Stem cells for craniofacial bone repair and regeneration

用于颅面骨修复和再生的干细胞

• 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
• 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

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.

摘要 这项计划的目的是研究新发现的颅面骨骼发育所必需的干细胞。 发展和疾病。由各种情况引起的大骨缺损，例如癌症手术、先天性 畸形、创伤和进行性畸形疾病是主要的健康问题。超过220万例 在整形外科、整形外科和口腔外科的不同领域，每年都要解决世界范围内的各种问题。的 对于这种大面积损伤或不愈合问题的唯一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，需要转移从其他部分的骨 尸体送到修复现场。然而，骨移植物受到许多缺点的阻碍，包括供体 部位发病率、骨供应有限和手术时间延长的并发症。这样的成功 重建工作也因一些限制因素而仍然极具挑战性。这导致了对 替代方法，特别是基于干细胞的治疗。然而，由于缺乏对STEM的了解， 颅面骨发生特异性细胞的存在大大限制了颅面骨发生的进一步发展。形成 颅面骨骼主要通过膜内骨化介导，这是一个不同于 身体骨骼中的软骨内骨化。因此，为长骨鉴定的骨骼干细胞可能 不适合颅面骨重建。使用最先进的小鼠遗传模型， 我们实验室最近的突破性工作成功地分离出了成体骨骼干细胞， 缝间充质和负责颅面骨的形成和维持。在损伤时 这些缝合干细胞反应迅速，并通过替换受损组织直接促进骨修复。 动物实验进一步证明，损伤诱导的愈合过程大大促进， 移植这些幼稚细胞。尽管我们的研究结果有望在未来用于基于细胞的治疗， 组织工程，迫切需要了解这些干细胞的特性， 再生颅面骨骼结构我们的目标是首先对缝线柄进行深入评价 动物模型中的细胞。我们将进一步研究它们在颅面骨发育和疾病中的作用， 阐明由缝合干细胞介导的潜在骨骼修复和再生。我们将强调 其特点是天生的颅面骨结构再生能力。下一步，向临床更近一步 应用，我们计划研究相应的人类干细胞，并表征其自我更新，克隆 扩增、增殖和分化能力。该提案具有推动 再生医学领域。通过研究人类细胞，我们更接近于将我们的发现转化为临床应用。 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。