Biomaterials-directed regenerative immunotherapies

项目摘要 因创伤、疾病或先天畸形造成的组织丢失仍是一个棘手的临床问题 挑战。在人类如何修复和从组织损伤中恢复方面存在严重的缺陷，很少有 再生医学的创新已经达到临床或改善了护理标准。形成 功能障碍的疤痕组织仍然是体内修复的默认途径。免疫系统是第一个 对创伤的反应然而这种反应及其协调组织修复的能力在很大程度上被忽视了。 工程组织通常包括将细胞和生物材料支架与一套生物线索相结合 以刺激新组织的发育。到目前为止，这些组织工程工具的设计目标是 干细胞、血管发育或组织形态发生。在这里，我们正在转移组织的焦点 直接对免疫系统进行治疗性操作的工程设计。取得的显著成功 癌症免疫疗法突显了适应性免疫系统是如何适应极其强大的 干预和再生免疫疗法的可能性。我们引入了再生的概念 结合并操纵T细胞效应类的免疫疗法。对组织的新认识 特异性免疫、衰老细胞在组织创伤和修复反应中的作用将与我们的 关于促再生T细胞的新发现和意想不到的发现。免疫亚群的单细胞基因组分析， 基质和衰老细胞将与新的计算算法相结合，用于开发组织- 在动态平衡、衰老、创伤和疾病中的特定衰老和免疫网络。这个基金会将 作为加强T细胞介导的促再生免疫的细胞和分子治疗设计的基础 回应。虽然广泛适用于许多组织，但我们将首先将再生免疫疗法应用于 肌肉骨骼组织，然后延伸到其他组织。总的来说，这些研究将改变 传统的免疫系统思想通过将免疫系统重新想象为人体的修复系统和 使用这个平台来设计再生工程。

Project Summary Tissue loss due to trauma, disease or congenital abnormalities remains an intractable clinical challenge. There are profound deficits in how humans heal and recover from tissue damage and few innovations in regenerative medicine have reached the clinic or improved standard of care. Formation of dysfunctional scar tissue remains the default pathway for repair in the body. The immune system is the first responder to trauma yet this response, and its capacity to orchestrate tissue repair, has been largely ignored. Engineering tissues generally involves combining cells and biomaterial scaffolds with a suite of biological cues to stimulate new tissue development. Until now, these tissue engineering tools have been designed to target stem cells, vascular development, or tissue morphogenesis. Here, we are shifting the focus of tissue engineering design towards direct therapeutic manipulation of the immune system. The remarkable success of cancer immunotherapies highlights how the adaptive immune system is amenable to exquisitely robust intervention and the potential for regenerative immunotherapies. We introduce the concept of regenerative immunotherapies that engage and manipulate the effector class of T cells. Emerging understanding of tissue specific immunity, the role of senescent cells in tissue trauma and repair responses will be combined with our new and unexpected findings on pro-regenerative T cells. Single cell genomic analysis of immune subsets, stromal, and senescent cells combined with novel computational algorithms will be used to develop tissue- specific senescent and immune networks in homeostasis, aging, trauma, and disease. This foundation will serve as the basis for cell and molecular therapy design to enhance T cell mediated pro-regenerative immune responses. While broadly applicable to many tissues, we will first apply regenerative immunotherapies to musculoskeletal tissues before extending to additional tissues. Collectively, these studies will transform traditional thinking of the immune system by re-imagining the immune system as the body’s repair system and use this platform to engineer regeneration.