorin, type VII collagen, laminin and other structural proteins. As many of identified genes have considerable therapeutic values for dermatological afflictions, particularly type VII collagen, we further evaluated the therapeutic potential of congenic MSCs in the skin of Col7a1-null mice recapitulating human Recessive Dystrophic Epidermolysis Bullosa (RDEB). Remarkably, MSCs-derived type VII collagen was sufficient for restoration of the damaged dermal-epidermal junction and partial reversal of the RDEB phenotype in Col7a1-null mouse skin. Additionally, our studies showed that CCL27-CCR10 chemotactic axis can be utilized to target systemically administered CCR10-expressing MSCs to the skin and to provide wide-spread distribution of stem cells within cutaneous tissue. Our data suggest that further analysis of MSCs sub-sets expressing specific chemokine receptors as well as development of approaches providing uniform expression of these receptors in freshly isolated cells may further improve application of adult stem cells for the treatment of congenital skin disorders and other afflictions. Collectively, our results strongly indicate that adult stem cells may offer a promising therapeutics for the treatment of RDEB and potentially other genodermatoses.