Small RNA-Modulated Exosome Mimetics For Craniofacial Regeneration
用于颅面再生的小 RNA 调节外泌体模拟物
基本信息
- 批准号:10394941
- 负责人:
- 金额:$ 2.29万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-05-01 至 2022-08-28
- 项目状态:已结题
- 来源:
- 关键词:AffectAllograftingAnimal ModelApatitesAutologousBMP2 geneBone RegenerationCaffeic AcidsCell TransplantationCellsCephalicCharacteristicsChronicClinicalCommunicationCraniofacial AbnormalitiesDataDefectDegenerative DisorderDepositionDevelopmentDiseaseDrug CarriersDrug KineticsExcisionExhibitsFaceFeedbackFoundationsFutureGelatinGenerationsGoalsGrowth FactorHeadHistologicHomeostasisHomingHumanImmobilizationImpairmentImplantLabelMandibleMeasurementMediatingMedicalMesenchymal Stem CellsMetabolismMicroRNAsMineralsModelingMorbidity - disease rateMusNatural regenerationOperative Surgical ProceduresOsteoblastsPlayProcessProductionPropertyQuality of lifeRattusRegulationResearchRodentRoleSignal TransductionSiteSmall Interfering RNASmall RNAStainsStimulusStructureSurgical FlapsTherapeuticTransfectionTransport ProcessTraumaTreatment EfficacyUp-RegulationVesicleWorkX-Ray Computed Tomographyantagonistbasebonebone healingclinical practicecomparison groupcostcraniofacialcraniofacial bonecraniofacial repairdosageexosomeextracellular vesiclesfluorescence imaginghealingimmunogenicityimprovedmicroCTmigrationmimeticsnovel strategiesnovel therapeuticsosteogenicparacrinepreventpublic health relevancereconstructionregenerativerepairedresponserestorationscaffoldskeletalskeletal regenerationskeletal stem celltissue regenerationtumor
项目摘要
Abstract
Large craniofacial defects remain an extraordinary challenge to clinical surgical reconstruction. Conventional
approaches of auto/allografting for clinical craniofacial reconstruction are significantly compromised by
availability and donor-site morbidity. Mesenchymal stem cells (MSCs) with multipotency are increasingly
employed as a cell-based approach for skeletal regeneration. Nonetheless, accumulative evidences suggest
that contribution of MSCs to regenerated tissues is limited while stimulation of local healing processes through
paracrine secretion exerts more important roles. MSC-derived extracellular vesicles (EVs) have shown
regenerative potency in varying animal models and displayed therapeutic advantages like intrinsic homing
effect, stability, low immunogenicity and effective signaling stimulation. However, the widespread use of
exosome-mediated treatment still requires the significant improvement of production yield and regenerative
ability. Developing a scalable approach like generation of exosome mimetics (EMs) with substantial yields has
been investigated in previous studies. Additionally, exosome-mediated cargo of exogenous therapeutic factors
like siRNAs has been conducted to improve its regenerative capability. The exogenous transport of these
factors is also growing concerns of high cost, poor pharmacokinetics and inefficiency. Herein, the
augmentation of intrinsic inductive/therapeutic molecules within exosomes exhibits a promising therapeutic
strategy. Skeletal cells secrete important growth factors like BMP2, which incite osteoblastic commitment of
skeletal progenitor cells and subsequent mineral deposition. In response to BMP stimulus, MSCs or
osteoblasts elevate BMP antagonist like noggin, suggesting a negative feedback to prevent overexposure of
BMP signaling. Introduction of exogenous noggin was revealed to impair cranial formation while inhibition of
endogenous noggin promoted cranial regeneration by activating endogenous BMP signaling. These
observations highlight the potency of noggin suppression on up-regulation of endogenous BMP activity and
subsequent osseous deposition. In our preliminary studies, EMs were generated from MSCs via a distinctive
extrusion approach, demonstrating high yields of exosomes with apparent osteogenic induction. Moreover,
EMs obtained from noggin-suppression MSCs (EM-NG) revealed the elevated noggin siRNA and osteogenic
potency. Together, we hypothesize that EM-NG could enhance osteoblastic commitment of endogenous
skeletal stem cells (SSCs) and craniofacial regeneration. Two specific aims are proposed to investigate this
hypothesis: 1) To investigate the effect of EM-NG on endogenous cranial SSCs and bone healing; 2) To
examine the implant of EM-NG-laden scaffold for restoration of segmental mandibular defects. The
completion of this proposal will offer significant foundation to further develop effective cell-free approaches for
clinical craniofacial defect repair. The additional roles of EMs on craniofacial restoration will be further explored
in large animal model in future. These future studies will be proposed in the subsequent R01 application.
摘要
颅面大面积缺损的修复是临床外科面临的一个巨大挑战。常规
用于临床颅面重建的自体/异体移植方法受到以下因素的严重影响:
可用性和供体部位发病率。具有多能性的间充质干细胞(MSC)越来越多地被用于治疗癌症。
作为一种基于细胞的骨骼再生方法。尽管如此,累积的证据表明
MSC对再生组织的贡献是有限的,而刺激局部愈合过程,
旁分泌发挥更重要的作用。MSC衍生的细胞外囊泡(EV)已经显示
在不同的动物模型中表现出再生能力,并显示出治疗优势,如内在归巢
有效、稳定、低免疫原性和有效的信号刺激。然而,广泛使用
外泌体介导的处理仍然需要显著提高产量和再生能力,
能力开发一种可扩展的方法,如产生具有大量产量的外泌体模拟物(EM),
在以前的研究中进行了调查。此外,外泌体介导的外源性治疗因子的货物
类似的siRNA已经被用来提高其再生能力。这些物质的外源性运输
此外,成本高、药代动力学差和效率低也是人们日益关注的因素。本文
外来体内的内在诱导/治疗分子的增加显示出有希望的治疗效果,
战略骨细胞分泌重要的生长因子,如BMP 2,刺激成骨细胞的承诺,
骨骼祖细胞和随后的矿物质沉积。响应于BMP刺激,MSC或
成骨细胞升高BMP拮抗剂,如noggin,提示负反馈,以防止过度表达,
BMP信号。外源性头蛋白的引入被揭示会损害颅骨的形成,而抑制
内源性noggin通过激活内源性BMP信号促进颅骨再生。这些
观察结果强调了头蛋白抑制对内源性BMP活性上调的效力,
随后的骨质沉积。在我们的初步研究中,通过一种独特的方法从MSC产生EM。
挤出方法,证明了具有明显成骨诱导的外泌体的高产率。此外,委员会认为,
从头蛋白抑制MSC(EM-NG)获得的EM揭示了升高的头蛋白siRNA和成骨细胞的表达。
力量总之,我们假设EM-NG可以增强成骨细胞的内源性骨转移,
骨骼干细胞(SSC)和颅面再生。提出了两个具体的目标来调查这一点
假设:1)研究EM-NG对内源性颅骨SSC和骨愈合的影响; 2)
研究负载EM-NG的支架植入修复下颌骨节段性缺损。的
该提案的完成将为进一步开发有效的无细胞方法提供重要基础,
临床颅面缺损修复EM在颅面修复中的其他作用将进一步探讨
在未来的大型动物模型中。这些未来的研究将在随后的R 01申请中提出。
项目成果
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Jiabing Fan其他文献
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{{ truncateString('Jiabing Fan', 18)}}的其他基金
Small RNA-Modulated Exosome Mimetics For Craniofacial Regeneration
用于颅面再生的小 RNA 调节外泌体模拟物
- 批准号:
10741983 - 财政年份:2022
- 资助金额:
$ 2.29万 - 项目类别:
Small RNA-Modulated Exosome Mimetics For Craniofacial Regeneration
用于颅面再生的小 RNA 调节外泌体模拟物
- 批准号:
10196364 - 财政年份:2021
- 资助金额:
$ 2.29万 - 项目类别:
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