School of Basic Medical Sciences, Anhui Medical University, 81 Meishan road, Hefei, 230032, China.
Department of Traumatic Orthopedics, Anhui Provincial Hospital, The first Affiliated Hospital of China University of Science and Technology, Hefei, 233000, China.
Stem Cell Res Ther. 2019 Jan 11;10(1):14. doi: 10.1186/s13287-018-1107-7.
Heterotopic ossification (HO), either acquired (aHO) or hereditary, such as fibrodysplasia ossificans progressiva (FOP), is a serious condition without effective treatment. Understanding of the core process of injury-induced HO is still severely limited.
Double-pulse thymidine analog labeling was used to explore the distinctive domains evolved in injury-induced lesions in an animal model of HO (Nse-BMP4). Histological studies were performed to see whether a similar zonal pattern is also consistently found in biopsies from patients with aHO and FOP. In vivo clonal analysis with Rainbow mice, genetic loss-of-function studies with diphtheria toxin A (DTA)-mediated depletion and lineage tracing with Zsgreen reporter mice were used to obtain further evidence that Tie2-cre-, Gli1-creERT-, and Glast-creERT-labeled cells contribute to HO as niche-dwelling progenitor/stem cells. Immunohistochemistry was used to test whether vasculature, neurites, macrophages, and mast cells are closely associated with the proposed niche and thus are possible candidate niche supportive cells. Similar methods also were employed to further understand the signaling pathways that regulate the niche and the resultant HO.
We found that distinctive domains evolved in injury-induced lesions, including, from outside-in, a mesenchymal stem cell (MSC) niche, a transient domain and an inner differentiated core in an animal model of HO (Nse-BMP4). A similar zonal structure was found in patients with aHO and FOP. In vivo clonal analysis with Rainbow mice and genetic loss-of-function studies with DTA provided evidence that Tie2-cre-, Gli1-creERT-, and Glast-creERT-labeled cells contribute to HO as niche-dwelling progenitor/stem cells; consistently, vasculature, neurites, macrophages, and mast cells are closely associated with the proposed niche and thus are possible candidate niche supportive cells. Further mechanistic study found that BMP and hedgehog (Hh) signaling co-regulate the niche and the resultant HO.
Available data provide evidence of a potential core mechanism in which multiple disease-specific cellular and extracellular molecular elements form a unique local microenvironment, i.e., an injury-induced stem cell niche, which regulates the proliferation and osteogenic differentiation of mesenchymal stem cells (MSCs). The implication for HO is that therapeutic approaches must consider several different disease specific factors as parts of a functional unit, instead of treating one factor at a time.
异位骨化（HO），无论是获得性（aHO）还是遗传性的，如纤维发育不良性骨化进展症（FOP），都是一种严重的疾病，目前尚无有效的治疗方法。对损伤诱导性 HO 的核心过程的理解仍然严重受限。
使用双脉冲胸苷类似物标记来探索在 HO 的动物模型（Nse-BMP4）的损伤诱导性病变中进化的独特区域。进行组织学研究，以观察类似的带状模式是否也一致存在于 aHO 和 FOP 患者的活检中。利用 Rainbow 小鼠进行体内克隆分析、使用白喉毒素 A（DTA）介导的消耗进行遗传功能丧失研究以及利用 Zsgreen 报告小鼠进行谱系追踪，以获得进一步的证据表明，Tie2-cre、Gli1-creERT 和 Glast-creERT 标记的细胞作为龛位居住的祖细胞/干细胞，有助于 HO 的形成。免疫组织化学用于测试血管、神经突、巨噬细胞和肥大细胞是否与拟议的龛位密切相关，因此是否可能成为龛位支持细胞的候选物。类似的方法也被用于进一步了解调节龛位和由此产生的 HO 的信号通路。
我们发现，在 HO 的动物模型（Nse-BMP4）中，损伤诱导性病变中进化出独特的区域，包括从外向内依次为间充质干细胞（MSC）龛位、短暂的区域和内部分化的核心。在 aHO 和 FOP 患者中也发现了类似的带状结构。利用 Rainbow 小鼠进行体内克隆分析和使用 DTA 进行遗传功能丧失研究为证据表明，Tie2-cre、Gli1-creERT 和 Glast-creERT 标记的细胞作为龛位居住的祖细胞/干细胞，有助于 HO 的形成；一致地，血管、神经突、巨噬细胞和肥大细胞与拟议的龛位密切相关，因此可能是龛位支持细胞的候选物。进一步的机制研究发现，BMP 和 hedgehog（Hh）信号共同调节龛位和由此产生的 HO。
现有数据提供了潜在核心机制的证据，其中多种疾病特异性的细胞和细胞外分子元素形成独特的局部微环境，即损伤诱导的干细胞龛位，调节间充质干细胞（MSCs）的增殖和成骨分化。HO 的意义在于，治疗方法必须考虑到几种不同的疾病特异性因素，作为功能单元的一部分，而不是一次只治疗一个因素。
