Immune regulation of tendon healing

肌腱愈合的免疫调节

• 批准号: 10242326
• 负责人: Alice H Huang
• 金额: $ 51.39万
• 依托单位: ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-02 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10242326
• 关键词: Adoptive Transfer; Adult; Affect; Anti-Inflammatory Agents; Biological; Cells; Chronic; Cicatrix; Clinical; Cues; Data; Environment; Event; Failure; Fibrosis; Immune; Immune response; Immunologic Factors; Immunologics; Impairment; In Vitro; Inflammation; Inflammatory; Injury; Modeling; Molecular; Mus; Muscle; Natural regeneration; Neonatal; Outcome; Pain; Phase; Population; Production; Recovery; Recovery of Function; Recurrence; Regulatory T-Lymphocyte; Research; Research Priority; Role; Signal Transduction; Spleen; Structure; T-Lymphocyte; Tendinopathy; Tendon Injuries; Tendon structure; Testing; Tissues; Toxin; base; chemokine; cytokine; experimental study; gain of function; healing; immunoregulation; improved; macrophage; mutant; neonate; novel; receptor; recruit; regenerative; repaired; response; stem cells; tendon rupture; transcriptome sequencing; wound healing

PROJECT SUMMARY Tendon injury is a common problem characterized by slow recovery and high recurrence. Improving tendon healing to a regenerative state is therefore a crucial research priority, however the basic biological mechanisms remain unknown. Our overall objective is therefore to identify the cellular and molecular events that distinguish tenogenic regeneration vs fibrosis to improve adult tendon healing. One key feature in all wound healing is the immune environment. Injury initially induces an inflammatory type 1 response, followed by transition to an anti-inflammatory type 2 response. Imbalanced type 1 or type 2 responses are often associated with fibrotic healing or degeneration. To date, adaptive immune cells have rarely been investigated, even though T cell subpopulations regulate type 1 and type 2 immune responses, macrophage polarization, and in some cases can directly active tissue-resident stem cells. Due to this gap in research, the mechanisms by which specific immune cell populations create permissive environments for regeneration vs fibrosis are not known, especially for normally non-regenerative tissues such as tendon. We recently established novel models of functional tendon regeneration (neonatal mouse) and fibrosis (adult mouse), and identified cellular mechanisms that distinguish regeneration from fibrosis. We now propose that neonatal immune cells and the immune environment are crucial for tendon regeneration. To test this hypothesis, we will characterize the immune landscape during healing, determine the requirement of specific T cells in healing using loss and gain of function experiments, and determine the role of IL33 signaling in adult tendon healing. Successful completion will establish the immune response underlying tendon healing and identify a new and exciting role for T cells and IL33 signaling in tendon regeneration and fibrosis, respectively.

项目摘要 肌腱损伤是一个常见的问题，其特征是缓慢恢复和高复发。改善肌腱 因此，康复至再生状态是至关重要的研究优先级，但是基本的生物学 机制仍然未知。因此，我们的总体目标是确定细胞和分子事件 这区分了终结性再生与纤维化，以改善成年肌腱愈合。 所有伤口愈合中的一个关键特征是免疫环境。受伤最初引起炎症 1型响应，然后过渡到抗炎2型响应。不平衡1或类型2 反应通常与纤维化愈合或变性有关。迄今为止，自适应免疫细胞具有 即使T细胞亚群调节1型和2型免疫反应，也很少研究。 巨噬细胞极化，在某些情况下可以直接活跃组织居住的干细胞。由于这个差距 研究，特定免疫细胞群体创造宽松环境的机制 再生与纤维化尚不清楚，尤其是对于正常非再生组织（例如肌腱）。 我们最近建立了功能性肌腱再生（新生小鼠）和纤维化的新型模型 （成年小鼠），并确定了区分再生与纤维化的细胞机制。我们现在建议 新生儿免疫细胞和免疫环境对于肌腱再生至关重要。测试这个 假设，我们将在愈合过程中表征免疫景观，确定特定t的需求 使用功能实验的损失和增益在愈合中的细胞，并确定IL33信号在成人中的作用 肌腱愈合。成功完成将确定肌腱愈合的基础免疫反应和 分别在肌腱再生和纤维化中确定T细胞和IL33信号传导的新作用。

项目成果

Reparative and Maladaptive Inflammation in Tendon Healing.

• DOI: 10.3389/fbioe.2021.719047
• 发表时间: 2021
• 期刊: Frontiers in bioengineering and biotechnology
• 影响因子: 5.7
• 作者: Arvind V;Huang AH
• 通讯作者: Huang AH

Macrophage depletion impairs neonatal tendon regeneration.

• DOI: 10.1096/fj.202100049r
• 发表时间: 2021-06
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Howell KL;Kaji DA;Li TM;Montero A;Yeoh K;Nasser P;Huang AH
• 通讯作者: Huang AH

Innate and adaptive immune system cells implicated in tendon healing and disease.

• DOI: 10.22203/ecm.v043a05
• 发表时间: 2022-02-18
• 期刊: European cells & materials
• 影响因子: 3.1