Enhanced Bone Healing Around Implants by Transplanted NF-kB Driven Immunomodulating MSCs
通过移植 NF-kB 驱动的免疫调节 MSC 增强植入物周围的骨愈合
基本信息
- 批准号:10222569
- 负责人:
- 金额:$ 33.52万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2012
- 资助国家:美国
- 起止时间:2012-09-15 至 2023-01-31
- 项目状态:已结题
- 来源:
- 关键词:AcuteAgeAgingAnimalsAnti-Inflammatory AgentsBiological AssayBone DensityBone DiseasesBone MarrowBone remodelingCMV promoterCellsChronicCoculture TechniquesCustomDiseaseElderlyEnvironmentExposure toFemaleFluorescenceGrantImmuneImplantInflammationInflammatoryInfusion proceduresInterleukin-4Lentivirus VectorLipopolysaccharidesLuciferasesMedical DeviceMesenchymal DifferentiationMesenchymal Stem Cell TransplantationMesenchymal Stem CellsModelingMolecularMusNF-kappa BOrthopedicsOsseointegrationOsteoclastsOsteogenesisOsteolysisOutcomePhasePhenotypePlasmidsPopulationProcessProductionProsthesisReplacement ArthroplastyReporterResearchSignal TransductionStimulusSystemTNF geneTherapeutic EffectTissuesTransplantationagedarginasebody systembonebone healingbone losschemokinechronic inflammatory diseaseclinically relevantcytokineefficacious treatmentimmunoregulationimplantationimprovedin vivoinflammatory bone lossmacrophagemaleminimally invasivenovelosteogenicparacrineparticlepreconditioningregenerativeregenerative tissuesexstem cell therapystem cellstranscription factortranslational approach
项目摘要
Acute transient inflammation is crucial for initiation of bone healing, osseointegration of implants, osteogenic
differentiation of MSCs, and immunomodulation. However, harmful chronic inflammation and bone loss
(osteolysis) are induced by adverse stimuli including wear byproducts from joint replacements (JR). Nuclear
Factor kappa B (NF-κB) is a critical transcription factor in both macrophages (mϕ) and MSCs that regulates
inflammation, bone formation/remodeling, and aging. We showed that preconditioning MSCs with lipopoly-
saccharide (LPS) and tumor necrosis factor-α (TNF-α) to induce acute transient activation of NF-κB
synergistically enhances osteogenesis, and modulates mϕ polarization from a pro-inflammatory (M1) to an
anti-inflammatory pro-regenerative (M2) phenotype. Furthermore, inhibition of persistent NF-κB signaling using
an NF-κB decoy OligoDeoxyNucleotide (ODN) was shown to mitigate inflammatory bone loss. We have
genetically modified MSCs to sense NF-κB activation and then increase production of the anti-inflammatory
pro-regenerative cytokine IL-4. The purpose of this grant is to accelerate net bone formation and mitigate
chronic inflammation and osteolysis via NF-kB driven immunomodulation using preconditioned or genetically
modified MSCs transplanted to the local environment.
Specific Aim #1a -To define the critical immunomodulatory interactions of preconditioned vs. NF-κB sensing
and IL-4 secreting MSCs on mϕ exposed to wear byproducts from orthopaedic implants.
Specific Aim #1b - To enhance osteogenesis by using preconditioned vs. NF-κB sensing and IL-4 secreting
MSCs in an MSC/mϕ co-culture model exposed to wear byproducts from orthopaedic implants.
Specific Aim #2a - To demonstrate the therapeutic effects of transplanted preconditioned MSCs on bone
during the acute inflammatory stage (simulating the stage of initial implantation of a prosthesis and
osseointegration) using the murine continuous femoral particle infusion model.
Specific Aim #2b - To demonstrate the therapeutic effects of preconditioned vs. NF-κB sensing and IL-4
secreting MSCs on net bone formation during the chronic inflammatory stage (simulating established wear
particle disease) using the murine continuous femoral particle infusion model.
Specific Aim #3 - To demonstrate that the above principles of modulating acute and chronic inflammation are
valid irrespective of animal sex (male vs. female mice) or age (young vs. elderly mice) in vivo. We hypothesize
that NF-κB preconditioning or NF-κB sensing and IL-4 secreting MSCs will enhance the osteogenic and
immunomodulatory signaling of MSCs, enhancing bone formation via crosstalk by mϕ and MSCs. NF-kB driven
immunomodulation of MSCs should mitigate particle-induced inflammation, osteoclast activation, and enhance
bone formation in young and aged, male and female mice. NF-kB driven immune modulation of MSCs is novel,
mechanistic, and directly translational to inflammatory disorders in other organ systems.
急性短暂性炎症对骨愈合、种植体骨整合、成骨至关重要
项目成果
期刊论文数量(76)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Innate immunity sensors participating in pathophysiology of joint diseases: a brief overview.
- DOI:10.1615/jlongtermeffmedimplants.2014010825
- 发表时间:2014
- 期刊:
- 影响因子:0
- 作者:Gallo J;Raska M;Konttinen YT;Nich C;Goodman SB
- 通讯作者:Goodman SB
Modulation of mouse macrophage polarization in vitro using IL-4 delivery by osmotic pumps.
- DOI:10.1002/jbm.a.35278
- 发表时间:2015-04
- 期刊:
- 影响因子:4.9
- 作者:Pajarinen, Jukka;Tamaki, Yasunobu;Antonios, Joseph K.;Lin, Tzu-Hua;Sato, Taishi;Yao, Zhenyu;Takagi, Michiaki;Konttinen, Yrjo T.;Goodman, Stuart B.
- 通讯作者:Goodman, Stuart B.
Preconditioning of murine mesenchymal stem cells synergistically enhanced immunomodulation and osteogenesis.
- DOI:10.1186/s13287-017-0730-z
- 发表时间:2017-12-06
- 期刊:
- 影响因子:7.5
- 作者:Lin T;Pajarinen J;Nabeshima A;Lu L;Nathan K;Jämsen E;Yao Z;Goodman SB
- 通讯作者:Goodman SB
Aging, inflammation, stem cells, and bone healing.
- DOI:10.1186/s13287-016-0300-9
- 发表时间:2016-03-22
- 期刊:
- 影响因子:7.5
- 作者:Gibon E;Lu L;Goodman SB
- 通讯作者:Goodman SB
Polymer-DNA Nanoparticle-Induced CXCR4 Overexpression Improves Stem Cell Engraftment and Tissue Regeneration in a Mouse Hindlimb Ischemia Model.
- DOI:10.7150/thno.12866
- 发表时间:2016
- 期刊:
- 影响因子:12.4
- 作者:Deveza L;Choi J;Lee J;Huang N;Cooke J;Yang F
- 通讯作者:Yang F
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STUART B GOODMAN其他文献
STUART B GOODMAN的其他文献
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{{ truncateString('STUART B GOODMAN', 18)}}的其他基金
Autologous Bone Marrow Aspirate Concentrate for the Treatment of Osteonecrosis of the Femoral Head
自体骨髓抽吸浓缩液治疗股骨头坏死
- 批准号:
10658324 - 财政年份:2023
- 资助金额:
$ 33.52万 - 项目类别:
Customized MSCs to Enhance Healing of Bone Defects
定制间充质干细胞促进骨缺损的愈合
- 批准号:
10115615 - 财政年份:2018
- 资助金额:
$ 33.52万 - 项目类别:
Tissue Engineering Approaches for Improved Treatment of Early Stage Osteonecrosis of the Hip
改善早期髋骨坏死治疗的组织工程方法
- 批准号:
10394866 - 财政年份:2018
- 资助金额:
$ 33.52万 - 项目类别:
Tissue Engineering Approaches for Improved Treatment of Early Stage Osteonecrosis of the Hip
改善早期髋骨坏死治疗的组织工程方法
- 批准号:
9921203 - 财政年份:2018
- 资助金额:
$ 33.52万 - 项目类别:
Tissue Engineering Approaches for Improved Treatment of Early Stage Osteonecrosis of the Hip
改善早期髋骨坏死治疗的组织工程方法
- 批准号:
9594129 - 财政年份:2018
- 资助金额:
$ 33.52万 - 项目类别:
Customized MSCs to Enhance Healing of Bone Defects
定制间充质干细胞促进骨缺损的愈合
- 批准号:
9897409 - 财政年份:2018
- 资助金额:
$ 33.52万 - 项目类别:
Enhanced Bone Healing Around Implants by Transplanted NF-kB Driven Immunomodulating MSCs
通过移植 NF-kB 驱动的免疫调节 MSC 增强植入物周围的骨愈合
- 批准号:
9528468 - 财政年份:2012
- 资助金额:
$ 33.52万 - 项目类别:
Wear Particle Disease and NF-kappa B Signaling
磨损颗粒病和 NF-kappa B 信号传导
- 批准号:
8419372 - 财政年份:2012
- 资助金额:
$ 33.52万 - 项目类别:
Wear Particle Disease and NF-kappa B Signaling
磨损颗粒病和 NF-kappa B 信号传导
- 批准号:
8543631 - 财政年份:2012
- 资助金额:
$ 33.52万 - 项目类别:
Wear Particle Disease and NF-kappa B Signaling
磨损颗粒病和 NF-kappa B 信号传导
- 批准号:
8733519 - 财政年份:2012
- 资助金额:
$ 33.52万 - 项目类别:
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