Facilitating cartilage regeneration by heterogeneous progenitor cells

通过异质祖细胞促进软骨再生

• 批准号: 7643619
• 负责人: Ryan Michael Porter
• 金额: $ 8.56万
• 依托单位: BETH ISRAEL DEACONESS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2010-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7643619
• 关键词: Address; Affect; Animal Model; Arthritis; Articular Range of Motion; Automobile Driving; Award; Behavior; Biological; Caring; Cartilage; Cartilage Matrix; Cartilage injury; Cell Count; Cells; Chondrocytes; Chondrogenesis; Clinical; Complex; Connective Tissue; Defect; Degenerative polyarthritis; Development; Differentiation and Growth; Environment; Free Radicals; Goals; Grant; Human; Imaging Techniques; In Situ; In Vitro; Inflammation; Inflammatory; Interleukin-1; Interleukins; Joints; Lead; Learning; Ligaments; Literature; Mediating; Mediator of activation protein; Mentors; Mesenchymal Stem Cells; Modality; Modeling; Monitor; Musculoskeletal; Natural regeneration; Nude Rats; Operative Surgical Procedures; Pain; Pathogenesis; Peptide Hydrolases; Phase; Play; Population; Positioning Attribute; Principal Investigator; Proliferating; Quality of life; Reporter; Research; Role; Secondary to; Signal Transduction; Site; Stem cells; Techniques; Time; Tissue Engineering; Tissues; Training; Training Support; Transplantation; Trauma; Treatment Protocols; Tumor Necrosis Factor-alpha; Tumor Necrosis Factors; Work; Wound Healing; articular cartilage; bone; cartilage regeneration; cytokine; in vivo; inhibitor/antagonist; injured; injury and repair; interest; joint injury; programs; regenerative; repaired; retinal rods; success; tissue regeneration; tool

DESCRIPTION (provided by applicant): Because articular cartilage lacks the ability for intrinsic repair, injuries following trauma persist and can ultimately lead to post-traumatic osteoarthritis (OA) with resulting pain, reduced range of joint motion and severely impaired quality-of-life. Current standards-of-care for cartilage injuries cannot reliably provide sustained clinical improvement, so there is much interest in the development of alternative, biological approaches towards repair/regeneration. Tissue engineering approaches typically involve the recruitment or transplantation of endogenous mesenchymal progenitor cells (MFCs) to the defect site. Under controlled conditions, these cells have the potential to proliferate, differentiate along the relevant musculoskeletal lineage and regenerate damaged tissue matrix. However, the intra-articular environment is often hostile to chondrogenesis; specifically, inflammation within the injured joint can inhibit tissue regeneration. Joint inflammation is mediated by local levels of cytokines such as interleukin (IL)-1 and tumor necrosis factor (TNF)'-a. Although pro-inflammatory cytokines play an important role in the pathogenesis of OA, there is almost no literature on how they affect cartilage repair strategies involving MFCs. The central hypothesis driving this research plan is that inflammation secondary to joint trauma or subsequent surgical intervention can inhibit the regenerative activity of MFCs introduced to the cartilage defect, thus inhibiting repair. During the mentored phase of this plan, additional tools will be learned to better characterize MPC activity both in vitro and in vivo. Specifically, a toolset of reporter constructs will be developed for monitoring the state of human MPC differentiation, characterizing this toolset in the context of chondrogenesis in vitro. This period will also be spent becoming proficient in imaging techniques for non-invasively tracking inflammatory and chondrogenic activity in vivo, using a nude rat model of MPC delivery to cartilage defects. Upon transition to the independent phase (ROD) of this award, inhibitors of pro-inflammatory cytokine activity will be evaluated for their capability to rescue the chondrogenic behavior of MPCs in vitro. Promising regenerative regimens will be applied to both immunologically-competent and -incompetent animal models of joint injury to determine the ability of MPCs to repair/regenerate cartilage when protected from pathological levels of pro- inflammatory cytokines. At the end of this project period, we will have a better understanding of how the joint environment - particularly inflammatory signaling cascades - impacts the ultimate success of cartilage regeneration strategies using heterogeneous progenitor cell populations.

描述（由申请人提供）：由于关节软骨缺乏内在修复能力，创伤后损伤持续存在，最终可能导致创伤后骨关节炎（OA），导致疼痛、关节活动范围减少和生活质量严重受损。目前软骨损伤的护理标准不能可靠地提供持续的临床改善，因此人们对开发替代的生物修复/再生方法很感兴趣。组织工程方法通常涉及将内源性间充质祖细胞（MFC）募集或移植到缺损部位。在受控条件下，这些细胞具有增殖、沿相关肌肉骨骼谱系沿着分化和再生受损组织基质的潜力。然而，关节内环境通常不利于软骨形成;具体而言，损伤关节内的炎症可抑制组织再生。关节炎症由局部水平的细胞因子如白细胞介素（IL）-1和肿瘤坏死因子（TNF α-α）介导。虽然促炎细胞因子在OA的发病机制中起着重要作用，但几乎没有关于它们如何影响涉及MFC的软骨修复策略的文献。推动这项研究计划的中心假设是，继发于关节创伤或随后的手术干预的炎症可以抑制引入软骨缺损的MFC的再生活性，从而抑制修复。在本计划的指导阶段，将学习其他工具，以更好地表征MPC在体外和体内的活性。具体而言，将开发报告构建体的工具集用于监测人MPC分化的状态，在体外软骨形成的背景下表征该工具集。这段时间也将花费成为熟练的成像技术，用于非侵入性跟踪体内炎症和软骨形成的活动，使用裸大鼠模型的MPC交付软骨缺损。在过渡到该奖项的独立阶段（ROD）后，将评估促炎细胞因子活性抑制剂在体外拯救MPC软骨形成行为的能力。有希望的再生方案将应用于关节损伤的免疫学上有能力的和免疫学上无能力的动物模型，以确定MPC在免受病理水平的促炎性细胞因子的影响时修复/再生软骨的能力。在本项目结束时，我们将更好地了解关节环境-特别是炎症信号级联-如何影响使用异质祖细胞群的软骨再生策略的最终成功。

项目成果

Sustained intra-cartilage delivery of low dose dexamethasone using a cationic carrier for treatment of post traumatic osteoarthritis.

• DOI: 10.22203/ecm.v034a21
• 发表时间: 2017-12-05
• 期刊: European cells & materials
• 影响因子: 3.1
• 作者: Bajpayee AG;De la Vega RE;Scheu M;Varady NH;Yannatos IA;Brown LA;Krishnan Y;Fitzsimons TJ;Bhattacharya P;Frank EH;Grodzinsky AJ;Porter RM
• 通讯作者: Porter RM

TNFα and IL-1β influence the differentiation and migration of murine MSCs independently of the NF-κB pathway.

• DOI: 10.1186/scrt492
• 发表时间: 2014-08-27
• 期刊: Stem cell research & therapy
• 影响因子: 7.5
• 作者: Sullivan CB;Porter RM;Evans CH;Ritter T;Shaw G;Barry F;Murphy JM
• 通讯作者: Murphy JM