Mechanism of skin-specific targeting of adult stem cells

基因皮肤病本质上是可遗传的，由正常所必需的各种基因突变引起。 皮肤的功能，代表最具挑战性和顽固性的皮肤病，临床上没有 可提供适用的治疗方法。营养不良性大疱性表皮松解症(DEB)是一种遗传性机械性 以皮肤和粘膜脆弱为特征的疾病。DEB的形态特征 包括真皮-表皮交界处的基底膜区的分裂，并有一个劈裂面 位于乳头状真皮内。锚定纤维的异常组装是由基因突变引起的 由上皮基底层角质形成细胞合成的基因(COL7A1)编码VII型胶原 乳头状真皮成纤维细胞。精确了解不同亚型的遗传性损伤 Deb，并在蛋白质水平上阐明了这种突变的后果，使我们能够继续我们的 试图开发治疗方法来对抗这种毁灭性的临床表现 皮肤病。临床干细胞研究的最新进展提高了使用成体干细胞的可能性 细胞(ASC)可能为DEB的治疗提供戏剧性的新疗法。这项提议是对 我们在干细胞治疗领域的工作。最近，我们已经证明了同源基因的移植 隐匿型营养不良性大疱性表皮松解症(RDEB)新生小鼠皮肤的ASC 导致VII型胶原的产生，基底膜区域的局部修复，以及 纠正皮肤脆性，从而支持了我们最初关于治疗的可行性的假设 ASC在DEB治疗中的应用但是，要使此方法广泛适用于 对于遗传性皮肤病的治疗，了解促进定向迁移的机制是至关重要的 皮肤中的天冬氨酸。ASC靶向归巢于皮肤组织的机制尚不清楚 虽然我们目前的研究表明趋化因子及其受体和其他黏附 分子参与其中。研究它们在ASC中的作用可能有助于开发治疗策略 增强体外培养的ASC在受损或病变组织中的募集。这反过来可能会导致 各种治疗可能性，如支持组织再生，纠正遗传性疾病，以及 使用ASC作为运送生物制剂的载体。总的来说，这项赠款申请的目的是确定 在正常和病理条件下，控制ASC向皮肤定向迁移的因素。这项建议 概述了以细胞为基础的治疗的专门策略，旨在治疗结缔组织病 临床相关的大疱性表皮松解症模型，这为建议的 心理治疗。这些研究的成功结果可能为开发一种新的治疗方法提供平台 治疗结缔组织疾病以及其他人类遗传性疾病的方法。

Genodermatoses are heritable in nature and arise from mutations in various genes essential for normal functioning of the skin and represent most challenging and intractable skin diseases with no clinically applicable therapies available. Dystrophic epidermolysis bullosa (DEB) is an inherited mechanobullous disorder characterized by fragility of the skin and mucous membranes. The morphological hallmark of DEB includes splitting of the basement membrane zone of the dermal-epidermal junction, with a cleavage plane lying within the papillary dermis. The abnormal assembly of anchoring fibrils is caused by genetic mutations in the gene (COL7A1) encoding collagen type VII synthesized by basal keratinocytes of the epithelium and the fibroblast of the papillary dermis. Precise understanding of the genetic lesions underlying different subtypes of DEB, and elucidation of the consequences of such mutations at the protein level, enabled us to continue our attempts to develop therapy approaches towards counteracting the clinical manifestations in this devastating skin disease. Recent advances in clinical stem cell research have raised the possibility that use of adult stem cells (ASC) may provide dramatic new therapy for treatment of DEB. This proposal is a logistical extension of our work in the field of stem cell-based therapy. Recently, we have shown that a transplantation of congenic ASC into skin of newborn mice affected with the recessive form of dystrophic epidermolysis bullosa (RDEB) leads to the production of the type VII collagen, localized restoration of the basement membrane zone, and correction of skin fragility, thus, supporting our original hypothesis on the feasibility of the therapeutic application of the ASC for the treatment of DEB. However, to make this approach broadly applicable for the treatment of genodermatoses, it is crucial to understand mechanisms that promote directional migration of ASC in the skin. The mechanisms underlying targeted-homing of ASC to cutaneous tissue remain to be elucidated, although our current studies suggest that both chemokines and their receptors and other adhesion molecules are involved. Studying their role on ASC may allow the development of therapeutic strategies to enhance the recruitment of ex vivo-cultured ASC to damaged or diseased tissues. This in turn could lead to various therapeutic possibilities such as supporting tissue regeneration, correcting inherited disorders, and using ASC as a vehicle for the delivery of biological agents. Overall, this grant application is aimed to identify factors that control directional migration of ASC into skin in normal and pathologic conditions. This proposal outlines a dedicated strategy of cell-based therapy aimed at the treatment of connective tissue disease in a clinically relevant model, epidermolysis bullosa, which provides an excellent genetic target for suggested therapy. A successful outcome of these studies may form a platform for development of a novel therapeutic approach for curing connective tissue disorders as well as other human genetic disorders.