Cell Transitions during Bone Fracture Healing

骨折愈合过程中的细胞转变

基本信息

项目摘要

Summary Our understanding of cell lineages is currently being challenged. Cell plasticity appears to be more prevalent than previously thought and cell fate switching, even among fully differentiated cells is being more fully uncovered and understood. For example, ‘paligenosis’ is an emerging concept whereby fully differentiated cells revert to a stem cell like state and give rise to a multitude of cell types in part due to mTOR signaling. These observations have important implications for bone fracture healing. Multiple differentiation events occur for the bone to heal. Initially, the mechanical environment directs cell fate decisions within the periosteum. Mechanical stability directs differentiation of osteoblasts and intramembranous ossification, while instability directs differentiation of chondrocytes and endochondral ossification. Concomitantly, the stem cell compartment is maintained, and a renewed stem cell pool will eventually populate the periosteum that covers the new bone. At later stages of endochondral ossification chondrocytes become osteoblasts as the cartilage transforms into bone. Disruptions to these distinct events can lead to delayed or failed healing, which is often associated with increased fibrosis of the fracture site. In this application we propose to examine the process of differentiation of periosteal cells in response to the mechanical environment (Aim1), to assess transformation of chondrocytes into osteoblasts (Aim 2), and maintenance of the stem cell pool and population of the newly formed periosteum by stem cells (Aim 3). This work utilizes a systems biology approach to examine molecular mechanisms that underlie these cell fate decisions, and in parallel a more standard hypothesis-based approach. We focus on the role of Nf1 and Sox2 during differentiation of periosteal cells and the transformation of chondrocytes into osteoblasts. Our preliminary data show that deletion of Nf1 from the developing periosteum leads to a fibrous non-union after fracture, and we focus on the role of mTOR in mediating these outcomes. Our data also show that Sox2 is necessary for endochondral ossification, and we test the requirement of Sox2 in hypertrophic chondrocytes for transformation to osteoblasts. Finally, we examine a role for Sox2 in maintaining the stem cell compartment in the periosteum using a set of loss-of-function experiments in serial fracture repair. In summary, combining a systems biology approach with hypothesis testing is a powerful way to develop deep understanding of the processes regulating cell differentiation during fracture healing.
总结 我们对细胞谱系的理解目前正受到挑战。细胞可塑性似乎更加普遍 细胞命运转换,即使在完全分化的细胞中, 发现并理解。例如,“Paligenosis”是一个新兴的概念, 恢复到干细胞样状态并部分由于mTOR信号传导而产生多种细胞类型。这些 观察结果对骨折愈合具有重要意义。多个分化事件发生在 骨愈合。最初,机械环境指导骨膜内的细胞命运决定。机械 稳定性指导成骨细胞的分化和膜内骨化,而不稳定性指导成骨细胞的分化和膜内骨化。 软骨细胞分化和软骨内骨化。与此同时,干细胞隔室是 维持,并且更新的干细胞池将最终填充覆盖新骨的骨膜。在 软骨内骨化的后期阶段,随着软骨转化为成骨细胞, 骨头这些不同事件的中断可能会导致愈合延迟或失败,这通常与 骨折部位的纤维化增加。在本申请中,我们提出检查 骨膜细胞对机械环境的反应(Aim 1),以评估软骨细胞的转化 成骨细胞(目标2),维持干细胞库和新形成的骨膜群 干细胞(Aim 3)这项工作利用系统生物学方法来研究分子机制, 这些细胞的命运决定的基础,并在平行更标准的假设为基础的方法。我们专注于 NF 1和Sox 2在骨膜细胞分化和软骨细胞转化为成骨细胞过程中的作用 成骨细胞我们的初步数据表明,从发育中的骨膜中缺失Nf1会导致纤维化, 骨折后骨不连,我们关注mTOR在介导这些结果中的作用。我们的数据还显示 Sox 2是软骨内骨化所必需的,我们测试了肥大细胞对Sox 2的需求。 软骨细胞转化成骨细胞。最后,我们研究了Sox 2在维持干细胞中的作用。 在连续骨折修复中使用一组功能丧失实验在骨膜中的隔室。总的来说, 将系统生物学方法与假设检验相结合是深入开发的有力方法 了解骨折愈合过程中细胞分化的调节过程。

项目成果

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RALPH S MARCUCIO其他文献

RALPH S MARCUCIO的其他文献

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{{ truncateString('RALPH S MARCUCIO', 18)}}的其他基金

Transcriptional regulatory landscapes underlying FEZ Formation
自由经济区形成的转录监管格局
  • 批准号:
    10216391
  • 财政年份:
    2020
  • 资助金额:
    $ 58.14万
  • 项目类别:
Transcriptional regulatory landscapes underlying FEZ Formation
自由经济区形成的转录监管格局
  • 批准号:
    10358628
  • 财政年份:
    2020
  • 资助金额:
    $ 58.14万
  • 项目类别:
Transcriptional regulatory landscapes underlying FEZ Formation
自由经济区形成的转录监管格局
  • 批准号:
    10581562
  • 财政年份:
    2020
  • 资助金额:
    $ 58.14万
  • 项目类别:
Transcriptional regulatory landscapes underlying FEZ Formation
自由经济区形成的转录监管格局
  • 批准号:
    10577995
  • 财政年份:
    2020
  • 资助金额:
    $ 58.14万
  • 项目类别:
Effects of Aging on Macrophages and Bone Regeneration
衰老对巨噬细胞和骨再生的影响
  • 批准号:
    8738567
  • 财政年份:
    2013
  • 资助金额:
    $ 58.14万
  • 项目类别:
Effects of Aging on Macrophages and Bone Regeneration
衰老对巨噬细胞和骨再生的影响
  • 批准号:
    8881043
  • 财政年份:
    2013
  • 资助金额:
    $ 58.14万
  • 项目类别:
Effects of Aging on Macrophages and Bone Regeneration
衰老对巨噬细胞和骨再生的影响
  • 批准号:
    9069665
  • 财政年份:
    2013
  • 资助金额:
    $ 58.14万
  • 项目类别:
Effects of Aging on Macrophages and Bone Regeneration
衰老对巨噬细胞和骨再生的影响
  • 批准号:
    8616534
  • 财政年份:
    2013
  • 资助金额:
    $ 58.14万
  • 项目类别:
MOLECULAR BASIS OF TISSUE INTERACTIONS THAT REGULATE CRANIOFACIAL DEVELOPMENT
调节颅面发育的组织相互作用的分子基础
  • 批准号:
    7249157
  • 财政年份:
    2007
  • 资助金额:
    $ 58.14万
  • 项目类别:
MOLECULAR BASIS OF TISSUE INTERACTIONS THAT REGULATE CRANIOFACIAL DEVELOPMENT
调节颅面发育的组织相互作用的分子基础
  • 批准号:
    7418921
  • 财政年份:
    2007
  • 资助金额:
    $ 58.14万
  • 项目类别:

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周围正常细胞对异常细胞簇的机械传感机制
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