Lymphoid Biased Hematopoietic Stem Cells are Maintained with Age and Retain Normal Developmental Potential in the Absence of Inflammatory Stimuli

The hematopoietic stem cell (HSC) compartment includes lymphoid biased (Ly-HSCs) and myeloid biased (My-HSCs) subsets. Current models propose that the number of Ly-HSCs declines with age and this contributes to the diminution of lymphopoiesis that is a feature of aging. This view is based on a reduction in the frequency of Ly-HSCs in old bone marrow, but we now show that when total HSCs are taken into account, the number of Ly-HSCs is not reduced in old mice. We further demonstrate that old Ly-HSCs exhibit a normal capacity to produce lymphoid progenitors when removed from the bone marrow. However, the production of inflammatory cytokines is known to increase with age, and when Ly-HSCs are exposed to these mediators, lymphocyte production is blocked. We also demonstrate that old Ly-HSCs generate myeloid cells that phenotypically resemble those produced by old My-HSCs, a finding consistent with the myeloid biased gene expression pattern of old Ly-HSCs. These observations indicate that current models of how aging impacts the lymphopoietic potential of HSCs need to be revised and point to changes in the in vivo environment, rather than intrinsic changes in HSCs, as the principal cause of the reduced lymphopoiesis and increased myelopoiesis during aging. We isolated Ly-HSCs (lineage negative, Sca-1+ CD117(c-kit)+ CD48- CD135- CD150low) and My-HSCs (lineage negative, Sca-1+ CD117(c-kit)+ (LSK) CD48- CD135- CD150high) from three independent groups of young (8-12 week-old) and old (18 months) mice and performed RNA-Seq.

造血干细胞（hematopoietic stem cell, HSC）池包含淋巴系偏向型造血干细胞（lymphoid biased HSC, Ly-HSCs）与髓系偏向型造血干细胞（myeloid biased HSC, My-HSCs）两个亚群。现有模型认为，Ly-HSCs的数量会随年龄增长而减少，这会导致作为衰老典型特征的淋巴生成能力衰退。该观点的实验依据为老年骨髓中Ly-HSCs的频率降低，但本研究发现，在统计总造血干细胞数量的前提下，老年小鼠体内的Ly-HSCs数量并未减少。我们进一步证实，从骨髓中分离出的老年Ly-HSCs，其生成淋巴系祖细胞的能力并未出现异常。不过已知衰老过程中炎症因子的分泌会增加，当Ly-HSCs暴露于这类炎症介质时，淋巴细胞的生成过程会被阻断。此外，我们还证实老年Ly-HSCs所产生的髓系细胞，在表型上与老年My-HSCs生成的髓系细胞高度相似，这一结果与老年Ly-HSCs的髓系偏向基因表达谱特征相符。上述研究结果表明，当前关于衰老如何影响造血干细胞淋巴生成潜能的理论模型亟需修正，同时指出衰老过程中淋巴生成能力下降、髓系生成能力增强的主要诱因并非造血干细胞的内在改变，而是体内微环境的变化。我们从三组独立的年轻（8~12周龄）与老年（18月龄）小鼠体内分别分离得到Ly-HSCs（谱系阴性、Sca-1+ CD117(c-kit)+ CD48- CD135- CD150low）与My-HSCs（谱系阴性、Sca-1+ CD117(c-kit)+（LSK）CD48- CD135- CD150high），并对其进行了RNA测序（RNA-Seq）。