Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon.
Scleraxis-Lineage Cells Contribute to Ectopic Bone Formation in Muscle and Tendon.
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DOI：
10.1002/stem.2515
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发表时间：
2017-03
期刊：
影响因子：
--
通讯作者：
Levi B
中科院分区：
文献类型：
--
作者：
Agarwal S;Loder SJ;Cholok D;Peterson J;Li J;Breuler C;Cameron Brownley R;Hsin Sung H;Chung MT;Kamiya N;Li S;Zhao B;Kaartinen V;Davis TA;Qureshi AT;Schipani E;Mishina Y;Levi B
异位骨化(HO)的病理发展在广泛创伤或伴有骨形态发生蛋白(BMP)受体ACVR1高活性突变的患者中得到了很好的描述。然而，对参与这一过程的祖细胞的识别仍然难以捉摸。在这里，我们使用出生后、他莫昔芬诱导的、硬化轴谱系受限的报告小鼠(scx-creERT2/tdTomatofl/fl)表明，结缔组织细胞对创伤引起的HO Anlagen有相当大的贡献。当硬化轴谱系在损伤前仅限于成人时，标记细胞参与了软骨内成骨的每个发育阶段，并共同表达软骨内成骨标记(Osterix，SOX9)。此外，这些成年损伤前受限细胞在HO中共表达间充质干细胞标记物，包括PDGFFRα、Sca1和S100A4。当在无损伤的SCX-cre细胞(SCX-cre/caACVR1fl/fl)中表达具有结构性活性的ACVR1(CaACVR1)时，肌腱和关节形成HO。出生后血统受限、他莫昔芬诱导的caACVR1表达(SCX-creERT2/caACVR1f1/f1)足以在心脏毒素诱导的肌肉损伤后形成HO。这些发现表明，在创伤或过度活跃的骨形态发生蛋白受体(如caACVR1)活动的背景下，肌肉或肌腱中表达硬化症的细胞参与了HO的发生。巩膜细胞在遗传性和创伤性HO中起重要作用。(A)巩膜血统(SCX-cre/ROSA26mTmG)是跟腱的特征。(B)硬化轴细胞系(scx-creert2/tdTomatofl/fl)与软骨和成骨分化标志物(OSX和SOX9)的共表达。(C)SCX-cre/CAACVR1fl/wt小鼠新生HO结构的大体成像和μCT重建。(D)在SCX-creerT2/caACVR1fl/wt小鼠注射CTX后诱导肌肉内HO。
The pathologic development of heterotopic ossification (HO) is well described in patients with extensive trauma or with hyperactivating mutations of the bone morphogenetic protein (BMP) receptor ACVR1. However, identification of progenitor cells contributing to this process remains elusive. Here we show that connective tissue cells contribute to a substantial amount of HO anlagen caused by trauma using post-natal, tamoxifen-inducible, scleraxis-lineage restricted reporter mice (Scx-creERT2/tdTomatofl/fl). When the scleraxis-lineage is restricted specifically to adults prior to injury marked cells contribute to each stage of the developing HO anlagen and co-express markers of endochondral ossification (Osterix, SOX9). Furthermore, these adult pre-injury restricted cells co-expressed mesenchymal stem cell markers including PDGFRα, Sca1, and S100A4 in HO. When constitutively active ACVR1 (caACVR1) was expressed in scx-cre cells in the absence of injury (Scx-cre/caACVR1fl/fl), tendons and joints formed HO. Post-natal lineage-restricted, tamoxifen-inducible caACVR1 expression (Scx-creERT2/caACVR1fl/fl) was sufficient to form HO after directed cardiotoxin-induced muscle injury. These findings suggest that cells expressing scleraxis within muscle or tendon contribute to HO in the setting of both trauma or hyperactive bone morphogenetic protein receptor (e.g. caACVR1) activity. Scleraxis lineage cells contribute to genetic and traumatic induced HO. (A) Scleraxis lineage (Scx-cre/ROSA26mTmG) characterizes Achilles tendon. (B) Co-expression of scleraxis lineage (Scx-creERT2/tdTomatofl/fl) cells with markers of chondrogenic and osteogenic differentiation (Osx and Sox9). (C) Gross imaging and μCT reconstruction of de novo HO formation in Scx-cre/caACVR1fl/wt mouse. (D) Induction of intramuscular HO following ctx injection in Scx-creERT2/caACVR1fl/wt mouse.
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影响因子：
30.8
作者：
Shore, EM;Xu, MQ;Kaplan, FS
通讯作者：
Kaplan, FS
影响因子：
3.7
作者：
Dyment NA;Hagiwara Y;Matthews BG;Li Y;Kalajzic I;Rowe DW
通讯作者：
Rowe DW
影响因子：
4.1
作者：
Kan, Lixin;Peng, Chian-Yu;McGuire, Tammy L.;Kessler, John A.
通讯作者：
Kessler, John A.
影响因子：
82.9
作者：
通讯作者：
--
影响因子：
5.2
作者：
Asai, Shuji;Otsuru, Satoru;Candela, Maria Elena;Cantley, Leslie;Uchibe, Kenta;Hofmann, Ted J.;Zhang, Kairui;Wapner, Keith L.;Soslowsky, Louis J.;Horwitz, Edwin M.;Enomoto-Iwamoto, Motomi
通讯作者：
Enomoto-Iwamoto, Motomi