Stem cells for craniofacial bone repair and regeneration

摘要 这项建议的目的是研究新发现的对头面部骨骼至关重要的干细胞。 发展和疾病。由各种情况引起的大的骨缺陷，例如癌症手术、先天性 畸形、创伤和进行性变形性疾病是主要的健康问题。超过220万起案件 在全世界，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些问题。这个 对于如此广泛的损伤或无法愈合的问题，唯一的解决方案是接受重建手术。 目前的黄金标准是进行自体移植，这种移植需要从骨的其他部分取出骨 身体被送到维修现场。然而，骨移植受到许多缺点的阻碍，包括供体。 部位发病率、有限的骨供应和延长手术时间的并发症。这样的成功 由于一些限制，重建工作仍然具有极大的挑战性。这导致了对 替代方法，特别是以干细胞为基础的治疗。然而，缺乏关于茎的知识 颅面部骨骼形成的特异性细胞极大地限制了进一步的进展。形成的组织 颅面骨骼主要通过膜内骨化来调节，这一过程不同于 身体骨骼中的软骨内骨化。因此，为长骨确定的骨骼干细胞可能 不适合颅面骨重建。使用最先进的老鼠遗传模型，一种 我们实验室最近的开创性工作成功地分离了成体骨骼干细胞， 缝合间充质，负责颅面骨的形成和维持。受伤后 这些缝合干细胞反应迅速，通过替换受损组织直接促进骨修复。 动物实验进一步证明，损伤诱导的愈合过程大大促进了 这些幼稚细胞的移植。尽管我们的发现预示着它们未来将用于基于细胞的治疗 组织工程学，迫切需要了解这些干细胞的特征，以便 再生颅面骨结构。我们的目标是首先对缝合柄进行深入的评估 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，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 说明它们天生具有再生颅面骨结构的能力。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，并表征它们的自我更新、克隆 扩增、增殖和分化能力。这项建议具有显著的潜力，可以推动 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 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。

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.