Ji-Hye Yea, Mario Gomez-Salazar, Sharon Onggo, Zhao Li, Neelima Thottappillil, Masnsen Cherief, Stefano Negri, Xin Xing, Qizhi Qin, Robert Joel Tower, Chen-Ming Fan, Benjamin Levi, Aaron W James
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For this purpose, Tppp3 (tubulin polymerization-promoting protein family member 3)-inducible reporter mice were used in combination with either Scx (Scleraxis) or Pdgfra (platelet derived growth factor receptor alpha) reporter mice. Both tendon injury- and arthroplasty-induced mouse experimental HO models were utilized. ScRNA-seq of tendon-associated traumatic HO suggested that Tppp3 is an early progenitor cell marker for either tendon or osteochondral cells. Upon HO induction, Tppp3 reporter<sup>+</sup> cells expanded in number and partially contributed to cartilage and bone formation in either tendon- or joint-associated HO. In double reporter animals, both Pdgfra<sup>+</sup>Tppp3<sup>+</sup> and Pdgfra<sup>+</sup>Tppp3<sup>-</sup> progenitor cells gave rise to HO-associated cartilage. Finally, analysis of human samples showed a substantial population of TPPP3-expressing cells overlapping with osteogenic markers in areas of heterotopic bone. 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引用次数: 0
摘要
异位骨化(HO)是一种导致骨形成异常的病理过程,通常涉及滑膜内组织。在这一过程中,间充质祖细胞会发生软骨内骨化。然而,驱动这一过程的特定细胞表型和机制并不十分清楚,部分原因是所涉及的祖细胞具有高度异质性。在这里,我们结合使用系谱追踪和单细胞 RNA 测序(scRNA-seq),研究了滑膜/腱鞘祖细胞对异位骨形成的贡献程度。为此,我们将Tppp3(管蛋白聚合促进蛋白家族成员3)诱导型报告小鼠与Scx(硬骨)或Pdgfra(血小板衍生生长因子受体α)报告小鼠结合使用。实验中使用了肌腱损伤和关节成形术诱导的小鼠 HO 实验模型。肌腱相关创伤性HO的ScRNA-seq表明,Tppp3是肌腱或骨软骨细胞的早期祖细胞标记。HO诱导后,Tppp3报告+细胞数量增加,部分促进了肌腱或关节相关HO中软骨和骨的形成。在双报告基因动物中,Pdgfra+Tppp3+和Pdgfra+Tppp3-祖细胞都能产生HO相关软骨。最后,对人体样本的分析表明,在异位骨区域有大量表达 TPPP3 的细胞与成骨标记重叠。总之,这些数据证明滑膜/腱鞘祖细胞会发生异常的骨软骨分化,并在创伤后导致HO。
Tppp3+ synovial/tendon sheath progenitor cells contribute to heterotopic bone after trauma.
Heterotopic ossification (HO) is a pathological process resulting in aberrant bone formation and often involves synovial lined tissues. During this process, mesenchymal progenitor cells undergo endochondral ossification. Nonetheless, the specific cell phenotypes and mechanisms driving this process are not well understood, in part due to the high degree of heterogeneity of the progenitor cells involved. Here, using a combination of lineage tracing and single-cell RNA sequencing (scRNA-seq), we investigated the extent to which synovial/tendon sheath progenitor cells contribute to heterotopic bone formation. For this purpose, Tppp3 (tubulin polymerization-promoting protein family member 3)-inducible reporter mice were used in combination with either Scx (Scleraxis) or Pdgfra (platelet derived growth factor receptor alpha) reporter mice. Both tendon injury- and arthroplasty-induced mouse experimental HO models were utilized. ScRNA-seq of tendon-associated traumatic HO suggested that Tppp3 is an early progenitor cell marker for either tendon or osteochondral cells. Upon HO induction, Tppp3 reporter+ cells expanded in number and partially contributed to cartilage and bone formation in either tendon- or joint-associated HO. In double reporter animals, both Pdgfra+Tppp3+ and Pdgfra+Tppp3- progenitor cells gave rise to HO-associated cartilage. Finally, analysis of human samples showed a substantial population of TPPP3-expressing cells overlapping with osteogenic markers in areas of heterotopic bone. Overall, these data demonstrate that synovial/tendon sheath progenitor cells undergo aberrant osteochondral differentiation and contribute to HO after trauma.
期刊介绍:
Established in 2013, Bone Research is a newly-founded English-language periodical that centers on the basic and clinical facets of bone biology, pathophysiology, and regeneration. It is dedicated to championing key findings emerging from both basic investigations and clinical research concerning bone-related topics. The journal's objective is to globally disseminate research in bone-related physiology, pathology, diseases, and treatment, contributing to the advancement of knowledge in this field.