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，胚胎发育程序是在对损伤的反应中重演的。这一观察结果的临床意义是明确的：通过了解骨骼形成的分子和细胞基础，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，我们已经开发了多种方法来研究胚胎中的骨骼发育，包括体内遗传方法，以及体内和体外骨骼发育的操作。从发育研究中获得的分子见解可以直接应用于我们开发的各种骨愈合模型的骨折修复研究。通过这些不同的方法，我们已经建立了一个框架来研究控制骨骼发育和修复的复杂细胞和分子机制。

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.