Expansion of the sagittal suture induces proliferation of skeletal stem cells and sustains endogenous calvarial bone regeneration.
Expansion of the sagittal suture induces proliferation of skeletal stem cells and sustains endogenous calvarial bone regeneration.
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DOI：
10.1073/pnas.2120826120
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发表时间：
2023-04-18
影响因子：
11.1
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中科院分区：
文献类型：
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意义 这项工作描述了以下发现：以受控机械扩张的形式“激活”颅骨缝合线，可以增加颅骨缝合线中存在的颅骨骨骼干细胞 (cSSC) 的数量，从而可以维持颅骨骨缺损的再生，否则这些缺损将无法愈合。值得注意的是，我们表明，使用这种策略，无需在骨缺损内植入生物材料或其他成骨组织即可发生骨再生。因此，机械诱导缝线扩张可用于在具有挑战性的颅骨再生过程中利用 cSSC。可以验证相同的策略来激活骨骼的其他骨骼干细胞生态位并促进其他骨骼节段的骨缺损的再生。对于新生儿和大约 2 岁的人来说，颅骨缺损可以自然再生。这种显着的再生潜力也在新生小鼠中被发现，而在成年小鼠中则不存在。由于先前的研究表明，小鼠颅骨缝线是颅骨骨骼干细胞（cSSC）的储存库，而cSSCs是负责颅骨骨再生的细胞，因此我们假设新生小鼠颅骨的再生潜力是由于新生扩张缝线中存在大量的cSSC。因此，我们测试了是否可以通过人为诱导成年小鼠颅骨缝内的 cSSC 增加来对成年小鼠进行逆向工程。 首先，我们分析了新生小鼠和老年小鼠（直至 14 个月大的小鼠）颅骨缝的细胞组成，结果表明年轻小鼠的颅骨缝富含 cSSC。然后，我们证明成年小鼠功能性闭合矢状缝的受控机械扩张会诱导 cSSC 显着增加。最后，我们表明，如果在矢状缝机械扩张的同时产生颅骨临界尺寸骨缺损，则其可以完全再生，而不需要额外的治疗辅助工具。使用遗传封锁系统，我们进一步证明这种内源性再生是由经典 Wnt 信号传导介导的。 这项研究表明，受控机械力可以利用 cSSC 并诱导颅骨再生。类似的利用策略可用于开发新颖且更有效的骨再生自体疗法。
Significance This work describes the discovery that an “activation” of a calvarial suture, in the form of a controlled mechanical expansion, can increase the number of calvarial skeletal stem cells (cSSCs) present in the suture and can, consequently, sustain the regeneration of calvarial bone defects that are otherwise unable to heal. Significantly, we show that using this strategy, bone regeneration occurs without implantations of biomaterials or other osteogenic tissues within the bone defects. Thus, mechanically induced suture expansion could be utilized to harness cSSCs in challenging calvarial bone regeneration procedures. The same strategy could be validated to activate other skeletal stem cell niches of the skeleton and foster regeneration of bone defects of other skeletal segments. In newborn humans, and up to approximately 2 y of age, calvarial bone defects can naturally regenerate. This remarkable regeneration potential is also found in newborn mice and is absent in adult mice. Since previous studies showed that the mouse calvarial sutures are reservoirs of calvarial skeletal stem cells (cSSCs), which are the cells responsible for calvarial bone regeneration, here we hypothesized that the regenerative potential of the newborn mouse calvaria is due to a significant amount of cSSCs present in the newborn expanding sutures. Thus, we tested whether such regenerative potential can be reverse engineered in adult mice by artificially inducing an increase of the cSSCs resident within the adult calvarial sutures. First, we analyzed the cellular composition of the calvarial sutures in newborn and in older mice, up to 14-mo-old mice, showing that the sutures of the younger mice are enriched in cSSCs. Then, we demonstrated that a controlled mechanical expansion of the functionally closed sagittal sutures of adult mice induces a significant increase of the cSSCs. Finally, we showed that if a calvarial critical size bone defect is created simultaneously to the mechanical expansion of the sagittal suture, it fully regenerates without the need for additional therapeutic aids. Using a genetic blockade system, we further demonstrate that this endogenous regeneration is mediated by the canonical Wnt signaling. This study shows that controlled mechanical forces can harness the cSSCs and induce calvarial bone regeneration. Similar harnessing strategies may be used to develop novel and more effective bone regeneration autotherapies.
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影响因子：
3
作者：
Homayounfar N;Park SS;Afsharinejad Z;Bammler TK;MacDonald JW;Farin FM;Mecham BH;Cunningham ML
通讯作者：
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影响因子：
3.6
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影响因子：
3.2
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影响因子：
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