Department of Hematology, Huashan Hospital, Fudan University, Shanghai, China.
Department of Hematology, The First Affiliated Hospital of Nanjing Medical University, Jiangsu Province Hospital, Nanjing, China.
Cell Death Dis. 2022 Jul 18;13(7):620. doi: 10.1038/s41419-022-05080-5.
Aplastic anemia (AA) is a blood disorder resulted from over-activated T-cell related hematopoietic failure, with the characterization of hypocellularity and enhanced adipogenic differentiation of mesenchymal stroma cells (MSCs) in bone marrow (BM). However, little is known about the relationship between immune imbalance and polarized adipogenic abnormity of BM microenvironment in this disease entity. In the present study, we differentiated BM-MSCs into osteoblastic or adipogenic lineages to mimic the osteo-adipogenic differentiation. Activated CD8 T cells and interferon-γ (IFN-γ) were found to stimulate adipogenesis of BM-MSCs either in vitro or in vivo of AA mouse model. Interestingly, myeloid-derived suppressive cells (MDSCs), one of the immune-regulating populations, were decreased within BM of AA mice. We found that it was not CD11bLy6GLy6C granulocytic-MDSCs (gMDSCs) but CD11bLy6GLy6C monocytic-MDSCs (mMDSCs) inhibiting both T cell proliferation and IFN-γ production via inducible nitric oxide synthetase (iNOS) pathway. Single-cell RNA-sequencing (scRNA-seq) of AA- and mMDSCs-treated murine BM cells revealed that mMDSCs transfusion could reconstitute BM hematopoietic progenitors by inhibiting T cells population and signature cytokines and decreasing immature Adipo-Cxcl12-abundant reticular cells within BM. Multi-injection of mMDSCs into AA mice reduced intra-BM T cells infiltration and suppressed BM adipogenesis, which subsequently restored the intra-BM immune balance and eventually prevented pancytopenia and hypo-hematopoiesis. In conclusion, adoptive transfusion of mMDSCs might be a novel immune-regulating strategy to treat AA, accounting for not only restoring the intra-BM immune balance but also improving stroma's multi-differentiating microenvironment.
再生障碍性贫血（AA）是一种由 T 细胞过度激活导致的造血衰竭的血液疾病，其特征是骨髓（BM）中细胞数量减少和间充质基质细胞（MSCs）的脂肪生成分化增强。然而，在这种疾病实体中，关于免疫失衡与 BM 微环境的极化脂肪生成异常之间的关系，人们知之甚少。在本研究中，我们将 BM-MSCs 分化为成骨细胞或脂肪生成细胞系，以模拟成骨-脂肪生成分化。我们发现，激活的 CD8 T 细胞和干扰素-γ（IFN-γ）在体外或 AA 小鼠模型的体内均可刺激 BM-MSCs 的脂肪生成。有趣的是，骨髓中的髓系来源抑制细胞（MDSCs），一种免疫调节细胞群，在 AA 小鼠的骨髓中减少。我们发现，抑制 T 细胞增殖和 IFN-γ产生的不是 CD11bLy6GLy6C 粒细胞 MDSCs（gMDSCs），而是 CD11bLy6GLy6C 单核细胞 MDSCs（mMDSCs），通过诱导型一氧化氮合酶（iNOS）途径。AA 和 mMDSCs 处理的鼠 BM 细胞的单细胞 RNA 测序（scRNA-seq）显示，mMDSCs 输注可通过抑制 T 细胞群体和特征细胞因子，并减少 BM 中幼稚的脂肪细胞衍生趋化因子 CXCL12 丰富的网状细胞，重建 BM 造血祖细胞。将 mMDSCs 多次注入 AA 小鼠体内可减少 BM 内 T 细胞浸润并抑制 BM 脂肪生成，从而恢复 BM 内免疫平衡，最终防止全血细胞减少和低造血。总之，mMDSCs 的过继输注可能是治疗 AA 的一种新的免疫调节策略，不仅可以恢复 BM 内的免疫平衡，还可以改善基质的多分化微环境。
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