Progenitors in Peripheral Nerves Launch Heterotopic Ossification.
Progenitors in Peripheral Nerves Launch Heterotopic Ossification.
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DOI：
10.1002/sctm.16-0347
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发表时间：
2017-04
影响因子：
6
通讯作者：
Davis AR
中科院分区：
文献类型：
--
作者：
Olmsted-Davis EA;Salisbury EA;Hoang D;Davis EL;Lazard Z;Sonnet C;Davis TA;Forsberg JA;Davis AR
本文介绍的使用骨形态发生蛋白2（BMP 2）诱导的异位骨化（HO）小鼠模型的研究表明，该蛋白通过外周神经内膜中的祖细胞信号传导启动HO。在小鼠中，使用针对磷酸SMAD（PS）1、5和8的抗体在BMP 2诱导后一天在神经内膜中鉴定这些细胞。在含有他莫昔芬调节的Wnt 1-Cre重组酶与td番茄红（TR）报告基因（Wnt 1CreErt：Ai 9 Tm）杂交的跟踪小鼠中进行的研究证实了它们的神经起源。在该模型中，诱导TR绝对需要BMP 2诱导和他莫昔芬。在第1天在神经内膜中发现SP 7+（osterix+）TR+细胞，并在第7天与骨结合。通过荧光激活细胞分选分离的TR+和TR−细胞的定量显示，在TR+群体中发现了所有SP 7+细胞，而只有约80%的TR+细胞表达SP 7。前软骨细胞（Sox 9+）和瞬时棕色脂肪（tBAT，UCP 1+）也共表达TR，表明神经中的祖细胞是多潜能的。HO周围神经的神经内膜含有大量PS+细胞，HO患者的神经和骨组织中也有SP 7+细胞。对照组织和神经不含这些PS+和SP 7+细胞。部分HO患者骨表面成骨细胞PS阳性，提示骨形成过程中BMP持续存在。这些数据表明，HO的祖细胞来源于HO小鼠模型和HO患者的神经内膜。干细胞转化医学2017;6：1109-1119
Studies presented here, using a murine model of bone morphogenetic protein type 2 (BMP2)‐induced heterotopic ossification (HO) show that the protein initiates HO by signaling through progenitors in the endoneurium of peripheral nerves. In the mouse, these cells were identified in the endoneurium one day after BMP2 induction using antibody against phosphoSMAD (PS) 1, 5, and 8. Studies conducted in a tracking mouse that contains a tamoxifen‐regulated Wnt1‐Cre recombinase crossed with a td Tomato red (TR) reporter (Wnt1CreErt:Ai9Tm) confirmed their neural origin. In this model both BMP2 induction and tamoxifen are absolutely required to induce TR. SP7+(osterix+)TR+ cells were found in the endoneurium on day 1 and associated with bone on day 7. Quantification of TR+ and TR− cells isolated by fluorescence‐activated cell sorting showed that all SP7+ cells were found in the TR+ population, whereas only about 80% of the TR+ cells expressed SP7. Pre‐chondrocytes (Sox 9+) and transient brown fat (tBAT, UCP1+) also coexpressed TR, suggesting that the progenitor in nerves is multi‐potential. The endoneurium of human nerves near the site of HO contained many PS+ cells, and SP7+ cells were found in nerves and on bone in tissue from patients with HO. Control tissues and nerves did not contain these PS+ and SP7+ cells. Some osteoblasts on bone from patients with HO were positive for PS, suggesting the continued presence of BMP during bone formation. The data suggests that the progenitors for HO are derived from the endoneurium in both the mouse model of HO and in humans with HO. Stem Cells Translational Medicine 2017;6:1109–1119