Analysis of αSMA-labeled progenitor cell commitment identifies notch signaling as an important pathway in fracture healing.
Analysis of αSMA-labeled progenitor cell commitment identifies notch signaling as an important pathway in fracture healing.
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DOI：
10.1002/jbmr.2140
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发表时间：
2014
期刊：
影响因子：
--
通讯作者：
Kalajzic I
中科院分区：
文献类型：
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作者：
Matthews BG;Grcevic D;Wang L;Hagiwara Y;Roguljic H;Joshi P;Shin DG;Adams DJ;Kalajzic I
骨折愈合是一个再生过程，涉及多种细胞类型的协调反应，但对特定细胞群在此过程中的作用的表征仍然有限。我们已经确定α平滑肌肌动蛋白（αSMA）是骨膜中间充质祖细胞群的标志物，在骨折愈合过程中有助于形成骨软骨成分。使用谱系追踪方法，我们标记了表达 αSMA 的细胞，并通过组织学、流式细胞术和基因表达谱来表征骨折愈合早期阶段骨膜群的变化。为了应对骨折，αSMA 标记的群体扩大并开始向成骨和软骨谱系分化。骨折后间充质祖细胞标志物如 Sca1 和 PDGFRα 的频率增加。骨折后 6 天，参与基质生成和重塑的基因升高。相比之下，与肌肉收缩和Notch信号相关的基因在骨折后下调。我们证实，激活αSMA标记细胞中的Notch信号传导可抑制体外成骨和脂肪形成谱系的分化以及体内异位骨形成。通过表征骨折愈伤组织形成过程中选定的αSMA标记祖细胞群的变化，我们发现Notch信号的调节可能决定骨愈合过程中表达αSMA的祖细胞的成骨潜力。
Fracture healing is a regenerative process that involves coordinated responses of many cell types, but characterization of the roles of specific cell populations in this process has been limited. We have identified alpha smooth muscle actin (αSMA) as a marker of a population of mesenchymal progenitor cells in the periosteum that contributes to osteochondral elements during fracture healing. Using a lineage tracing approach, we labeled αSMA-expressing cells, and characterized changes in the periosteal population during the early stages of fracture healing by histology, flow cytometry, and gene expression profiling. In response to fracture, the αSMA-labeled population expanded and began to differentiate toward the osteogenic and chondrogenic lineages. The frequency of mesenchymal progenitor cell markers such as Sca1 and PDGFRα increased after fracture. By 6 days after fracture, genes involved in matrix production and remodeling were elevated. In contrast, genes associated with muscle contraction and Notch signaling were downregulated after fracture. We confirmed that activating Notch signaling in αSMA-labeled cells inhibited differentiation into osteogenic and adipogenic lineages in vitro and ectopic bone formation in vivo. By characterizing changes in a selected αSMA-labeled progenitor cell population during fracture callus formation, we have shown that modulation of Notch signaling may determine osteogenic potential of αSMA-expressing progenitor cells during bone healing.