Immune regulation of tendon healing

项目总结 肌腱损伤是一种常见的问题，其特点是恢复慢，复发率高。改良肌腱 因此，修复到再生状态是一个关键的研究重点，然而基础生物学 机制仍不清楚。因此，我们的总体目标是确定细胞和分子事件 区分肌腱再生和纤维化，以促进成人肌腱愈合。 所有伤口愈合的一个关键特征是免疫环境。损伤最初会导致炎症 第一型反应，然后过渡到抗炎第二型反应。不平衡类型1或类型2 反应通常与纤维性愈合或变性有关。到目前为止，适应性免疫细胞已经 很少有人研究，即使T细胞亚群调节1型和2型免疫反应， 巨噬细胞极化，在某些情况下可以直接激活组织驻留的干细胞。由于这一差距， 研究，特定免疫细胞群体创造允许环境的机制 再生与纤维化之间的关系尚不清楚，尤其是对于正常情况下不可再生的组织，如肌腱。 我们最近建立了新的功能性肌腱再生(新生小鼠)和纤维化模型。 (成年小鼠)，并确定了区分再生和纤维化的细胞机制。我们现在提议 新生儿免疫细胞和免疫环境对肌腱再生至关重要。为了测试这一点 假设，我们将描述愈合过程中的免疫环境，确定特定T细胞的需求 利用细胞在愈合过程中的功能丧失和获得实验，确定IL33信号在成人中的作用 肌腱愈合。成功完成后将建立肌腱愈合和修复的免疫反应 确定T细胞和IL33信号分别在肌腱再生和纤维化中的新的和令人兴奋的作用。

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.