Direct and indirect contributions of perivascular stem cells to bone healing

血管周围干细胞对骨愈合的直接和间接贡献

• 批准号: 10203809
• 负责人: AARON W JAMES
• 金额: $ 27.59万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-08-28 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10203809
• 关键词: Address; Adipose tissue; Affect; Age; Animals; Autologous Transplantation; Basic Science; Blood; Blood Vessels; Bone Marrow Stem Cell; Bone Regeneration; Bone Tissue; Bypass; Cell Communication; Cell Differentiation process; Cells; Clinical; Complex; Data; Defect; Diagnostic radiologic examination; Disadvantaged; Endothelial Cells; Endothelium; Fatty acid glycerol esters; Fluorescence-Activated Cell Sorting; Frequencies; Growth Factor; Head; Heterogeneity; Hour; Human; Implant; In Vitro; Literature; Mediating; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Modeling; Mus; Operative Surgical Procedures; Oral; Orthopedics; Osteoblasts; Osteoporosis; Osteoporotic; Outcome; Pathology; Reporter; Research Personnel; Resistance; Risk; Series; Signal Transduction; Source; Tissue Donors; Tissue Engineering; Tissues; Translational Research; Transplantation; Visualization; angiogenesis; bone; bone healing; bone loss; bone marrow mesenchymal stem cell; cell motility; cell preparation; cell type; clinical application; clinical translation; cost; dental surgery; improved; in vivo; insight; morphogens; neovascularization; novel; osteogenic; osteoporotic bone; osteoprogenitor cell; paracrine; prospective; repaired; skeletal regeneration; stem cells; transplant model; treatment comparison; treatment group

PROJECT SUMMARY As an alternative to autograft bone, mesenchymal stem cells (MSC) have been employed to accelerate bone repair. However, current MSC sources have significant drawbacks, including: (1) scarce availability, (2) need for culture, and (3) significant cell heterogeneity with decreased bone-forming efficacy. Our solution is the use of a novel, purified and uncultured stem cell source, known as Perivascular Stem Cells (PSC). PSC are prospectively purified ancestors of culture-derived, traditional MSC, and are identified by their presence around vessels. Unlike bone marrow stem cells (BMSC), PSC have significant advantages for clinical translation, including: (1) isolation by fluorescence activated cell sorting (FACS) rather than culture, (2) high homogeneity, and (3) high quantity for clinical application. Our data show that PSC exert bone healing effects via both direct and paracrine mechanisms, including a combination of pro-osteogenic and pro-vasculogenic effects on host bone tissue. Exciting recent data suggest that PSC frequency, viability, growth and differentiation factor (GDF) elaboration and osteogenic differentiation are resistant to the detrimental effects of osteoporotic bone loss. In contrast, BMSC show reduced numbers, proliferation, and osteogenic differentiation potential with osteoporosis. This marked difference has led us to directly and systematically compare the bone healing potential of PSC versus BMSC in the current proposal. Overall, the following Early Stage / New Investigator application will address the cellular and signaling mechanisms through which perivascular stem cells promote bone healing through direct and indirect effects, and their unique resistance to osteoporotic conditions. AIM 1: Evaluate the direct and paracrine effects of PSC in bone healing. Through a systematic series of studies, we will examine the effects of PSC on osteoprogenitor cell migration and differentiation, as well as angiogenesis and neovascularization in bone healing. Osteoblast and endothelial cell reporter animals will be utilized to compare host:donor cell contributions in our previously described femoral segmental defect (FSD) model. Studies will be performed head-to-head with culture-derived BMSC application. Differences in bone healing outcomes between treatment groups will be statistically correlated with in vitro GDF elaboration. AIM 2: Demonstrate the importance of host versus donor osteoporosis in PSC bone healing. As mentioned, PSC demonstrate marked resistance to the detrimental effects of osteoporotic bone loss. However, our pilot data suggest that osteoporotic status of the ‘host bone’ but not ‘donor MSC’ may impact bone healing. Here, we will determine the extent to which osteoporosis within transplanted PSC or host bone tissue affects bone healing. Studies will be performed head-to-head with culture-derived BMSC application in our FSD model. Differences in bone healing will be correlated with GDF and bone inhibitory signal expression.

项目摘要 作为自体移植骨的替代方案，间充质干细胞（MSC）已被雇用以加速 骨修复。但是，当前的MSC来源具有明显的缺点，包括：（1）稀缺性，（2） 培养的需求，以及（3）显着的细胞异质性，骨形成效率降低。我们的解决方案是 新型，纯化和未培养的干细胞源的使用，称为血管周围干细胞（PSC）。 PSC可能是文化衍生的传统MSC的纯化祖先，并由其确定 船只周围的存在。与骨髓干细胞（BMSC）不同，PSC具有显着的优势 临床翻译，包括：（1）通过荧光激活的细胞分类（FACS）而不是培养分离，（2） 高均匀性，（3）临床应用的大量。 我们的数据表明，PSC通过直接和旁分泌机制执行骨骼愈合效果，包括 对宿主骨组织的促稳态和促血管生成作用的结合。令人兴奋的最近数据暗示 PSC频率，生存力，生长和分化因子（GDF）阐述和成骨分化 对骨质疏松骨质流失的有害作用有抵抗力。相反，BMSC显示数量减少， 骨质疏松症的增殖和成骨分化潜力。这种明显的差异使我们进入了 直接和系统地比较当前建议中PSC与BMSC的骨骼愈合潜力。 总体而言，以下早期 /新研究者的应用将解决细胞和信号传导 血管周干细胞通过直接和间接作用促进骨愈合的机制， 以及它们对骨质疏松条件的独特耐药性。 目标1：评估PSC在骨愈合中的直接和旁分泌作用。通过系统的系列 在研究中，我们将研究PSC对骨基因的细胞迁移和分化的影响，以及 骨愈合中的血管生成和新血管形成。成骨细胞和内皮细胞报告基因动物将是 用于比较宿主：我们先前描述的股骨分段缺陷（FSD）中的供体细胞贡献 模型。研究将通过培养衍生的BMSC应用正面进行。骨骼的差异 治疗组之间的愈合结果将在统计上与体外GDF阐述相关。 AIM 2：证明宿主与供体骨质疏松症在PSC骨愈合中的重要性。作为 提到，PSC证明了对骨质疏松骨质流失的有害影响的明显抗性。 但是，我们的试点数据表明，“宿主骨骼”的骨质疏松状态可能会影响“宿主骨骼”，而不是“供体MSC” 骨骼愈合。在这里，我们将确定移植的PSC或宿主骨中的骨质疏松症的程度 组织会影响骨骼愈合。研究将与培养衍生的BMSC在中的面对面进行。 我们的FSD模型。骨愈合的差异将与GDF和骨抑制信号表达相关。

项目成果

Overlapping features of rapidly progressive osteoarthrosis and Charcot arthropathy.

• DOI: 10.1016/j.jor.2019.02.015
• 发表时间: 2019-05
• 期刊: Journal of orthopaedics
• 影响因子: 1.5
• 作者: Takashi Sono;C. Meyers;Daniel Miller;Catherine Ding;E. McCarthy;A. James

Pericytes for Therapeutic Bone Repair.

用于治疗性骨修复的周细胞。

• DOI: 10.1007/978-3-030-02601-1_3
• 发表时间: 2018
• 期刊: Advances in experimental medicine and biology
• 作者: Meyers,CarolynA;Casamitjana,Joan;Chang,Leslie;Zhang,Lei;James,AaronW;Péault,Bruno
• 通讯作者: Péault,Bruno

Pharmacological inhibition of DKK1 promotes spine fusion in an ovariectomized rat model.

DKK1 的药理学抑制可促进卵巢切除大鼠模型中的脊柱融合。

• DOI: 10.1016/j.bone.2022.116456
• 发表时间: 2022
• 期刊: Bone
• 影响因子: 4.1
• 作者: Li,Zhao;Xing,Xin;Gomez-Salazar,MarioArmando;Xu,Mingxin;Negri,Stefano;Xu,Jiajia;James,AaronW
• 通讯作者: James,AaronW

Aldehyde Dehydrogenase, a Marker of Normal and Malignant Stem Cells, Typifies Mesenchymal Progenitors in Perivascular Niches.

• DOI: 10.1093/stcltm/szad024
• 发表时间: 2023-07-14
• 期刊: Stem cells translational medicine
• 影响因子: 6

NGF-p75 signaling coordinates skeletal cell migration during bone repair.

• DOI: 10.1126/sciadv.abl5716
• 发表时间: 2022-03-18
• 期刊: Science advances
• 影响因子: 13.6
• 作者: Xu J;Li Z;Tower RJ;Negri S;Wang Y;Meyers CA;Sono T;Qin Q;Lu A;Xing X;McCarthy EF;Clemens TL;James AW
• 通讯作者: James AW