Role and regulation of PRX1 expressing cells during calvarial bone regeneration

颅面外科医生和神经外科医生进行大量的骨再生手术来治疗颅骨 先天畸形由于创伤和癌症造成的先天异常或损害。目前的治疗程序需要治疗辅助手段 促进骨再生，因为颅骨骨缺损的愈合往往会导致纤维性骨不连无法保护 大脑因受伤而死亡。不幸的是，现有的基于重组生长因子的治疗辅助手段已经出现。 在有效性和安全性方面存在严重限制。骨骼干细胞的体外操作和扩增 也被建议作为基于生长因子的疗法的替代方案。然而，这些基于细胞的 再生战略表现出再生结果的多变性。因此，更有效的骨骼 颅面缺损的再生策略是非常必要的。 我们最近发现，PRX1是存在于小鼠颅骨缝中的干细胞的标志。 出生后表达PRX1的细胞(pnPRX1细胞)仅驻留在颅缝内，是 颅骨缺损区的再生，且数量随年龄增长而减少。我们目前的数据进一步表明， PnPRX1细胞通过向成骨细胞分化来响应Wnt信号的激活和Wnt的抑制 通过增殖来传递信号。根据这些发现，并以开发临床可行的替代药物为目标 目前的颅骨再生疗法，在目标1中，我们建议研究Wnt调节的细胞 控制pnPRX1细胞从缝合区向颅骨缺损区迁移的机制 离缝合线很远。在目标2中，我们建议测试Wnt抑制剂小分子或小分子的能力 移植缝线碎片诱导颅骨缺损区再生。 通过了解支配缝合的干细胞对血管的贡献的分子机制 颅骨缺损的再生和定义新的策略来利用这些干细胞在其 利基，我们的研究可能导致颅骨再生的新疗法的开发，帮助 颅面外科医生和神经外科医生需要再生骨骼的一部分，对 保护大脑。

Craniofacial surgeons and neurosurgeons perform numerous bone regeneration procedures to treat calvarial congenital abnormalities or lesions due to trauma and cancer. Current procedures require therapeutic aids to foster bone regeneration, as healing of calvarial bone defects often results in fibrous non-unions unable to protect the brain from injuries. Unfortunately, the available therapeutic aids based on recombinant growth factors present with severe limitations in terms of efficacy and safety. Ex vivo manipulation and expansion of skeletal stem cells has also been proposed as an alternative to the growth-factor based therapies. However, these cell-based regenerative strategies have shown variability of the regenerative outcomes. Therefore, more effective bone regenerative strategies for craniofacial defects are critically needed. We have recently shown that PRX1 is a marker of stem cells residing in the sutures of the mouse calvaria. Postnatal PRX1 expressing cells (pnPRX1+ cells) reside exclusively within the calvarial sutures, are required for regeneration of calvarial bone defects, and decline in number with age. Our current data further indicates that pnPRX1+ cells respond to activation of Wnt signaling by differentiating into osteoblasts and to inhibition of Wnt signaling by proliferating. With these findings and with the goal of developing clinically viable alternatives to the current calvarial bone regeneration therapies, in Aim 1 we propose to study the Wnt-regulated cellular mechanisms that control the migration of pnPRX1+ cells from the suture niche to a calvarial bone defect located remotely from the suture. In Aim 2 we propose to test the ability of Wnt inhibitor small molecules or of small fragments of transplanted sutures to induce regeneration of calvarial bone defects. By understanding the molecular mechanisms that govern the contribution of the stem cells of the suture to the regeneration of a calvarial bone defect and by defining novel strategies to harness these stem cells within their niches, our studies may lead to the development of novel therapies for calvarial bone regeneration, helping craniofacial surgeons and neurosurgeons with their need to regenerate a part of the skeleton so vital for protection of the brain.