Marrow-derived stem cells in cranial skeletal repair

描述（由申请人提供）：我们的长期目标是确定骨骼发育和修复的细胞和分子基础。越来越多的证据表明，胚胎发育的程序是对损伤的反应。这一观察结果的临床意义是明确的：通过了解骨骼发生的分子和细胞基础，我们可以制定治疗人类肌肉骨骼损伤，缺陷和疾病的治疗策略。为了实现这些目标，我们开发了多种方法来研究胚胎中的骨发育，包括体内遗传方法，以及发育中骨的体内和体外操作。从发育研究中获得的分子见解可以直接应用于我们使用我们开发的各种骨愈合模型进行的骨折修复研究。通过这些不同的方法，我们已经开发了一个框架，研究复杂的细胞和分子机制控制骨骼发育和修复。 在骨折修复过程中控制干细胞分化的分子机制，从而控制骨骼组织再生的有序过程，在很大程度上仍然未知。我们的研究计划集中在这些干细胞的起源，以及它们促进骨再生的能力。虽然大部分骨骼来自中胚层，但面部和颌骨骨骼中的所有软骨和骨骼都来自颅神经嵴。这些骨骼组织来源于不同的谱系这一事实增加了这样的可能性，即每个谱系提供了独特的干细胞群，有助于再生骨骼组织。我们假设颅骨骨骼损伤愈合主要是通过招募神经嵴来源的干细胞，而长骨损伤愈合通过优先招募中胚层来源的干细胞。为了检验这些假设，我们将确定骨髓源性干细胞在下颌骨骨折骨痂中的贡献与骨髓源性干细胞在长骨骨折骨痂中的贡献相比。我们将确定成年动物中是否存在来自颅神经嵴的干细胞，以及这些细胞在多大程度上有助于神经嵴来源的骨骼组织再生。该项目对于使用新方法研究骨折修复的调控具有重要意义，并将为愈合缺陷提供有价值的见解。

DESCRIPTION (provided by applicant): Our long-term objectives are to determine the cellular and molecular bases for skeletal development and repair. Growing evidence indicates that the program of embryonic development is recapitulated in response to injury. The clinical significance of this observation is clear: by understanding the molecular and cellular basis of skeletogenesis, we can develop therapeutic strategies for the treatment of musculoskeletal injuries, defects, and diseases in humans. To pursue these objectives, we have developed multiple methods to study bone development in the embryo including in vivo genetic approaches, and in vivo and in vitro manipulations of developing bones. Molecular insights gained from developmental studies can be directly applied to our studies of fracture repair using the various bone healing models we have developed. Through these diverse approaches we have developed a framework for studying complex cellular and molecular mechanisms controlling skeletal development and repair. The molecular mechanisms that govern the differentiation of stem cells during fracture repair, and thus govern the orderly process of skeletal tissue regeneration, remain largely unknown. Our research proposal focuses on the origins of these stem cells, and their ability to contribute to bony regeneration. Whereas the majority of the skeleton is derived from mesoderm, all of the cartilages and bones in the facial and jaw skeleton are derived from the cranial neural crest. The fact that these skeletal tissues originate from distinct lineages raises the possibility that each lineage provides a unique stem cell population that contributes to the regenerating skeletal tissue. We hypothesize that cranial skeletal injuries heal predominantly through the recruitment of neural crest-derived stem cells, whereas long bone injuries heal through the preferential recruitment of mesoderm-derived stem cells. To test these hypotheses, we will determine the contribution of marrow-derived stem cells in a mandibular fracture callus compared to the contribution of marrow-derived stem cells in a long bone fracture callus. We will determine if stem cells derived from the cranial neural crest exist in adult animals, and the extent to which these cells contribute to regeneration of neural crest-derived skeletal tissues. This project is significant in using a novel approach to investigate regulation of fracture repair and will provide valuable insights on healing defect.