Marrow-derived stem cells in cranial skeletal repair

骨髓干细胞在颅骨修复中的作用

• 批准号: 6653945
• 负责人: Jill Helms A Helms
• 金额: $ 12.14万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-15 至 2004-07-16
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6653945
• 关键词: bone development; bone fracture; bone marrow; bone marrow transplantation; bone regeneration; cell differentiation; craniofacial; flow cytometry; green fluorescent proteins; head; immunocytochemistry; in situ hybridization; laboratory mouse; mandible /maxilla; mesenchyme; mesoderm; morphometry; neural crest; osteogenesis; periosteums; radiation immunosuppression; stem cells; substantia spongiosa; tibia

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.

描述（由申请人提供）：我们的长期目标是确定用于骨骼发育和修复的细胞和分子碱基。越来越多的证据表明，胚胎发育计划是响应损伤的。该观察结果的临床意义很明显：通过了解骨骼生成的分子和细胞基础，我们可以开发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骼发育，包括体内遗传方法，体内和体外操纵的骨骼。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骼愈合模型的裂缝修复研究。通过这些多种方法，我们开发了一个框架，用于研究控制骨骼发育和修复的复杂细胞和分子机制。 在断裂修复过程中控制干细胞分化并因此控制骨骼组织再生过程的分子机制仍然很大未知。我们的研究建议着重于这些干细胞的起源，以及它们有助于骨再生的能力。大多数骨骼均来自中胚层，而面部和颌骨骨骼中的所有软骨和骨骼均来自颅神经rest。这些骨骼组织起源于独特的谱系这一事实增加了每个谱系提供独特的干细胞种群，从而有助于再生骨骼组织。我们假设颅骨骼损伤主要通过募集神经rest衍生的干细胞愈合，而长骨损伤通过优先募集中胚层衍生的干细胞而愈合。为了检验这些假设，我们将确定骨髓衍生的干细胞在下颌断裂愈伤组织中的贡献，而骨髓衍生的干细胞在长骨断裂愈伤组织中的贡献。我们将确定成年动物中是否存在源自颅神经rest的干细胞，以及这些细胞在多大程度上有助于神经rest衍生的骨骼组织的再生。该项目对于使用一种新颖的方法来研究断裂修复的调节非常重要，并将为治愈缺陷提供宝贵的见解。