淋巴组织间质干细胞的分离鉴定及在组织稳定维持中的作用

Mesenchymal stem cells (MSCs) are widespread in many tissues of the body with the capacities of multi-lineage differentiation, immunomodulation and paracrine function, thus have a broad application potential in cell therapy. Due to the lack of specific molecular markers, the elusive nature and function of mesenchymal stem cells are not clarified clearly. We have demonstrated that Nestin+ cells isolated from bone marrow, testis, lymph nodes possessed the characteristics of MSCs and the ability of tissue regeneration (Cell Res, Biomaterials). Among them, nestin+ cells obtained from lymph node have long-term self-renewal, differentiation potentials into lymphatic stromal cells, such as follicular dendritic cells and reticular fibroblasts, the capacity to develop into artificial lymphoid tissue in vivo. In addition, Nestin+ cell from lymph node have shown the superior functions of immunomodulation and repairing damaged tissues, compared with bone marrow-derived MSCs. Based on our previous reports and recent progress, we are going to investigate the possibility of Nestin as marker of lymphatic MSCs using lineage tracing, differentiation experiment in vitro and tissue restoration in vivo. Furthermore, we wil explore the development correlation between MSCs and lymphatic stromal cells, such as MRCs, FDCs and FRCs. Finally, we will identify the function of Nestin+ cells in forming lymphatic stromal cells network and maintaining hemostasis, and mechanisms in repairing damaged tissues. Both of the findings will provide the direct evidence for isolating the human MSCs from secondary lymphoid organs to treat the human diseases.

间质干细胞（MSC）来源广泛、具有多向分化，免疫调节与旁分泌功能，在疾病治疗中具有广阔应用前景。但由于缺乏特异分子标志，目前对MSC的发育起源、组织分布、生理功能远未阐明。申请人研究发现，骨髓、睾丸、淋巴结等组织中Nestin+细胞具有MSC的特征和修复病损组织的能力(Cell Res, Biomaterials)。其中淋巴结来源的Nestin+细胞可长期扩增、向滤泡树突状细胞、成纤维网状细胞等淋巴基质细胞分化，体内形成类淋巴组织结构，并表现出优于骨髓MSC的免疫调节与损伤修复功能。本研究拟在前期基础上，利用谱系追踪、体外分化与体内重建等技术，证明Nestin作为淋巴组织MSC标志的可行性，探究MSCs与MRCs、FDCs、FRCs等淋巴基质细胞的发育相关性，阐明其在淋巴器官基质细胞网络形成与稳定维持的作用，探讨MSC在组织损伤修复中的机制，为利用淋巴间质干细胞用于疾病治疗提供有力的依据。

本研究旨在发现淋巴组织间质干细胞（mesenchymal stem cells, MSC）的特异性标志物，探究淋巴组织MSC的发育起源与功能特性，阐明其在淋巴组织稳态维持与再生修复中作用机制，并最终获得适合组织损伤修复的MSC功能亚群。团队率先阐明了中间丝蛋白Nestin在调控MSC内环境稳态中发挥关键作用，发现Nestin不仅可以调控核膜稳态延缓MSC衰老，而且还可通过维持Keap1-Nrf2氧化还原系统稳态促进MSC存活；进一步证实Nestin是成体组织MSC的特异标志，揭示了不同组织来源MSC具有独特的功能特性，次级淋巴器官来源（脾脏、派氏结）的MSC具有更强的免疫调节功能，为发现适合损伤修复的MSC功能亚群提供了重要依据；阐明内源性Nestin+MSC维持组织器官稳态的作用机制，在器官修复过程，组织原位MSC的过度增殖会导致纤维化的发生，靶向抑制间质细胞中Nestin表达可显著改善纤维化症状，而组织原位Nestin+MSC减少，则会引起组织器官萎缩，揭示了MSC在维持组织稳态与再生修复中的重要功能；深入解析MSC在不同病理微环境下的作用模式，揭示了MSC多维度、多靶点的损伤修复机制，建立了MSC精准靶向递送的新策略，显著提高MSC靶向能力和治疗效果。为深入理解MSC治疗的细胞与分子机制，推动其临床转化提供了重要依据。