Skin Regeneration with Stem Cells and Scaffolds

干细胞和支架的皮肤再生

• 批准号: 7921567
• 负责人: Jeffrey M. Davidson
• 金额: $ 72.31万
• 依托单位: VANDERBILT UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921567
• 关键词: Ablation; Adult; Affect; Architecture; Arts; Automobile Driving; Behavior; Biocompatible; Biological Models; Biomedical Engineering; Blood Circulation; Body part; Bone Marrow; Burn Trauma; Burn injury; Calgranulin A; Cancer Biology; Cell Differentiation process; Cells; Cellular biology; Chemical Engineering; Chemistry; Chemotactic Factors; Chemotaxis; Cicatrix; Clinical; Collaborations; Complex; Complex Mixtures; Connective Tissue; Contracts; Contracture; Cutaneous; Data; Databases; Dermal; Dermatology; Development; Devices; Dissection; Dorsal; Ear; Elastic Fiber; Electrons; Environment; Epidermis; Epithelial; Esthetics; Excision; Exhibits; Faculty; Fertilization; Fibroblasts; Fostering; Generations; Genotype; Goals; Growth Factor; Hair follicle structure; Healed; Human; Image; Immunohistochemistry; Implant; Infiltration; Injury; Interleukin-2; Joint Ventures; Laser Surgery; Lasers; Lead; Location; MRL/MpJ Mouse; Maintenance; Mammals; Measures; Medical; Mesenchymal; Mesenchymal Stem Cells; Mesenchyme; Methods; Microfluidic Microchips; Microfluidics; Microspheres; Modeling; Molecular Profiling; Mouse Strains; Mus; Natural regeneration; Operative Surgical Procedures; Outcome; Pathology; Phenotype; Physics; Physiologic pulse; Plastic Surgical Procedures; Platelet-Derived Growth Factor; Polymer Chemistry; Polyurethanes; Population; Process; Production; Proteins; Proteome; Proteomics; Publishing; Qualifying; Recruitment Activity; Relative (related person); Reporting; Research; Research Personnel; Resolution; Screening procedure; Seasons; Series; Signal Transduction; Signaling Molecule; Signaling Protein; Site; Skin; Source; Staging; Stem cells; Structure; Study models; System; Talents; Techniques; Testing; Thick; Thymosin; Tissue Engineering; Tissues; Transplantation; Two-Dimensional Gel Electrophoresis; Ulcer; Universities; Validation; Work; Wound Healing; appendage; base; blastema; cell behavior; cell motility; comparative; controlled release; coping; design; elastomeric; flexibility; healing; human SFRP4 protein; innovation; interest; medical schools; migration; morphogens; multidisciplinary; novel; novel strategies; polyurethane foam; progenitor; prospective; protein profiling; public health relevance; reconstruction; regenerative; release factor; repaired; response; restoration; scaffold; skin regeneration; stem cell biology; stem cell population; success; tissue regeneration; two-dimensional; wound

DESCRIPTION (provided by applicant): In damaged skin, regeneration is not the same as filling and resurfacing. Healing by scarring results from the faulty, exuberant reconstruction of the dermal architecture and the formation of an epidermis lacking appendages. The overriding hypothesis of this multi-investigator proposal is that the MRL/MpJ mouse, in which ear wounds regenerate, expresses proteins during wound healing that favor regeneration. This concept is bolstered by our recently published work and our current findings that the MRL wound proteome has distinct differences from other mouse strains. We have published evidence that the bone marrow is a rich source of wound fibroblasts, and mesenchymal stem cells (MSC) from the MRL mouse enhance healing due in part to elevated sFRP-1. The first goal is to identify the key proteomic differences between regenerating and non-regenerating wounds within the MRL and between strains, using a novel, precise surgical method with the free-electron laser. Analysis will be accomplished with state of the art, high-resolution proteomic techniques and verified by immunohistochemistry. The second goal is to determine how the migration and differentiation of several stem cell populations is affected by known and newly-identified, regeneration-specific factors in a novel, microfluidic device that can generate complex, two-dimensional concentration gradients. Further validation will use novel wound chambers. The third goal is to build a scaffold, based on a novel polyurethane chemistry, to provide a three-dimensional environment into which factors that recruit stem cells or promote stem cell activity can be released, under controlled conditions, to drive a regenerative response in skin that normally heals by scarring. The project will test known candidates and then those newly identified. The key criteria for regeneration will be restoration of connective tissue architecture, including the formation of functional elastic fibers and the initiation of hair follicle formation. The translational outcome of this joint venture will be the identification of regeneration-promoting molecules, the use of bone marrow-derived cells to promote regeneration, the development of a new device for studying cell behavior, and the production of a bioactive scaffold for recruitment, differentiation, and delivery of morphogens that promote fully functional repair. This will be accomplished by the collaboration of a seasoned team of investigators with expertise in tissue analysis, proteomics, stem cell biology, microfluidics, and polymer chemistry. PUBLIC HEALTH RELEVANCE: Wounds and burns frequently scar and fail to regenerate the original architecture of the skin. Certain strains of mice heal skin much better in some regions of their body, and part of this may be due to differences in their circulating stem cells or the way they are recruited to the wound. This is a study to identify the cell signals that differ between normal healing and regeneration, to see how they affect the behavior of stem cells, and to devise a temporary, synthetic scaffold that can deliver these regenerative signals to restore skin structure and function.

描述（由申请人提供）：在受损的皮肤中，再生与填充和重新铺面不同。通过疤痕造成的康复是由于皮肤架构的错误，旺盛的重建以及缺乏附属物的表皮形成而导致的。这种多侵袭者建议的推翻假设是，在伤口愈合过程中，MRL/MPJ小鼠在其中的MRL/MPJ小鼠表达蛋白质，有利于再生。我们最近发表的工作和我们目前的发现，MRL伤口蛋白质组与其他小鼠菌株具有明显的差异，这一概念得到了支持。我们已经发表了证据表明，骨髓是伤口成纤维细胞的丰富来源，而来自MRL小鼠的间充质干细胞（MSC）则增强了SFRP-1升高的愈合。第一个目标是使用自由电子激光器使用新颖的精确手术方法来确定MRL内再生和非再生伤口之间的关键蛋白质组学差异。分析将通过最新的，高分辨率的蛋白质组学技术来完成，并通过免疫组织化学进行验证。第二个目标是确定几个干细胞种群的迁移和分化如何受到已知和新鉴定的，新的再生特异性因素的影响，在新型的微流体设备中，可以产生复杂的二维浓度梯度。进一步的验证将使用新颖的伤口室。第三个目标是基于新型聚氨酯化学的脚手架，以提供三维环境，以在该环境中募集干细胞或促进干细胞活性的因素在受控条件下可以释放出皮肤中通常通过疤痕愈合的皮肤再生反应。该项目将测试已知候选人，然后测试新候选人。再生的关键标准将是恢复结缔组织结构，包括功能性弹性纤维的形成和毛囊形成的启动。该合资企业的转化结果将是鉴定促进再生分子，使用骨髓衍生的细胞促进再生的使用，开发用于研究细胞行为的新装置以及生物活性支架以招募招募，差异化，差异化和促进全部功能维修的多型物质。这将通过经验丰富的研究人员的合作来完成，该团队在组织分析，蛋白质组学，干细胞生物学，微流体和聚合物化学方面具有专业知识。公共卫生相关性：伤口和烧伤经常疤痕，无法再生皮肤的原始建筑。某些小鼠在身体的某些区域的治疗性更好得多，其中一部分可能是由于其循环干细胞的差异或将其招募到伤口的方式所致。这是一项研究，旨在识别正常愈合和再生之间不同的细胞信号，以了解它们如何影响干细胞的行为，并设计暂时的合成支架，以恢复这些再生信号以恢复皮肤结构和功能。