Role and regulation of PRX1 expressing cells during calvarial bone regeneration

PRX1表达细胞在颅骨骨再生过程中的作用和调控

• 批准号: 10615414
• 负责人: Giuseppe Intini
• 金额: $ 4.9万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10615414
• 关键词: Adipose tissue; Adult; Age; Biocompatible Materials; Biology; Blood Circulation; Bone Marrow; Bone Regeneration; Brain; Brain Injuries; Calvaria; Cells; Clinical; Congenital Abnormality; Consensus; Craniofacial Abnormalities; Dangerousness; Data; Defect; Development; Distant; Edema; Embryo; Flow Cytometry; Fostering; Funding; Goals; Growth Factor; Inflammation; Investigation; Lead; Lesion; Malignant Neoplasms; Molecular; Mus; Muscle; Natural regeneration; Neurosurgeon; Operative Surgical Procedures; Osteoblasts; Osteogenesis; Outcome; Positioning Attribute; Procedures; Process; Proliferating; Recombinant Growth Factor; Regulation; Research; Research Personnel; Research Proposals; Role; Safety; Skeleton; Source; Surgeon; Surgical sutures; Testing; Therapeutic; Tissues; Transplantation; Trauma; Validation; WNT Signaling Pathway; autocrine; base; bone; brain tissue; craniofacial; cranium plastic repair; effective therapy; healing; in vivo; inhibitor; intravital microscopy; migration; novel; novel strategies; novel therapeutics; osteoblast differentiation; osteogenic; postnatal; regenerative; regenerative approach; regenerative therapy; skeletal stem cell; small molecule inhibitor; stem cell biomarkers; stem cell niche; stem cells; tool; transcription factor

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.

颅面外科医生和神经外科医生进行许多骨再生程序，以治疗颅骨 由于创伤和癌症而造成的先天性畸形或损伤。目前的程序需要治疗辅助手段， 促进骨再生，因为颅骨缺损的愈合通常会导致纤维性骨不连，无法保护 大脑受伤。不幸的是，现有的基于重组生长因子的治疗辅助剂 在功效和安全性方面具有严重的局限性。骨骼干细胞的体外操作和扩增 也被提出作为基于生长因子的疗法的替代物。然而，这些细胞 再生策略已经显示出再生结果的可变性。因此，更有效的骨 对于颅面缺损的再生策略是迫切需要的。 我们最近已经证明PRX1是驻留在小鼠颅骨缝中的干细胞的标志物。 出生后表达PRX1的细胞（pnPRX1+细胞）仅存在于颅骨缝内， 颅骨缺损的再生，数量随年龄增长而下降。我们目前的数据进一步表明， pnPRX1+细胞通过分化成成骨细胞和抑制Wnt信号传导对Wnt信号传导的激活作出响应 通过增殖来传递信号。有了这些发现，并以开发临床上可行的替代方案为目标， 目前颅骨骨再生疗法，在目的1中，我们提出研究Wnt调节的细胞， 控制pnPRX1+细胞从缝龛迁移到颅骨缺损的机制， 远离缝合线在目的2中，我们提出测试Wnt抑制剂小分子或小分子化合物的能力。 移植缝线的碎片以诱导颅骨缺损的再生。 通过了解控制缝合线干细胞对移植物的贡献的分子机制， 再生的颅骨骨缺损，并通过定义新的策略，利用这些干细胞在其 利基，我们的研究可能会导致开发新的颅骨再生疗法， 颅面外科医生和神经外科医生需要再生骨骼的一部分， 保护大脑。