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颅面骨骼必不可少的新发现的干细胞发展与疾病。由各种条件引起的大骨缺陷，例如癌症手术，先天性畸形，创伤和渐进型畸形疾病是主要的健康问题。超过220万例每年都必须在骨科，塑料和口腔手术的潜水员领域中解决全球。这唯一解决这种广泛伤害或非治疗问题的解决方案是进行重建操作。当前的黄金标准是执行自体移植，需要转移骨头从其他部位转移车身到维修地点。但是，骨移植物被许多疾病所包围，包括供体现场发病率，有限的骨骼供应和延长的工作时间并发症。这样的成功由于许多局限性，重建也仍然是高度挑战。这导致探索替代方法，尤其是基于干细胞的治疗。但是，缺乏有关茎的知识针对颅面骨骼生成的细胞极大地限制了进一步的进步。形成颅面骨骼主要是通过膜内骨化介导的，这一过程不同于身体骨骼中的内软骨骨化。因此，为长骨确定的骨骼干细胞可能不适合重建颅面骨骼。使用最先进的小鼠遗传模型，一个我们实验室最近的开创性工作已成功地隔离了成人骨骼干细胞，居住在缝合缝隙，负责形成和维持颅面骨骼。受伤这些缝合线干细胞迅速反应，并通过更换受损的组织来直接促进骨骼修复。动物实验进一步证明了损伤引起的愈合过程是大力准备的这些幼稚细胞的移植。尽管我们的发现有望在基于细胞的疗法和组织工程，迫切需要了解这些干细胞的特征再生颅面骨结构。在这里，我们的目标是首先对缝合线进行深入评估动物模型中的细胞。我们将进一步研究它们在颅面发育和疾病中的作用，以及阐明缝合干细胞介导的潜在骨骼修复和再生。我们将强调表征他们先天的精炼颅面骨结构的能力。接下来，将一步走近临床应用，我们计划研究相应的人类干细胞并表征其自我更新的克隆扩展，增殖和差异能力。该提议具有推进的杰出潜力再生医学领域。通过研究人类细胞，我们更接近转化我们的临床发现使用，改善重建手术修复，并最大程度地提高再生医学的益处。