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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：
STUART B GOODMAN
金额：
$ 33.52万
依托单位：
STANFORD UNIVERSITY
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：
https://reporter.nih.gov/project-details/10222569
关键词：
Acute Age Aging Animals Anti-Inflammatory Agents Biological Assay Bone Density Bone Diseases Bone Marrow Bone remodeling CMV promoter Cells Chronic Coculture Techniques Custom Disease Elderly Environment Exposure to Female Fluorescence Grant Immune Implant Inflammation Inflammatory Infusion procedures Interleukin-4 Lentivirus Vector Lipopolysaccharides Luciferases Medical Device Mesenchymal Differentiation Mesenchymal Stem Cell Transplantation Mesenchymal Stem Cells Modeling Molecular Mus NF-kappa B Orthopedics Osseointegration Osteoclasts Osteogenesis Osteolysis Outcome Phase Phenotype Plasmids Population Process Production Prosthesis Replacement Arthroplasty Reporter Research Signal Transduction Stimulus System TNF gene Therapeutic Effect Tissues Transplantation aged arginase body system bone bone healing bone loss chemokine chronic inflammatory disease clinically relevant cytokine efficacious treatment immunoregulation implantation improved in vivo inflammatory bone loss macrophage male minimally invasive novel osteogenic paracrine particle preconditioning regenerative regenerative tissue sex stem cell therapy stem cells transcription factor translational 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：
Journal of long-term effects of medical implants
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：
JOURNAL OF BIOMEDICAL MATERIALS RESEARCH PART A
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.