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: 8630229
• 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/8630229
• 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

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.

遗传性皮肤病在本质上是遗传性的，并且是由正常皮肤发育所必需的各种基因的突变引起的。 皮肤的功能和代表最具挑战性和难治性的皮肤疾病，没有临床 可用的治疗方法。营养不良性大疱性表皮细胞瘤（DEB）是一种遗传性机械性大疱性 以皮肤和粘膜脆弱为特征的疾病。DEB的形态学特征 包括真皮-表皮交界处的基底膜区的分裂， 位于乳头状真皮内。锚定纤维的异常组装是由以下基因突变引起的： 编码由上皮的基底角质形成细胞合成的VII型胶原蛋白的基因（COL 7A 1）和 乳头状真皮的成纤维细胞。对不同亚型的遗传病变的准确理解， DEB，以及在蛋白质水平上阐明这种突变的后果，使我们能够继续我们的研究。 试图开发治疗方法，以抵消这种破坏性的临床表现， 皮肤病临床干细胞研究的最新进展提高了使用成人干细胞的可能性 细胞（ASC）可能为治疗DEB提供戏剧性的新疗法。 我们在干细胞治疗领域的工作最近，我们发现同种异体移植 ASC进入患有隐性形式营养不良性大疱性表皮病（RDEB）的新生小鼠的皮肤 导致VII型胶原蛋白的产生，基底膜区的局部恢复，和 因此，支持我们关于治疗可行性的原始假设。 然而，为了使这种方法广泛适用于 治疗遗传性皮肤病，关键是要了解机制，促进定向迁移， 皮肤中的ASC ASC靶向归巢至皮肤组织的机制仍有待进一步研究。 阐明，虽然我们目前的研究表明，趋化因子及其受体和其他粘附， 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， 增强离体培养的ASC向受损或患病组织的募集。这反过来可能导致 各种治疗可能性，如支持组织再生，纠正遗传性疾病， 使用ASC作为递送生物制剂的载体。总的来说，这项赠款申请旨在确定 在正常和病理条件下控制ASC向皮肤定向迁移的因素。这项建议 概述了一个专门的战略，以细胞为基础的治疗，旨在治疗结缔组织疾病， 临床相关模型，大疱性表皮病，这提供了一个很好的遗传目标，建议 疗法这些研究的成功结果可能为开发新的治疗药物提供平台。 治疗结缔组织疾病以及其他人类遗传疾病的方法。