Mechanism of skin-specific targeting of adult stem cells

成体干细胞皮肤特异性靶向机制

• 批准号: 8735845
• 负责人: OLGA IGOUCHEVA
• 金额: $ 32.94万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-17 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8735845
• 关键词: Adhesions; Affect; Animal Model; Applications Grants; Basement membrane; Biological Products; Blood Circulation; Bulla; CCR; Cell Adhesion Molecules; Cell Therapy; Cells; Chemotaxis; Clinical; Collagen Type VII; Connective Tissue Diseases; Cues; Cutaneous; Data; Dermal; Dermis; Development; Disease; Disorder by Site; E-Selectin; Endothelium; Engraftment; Epidermis; Epidermolysis Bullosa; Epidermolysis Bullosa Dystrophica; Epithelium; Extravasation; Fibroblasts; GPR2 gene; Gene Mutation; Generations; Genes; Genetic; Goals; Hereditary Disease; Homing; Human; Human Genetics; In Vitro; Inborn Genetic Diseases; Inherited; Injury; Integrins; Lead; Lesion; Ligands; Liquid substance; Mediating; Modeling; Molecular; Mucous Membrane; Mus; Mutation; Natural regeneration; Nature; Newborn Infant; Outcome Study; Papillary; Pathologic; Population; Pre-Clinical Model; Production; Property; Proteins; Public Health; Recruitment Activity; Research; Role; Signal Transduction; Skin; Stem Cell Research; Stem cell transplant; Stem cells; Symptoms; Testing; Therapeutic; Therapeutic Effect; Tissues; Transplantation; Wild Type Mouse; Work; adult stem cell; base; cell motility; chemokine; chemokine receptor; clinically relevant; congeneic transplantation; in vivo; interest; keratinocyte; migration; novel; novel therapeutic intervention; pre-clinical; public health relevance; receptor; repaired; response; restoration; skin disorder; therapeutic development; therapeutic protein; therapeutic target; therapy development; tissue regeneration; trafficking

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：遗传性皮肤病本质上是遗传性的，由皮肤正常功能所必需的各种基因突变引起，是最具挑战性和难治性的皮肤病，目前尚无临床适用的治疗方法。营养不良性大疱性表皮病（DEB）是一种以皮肤和粘膜脆弱为特征的遗传性机械性大疱性疾病。DEB的形态学特征包括真皮-表皮交界处的基底膜区分裂，其中分裂平面位于乳头状真皮内。锚定原纤维的异常组装是由编码VII型胶原的基因（COL 7A 1）中的基因突变引起的，所述VII型胶原由上皮的基底角质形成细胞和乳头状真皮的成纤维细胞合成。对DEB不同亚型的遗传病变的精确理解，以及对这种突变在蛋白质水平上的后果的阐明，使我们能够继续尝试开发治疗方法，以抵消这种毁灭性皮肤病的临床表现。临床干细胞研究的最新进展提出了使用成体干细胞（ASC）可能为治疗DEB提供戏剧性的新疗法的可能性。这一建议是我们在干细胞治疗领域工作的后勤延伸。最近，我们已经表明，将同源ASC移植到患有隐性形式的营养不良性大疱性表皮病（RDEB）的新生小鼠的皮肤中导致VII型胶原蛋白的产生、基底膜区的局部恢复和皮肤脆性的矫正，因此，支持我们关于ASC用于治疗DEB的治疗应用的可行性的原始假设。然而，为了使这种方法广泛应用于遗传性皮肤病的治疗，了解促进ASC在皮肤中定向迁移的机制至关重要。尽管我们目前的研究表明，趋化因子及其受体和其他粘附分子都参与了ASC向皮肤组织的靶向归巢，但其机制仍有待阐明。研究它们对ASC的作用可以允许开发治疗策略以增强离体培养的ASC向受损或患病组织的募集。这反过来又可能导致各种治疗可能性，例如支持组织再生，纠正遗传性疾病，以及使用ASC作为递送生物制剂的载体。总的来说，这项资助申请旨在确定在正常和病理条件下控制ASC向皮肤定向迁移的因素。该提案概述了一种专门的基于细胞的治疗策略，旨在治疗临床相关模型大疱性表皮松解症中的结缔组织疾病，这为建议的治疗提供了绝佳的遗传靶点。这些研究的成功结果可能会形成一个平台，用于开发一种新的治疗方法，用于治疗结缔组织疾病以及其他人类遗传疾病。