Stem cells for craniofacial bone repair and regeneration

用于颅面骨修复和再生的干细胞

基本信息

批准号：
10473883
负责人：
Wei Hsu
金额：
$ 65.78万
依托单位：
ADA FORSYTH INSTITUTE, INC.
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-06-30 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10473883
关键词：
Address Adult Affect Animal Experiments Animal Model Apoptosis Autocrine Communication Autologous Transplantation Behavior Biology Body part Bone Development Bone Diseases Bone Regeneration Bone Transplantation Bone structure Brain Calvaria Cell Culture System Cell Therapy Cells Characteristics Childhood Clinical Clonal Expansion Congenital Abnormality Congenital abnormal Synostosis Craniosynostosis Data Defect Deformity Development Disadvantaged Disease Drosophila genus Engraftment Evaluation Exhibits Future Genetic Models Genetic Transcription Goals Gold Growth Health Homeostasis Human In Vitro Individual Infant Injury Intracranial Pressure Joint structure of suture of skull Kidney Knowledge Laboratories Lead Ligands Maintenance Mediating Mesenchyme Methods Modeling Morbidity - disease rate Morphogenesis Mouse Strains Mus Natural regeneration Operative Surgical Procedures Oral Surgical Procedures Orthopedic Surgery Paracrine Communication Patients Physiologic Ossification Plastic Surgical Procedures Population Process Property Protocols documentation Regenerative Medicine Regenerative capacity Regulation Role Signal Transduction Site Skeletal Development Skeleton Stem Cell Development Stem cell pluripotency Stem cell transplant Surgical sutures Syndrome Testing Time Tissue Engineering Tissues Translating Transplantation Trauma WNT Signaling Pathway Work autocrine beta catenin bone bone healing bone repair cancer surgery capsule cell type clinical application craniofacial craniofacial bone cranium healing human stem cells improved in vivo injured injury and repair insight intramembranous bone formation long bone malformation mouse genetics mouse model mutant novel strategies operation osteogenic pluripotency premature prevent reconstruction regenerative repair model repaired self-renewal skeletal skeletal disorder skeletal stem cell skeletogenesis stem cell population stem cell self renewal stem cell therapy stem cells success

项目摘要

Abstract The objective of this proposal is to study newly identified stem cells essential for craniofacial skeletal development and disease. Large bone defects caused by various conditions, e.g. cancer surgery, congenital malformation, trauma and progressive deforming diseases, are major health issues. Over 2.2 million cases worldwide each year have to be addressed in the diverse fields of orthopedic, plastic and oral surgeries. The only solution for such extensive injuries or non-healing issues is to undergo a reconstructive operation. Current gold standard is to perform autograft that requires transferring bones taken from other parts of the body to the repair site. However, bone grafts are encumbered by numerous disadvantages, including donor site morbidity, limited bone supply and complications of extended operating time. The success of such reconstructions also remains highly challenging owing to a number of limitations. This leads to exploration of alternative approaches, especially stem cell-based therapy. However, the lack of knowledge regarding stem cells specific for craniofacial skeletogenesis greatly restricted further advancement. Formation of the craniofacial skeleton is mainly mediated through intramembranous ossification, a process distinct from endochondral ossification in the body skeleton. Therefore, skeletal stem cells identified for the long bone may not be suitable for reconstruction of the craniofacial bones. Using state-of-the-art mouse genetic models, a recent groundbreaking work from our laboratory has successfully isolated adult skeletal stem cells, residing in the suture mesenchyme and responsible for formation and maintenance of the craniofacial bones. Upon injury these suture stem cells react quickly and contribute directly to bone repair by replacing the damaged tissue. Animal experiments further demonstrated that the injury-induced healing process is greatly facilitated with transplantation of these naïve cells. Although our findings promise their future use in cell-based therapy and tissue engineering, there is an urgent need to understand the characteristics of these stem cells for regenerating craniofacial bone structures. Here our goal is to first perform in-depth evaluations on suture stem cells in animal models. We will further investigate their role in craniofacial bone development and disease, and elucidate the underlying skeletal repair and regeneration mediated by suture stem cells. We will emphasize characterizing their innate ability to regrow craniofacial bone structures. Next, to move a step closer to clinical applications, we plan to study the corresponding human stem cells and characterize their self-renewal, clonal expansion, proliferation, and differentiation abilities. This proposal has outstanding potential to advance the field of regenerative medicine. By studying human cells, we are closer to translating our findings for clinical use, improving reconstructive surgical repair, and maximizing the benefits of regenerative medicine.

抽象的该提案的目的是研究新发现的颅面骨骼必需的干细胞各种情况引起的大骨缺损，例如癌症手术、先天性骨缺损。畸形、创伤和进行性畸形疾病是超过 220 万例的主要健康问题。全世界每年都必须在整形外科、整形外科和口腔外科等不同领域解决这一问题。对于如此严重的伤害或无法治愈的问题，唯一的解决方案是进行重建手术。目前的黄金标准是进行自体移植，需要转移从身体其他部位取出的骨头然而，骨移植存在许多缺点，包括供体。部位发病率、骨供应有限和手术时间延长等并发症。重建工作也仍然面临诸多限制，这导致了对债务的高度挑战。替代方法，特别是基于干细胞的治疗然而，缺乏有关干细胞的知识。颅面骨骼发生的特异性细胞极大地限制了颅面骨骼形成的进一步发展。颅面骨骼主要通过膜内骨化介导，这一过程不同于因此，骨骼干细胞可能被鉴定为长骨的软骨内骨化。不适合使用最先进的小鼠遗传模型重建颅面骨。我们实验室最近的突破性工作成功分离了成体骨骼干细胞，位于缝合间质负责受伤后颅面骨的形成和维持。这些缝线干细胞反应迅速，通过替换受损组织直接促进骨修复。动物实验进一步表明，损伤诱导的愈合过程可以大大促进尽管我们的研究结果有望将其用于基于细胞的治疗和治疗。组织工程中，迫切需要了解这些干细胞的特性在这里，我们的目标是首先对缝合杆进行深入评估。我们将进一步研究它们在颅面骨发育和疾病中的作用，以及我们将强调阐明缝合干细胞介导的潜在骨骼修复和再生。表征他们再生颅面骨结构的先天能力，下一步，更接近临床。应用，我们计划研究相应的人类干细胞并表征它们的自我更新、克隆该提案具有促进扩展、增殖和分化能力的巨大潜力。通过研究人体细胞，我们更接近于将我们的发现转化为临床。使用，改善重建手术修复，并最大限度地发挥再生医学的好处。