Transitional Growth-Associated Skeletal Stem Cells

过渡生长相关的骨骼干细胞

• 批准号: 9227257
• 负责人: Diana Lynn Carlone
• 金额: $ 17.7万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9227257
• 关键词: Adolescence; Adolescent; Adult; Aging; Biology; Bone Development; Bone Diseases; Bone Growth; Cell Aging; Cell Count; Cell physiology; Cells; Childhood; Data; Defect; Development; Diphtheria Toxin; Doxycycline; Estrogens; Exhibits; Gene Expression; Goals; Growth; Histologic; Homeostasis; Human; Impairment; Laboratories; Lead; Length; Life; Maintenance; Mediator of activation protein; Modeling; Molecular; Mus; Osteogenesis; Osteoporosis; PTH gene; Patients; Pattern; Phase; Phase Transition; Physiological; Physiology; Play; Population; RNA; Regulation; Reporter; Role; Stem cells; System; Techniques; Telomerase; Testing; Therapeutic; Time; Tissues; Transgenic Organisms; Translating; Weaning; age related; base; bone; bone health; bone mass; constriction; experience; in vivo; insight; long bone; microCT; mouse model; new therapeutic target; osteochondral tissue; postnatal; prevent; progenitor; rapid growth; regenerative; response; self-renewal; skeletal; stem cell population; telomere

Postnatal bone formation relies on skeletal progenitor/stem cells (SSCs). Recent in vivo lineage-tracing studies indicate that SSC populations are temporally and spatially- regulated with distinct SSC populations functioning during bone growth and maintenance. In addition, it has been suggested that growth-associated SSCs are the predecessors to adult SSCs implying that a hierarchy may exist among the various progenitor/stem cell populations demonstrating a high degree of complexity within this system. Given this, it is likely that disruption in growth-associated SSC number, function or timing will translate into altered bone mass in adulthood. Telomerase (Tert) activity prevents cellular senescence and is required for maintenance of stem cells in regenerative tissues. Prior studies have shown that telomerase is necessary for SSC self-renewal and differentiation. In addition, decline of telomerase activity in humans correlates with a decrease in bone homeostasis leading to osteoporosis. Utilizing mTert-GFP and mTert-rtTA transgenic reporter mouse lines we investigated the role of mTert-expressing cells in postnatal mouse bone development. Quantitative RNA and histological analyses of long bones revealed that mTert is expressed predominantly at the time of weaning, suggesting these cells are temporally regulated and mark a discrete developmental time point between rapid bone growth and bone maintenance, which we have termed “transitional growth.” Further analysis using in vivo lineage-tracing showed that mTert+ cells function as osteochondral progenitor cells. What physiological factors regulate the temporal pattern of mTert+ SSCs and whether their presence during this specific postnatal developmental stage is crucial for proper adult bone maintenance remains to be determined. Therefore, this proposal will 1) investigate the effect of two well-known physiological growth-regulating factors, estrogen and parathyroid hormone, on mTert+ SSCs and 2) investigate whether altering the temporal pattern, number or function of these cells translates into changes in adult bone.

出生后的骨形成依赖于骨骼祖细胞/干细胞（SSCs）。中最近 体内谱系追踪研究表明，SSC种群在时间和空间上- 在骨生长和维持过程中由不同的SSC群体调节。在 此外，有人认为，生长相关的SSC是成人的前身， SSCs暗示在不同的祖细胞/干细胞群体中可能存在等级 在这个系统中表现出高度的复杂性。考虑到这一点， 与生长相关的SSC数量、功能或时间的中断将转化为改变 成年后的骨量端粒酶（Tert）活性可防止细胞衰老， 再生组织中的干细胞的维持所需的。先前的研究表明， 端粒酶是SSC自我更新和分化所必需。此外， 人的端粒酶活性与骨稳态的降低相关， 骨质疏松利用mTert-GFP和mTert-rtTA转基因报告小鼠系， 研究了mTert表达细胞在出生后小鼠骨发育中的作用。 长骨的定量RNA和组织学分析显示mTert表达 主要是在断奶时，这表明这些细胞是暂时调节的， 标记快速骨生长和骨维持之间的离散发育时间点， 我们称之为“过渡性增长”使用体内谱系追踪的进一步分析 显示mTert+细胞作为骨软骨祖细胞发挥功能。什么生理上的 因素调节mTert+ SSC的时间模式，以及它们在此期间的存在是否 特定的出生后发育阶段对于适当的成人骨骼维持是至关重要的 待定。因此，本建议将1）调查两个众所周知的 生理生长调节因子，雌激素和甲状旁腺激素，对mTert+ SSC的影响 以及2）研究是否改变这些细胞的时间模式、数量或功能 转化为成人骨骼的变化