Division of Pulmonary, Allergy, Critical Care & Sleep Medicine, Emory University, Atlanta, GA, USA.
School of Biological Sciences, Georgia Institute of Technology, Atlanta, GA, USA.
Nat Commun. 2018 Sep 12;9(1):3698. doi: 10.1038/s41467-018-05853-7.
Human antibody-secreting cells (ASC) in peripheral blood are found after vaccination or infection but rapidly apoptose unless they migrate to the bone marrow (BM). Yet, elements of the BM microenvironment required to sustain long-lived plasma cells (LLPC) remain elusive. Here, we identify BM factors that maintain human ASC > 50 days in vitro. The critical components of the cell-free in vitro BM mimic consist of products from primary BM mesenchymal stromal cells (MSC), a proliferation-inducing ligand (APRIL), and hypoxic conditions. Comparative analysis of protein-protein interactions between BM-MSC proteomics with differential RNA transcriptomics of blood ASC and BM LLPC identify two major survival factors, fibronectin and YWHAZ. The MSC secretome proteins and hypoxic conditions play a role in LLPC survival utilizing mechanisms that downregulate mTORC1 signaling and upregulate hypoxia signatures. In summary, we identify elements of the BM survival niche critical for maturation of blood ASC to BM LLPC.
外周血中的人抗体分泌细胞 (ASC) 在接种疫苗或感染后即可被发现，但会迅速凋亡，除非它们迁移到骨髓 (BM)。然而，维持长寿浆细胞 (LLPC) 所需的 BM 微环境元素仍然难以捉摸。在这里，我们确定了维持人 ASC 在体外存活超过 50 天的 BM 因素。无细胞体外 BM 模拟物的关键成分包括来自原代 BM 间充质基质细胞 (MSC) 的产物、增殖诱导配体 (APRIL) 和缺氧条件。对 BM-MSC 蛋白质组学与血液 ASC 和 BM LLPC 的差异 RNA 转录组学之间的蛋白质-蛋白质相互作用进行比较分析，确定了两种主要的存活因子，即纤维连接蛋白和 YWHAZ。MSC 分泌蛋白和缺氧条件通过下调 mTORC1 信号和上调缺氧特征来发挥作用，从而促进 LLPC 的存活。总之，我们确定了 BM 存活龛的关键元素，这些元素对于血液 ASC 向 BM LLPC 的成熟至关重要。
