Intrinsic molecular programs and extrinsic factors including proinflammatory molecules are understood to regulate hematopoietic aging. This is based on foundational studies using genetic perturbation to evaluate causality. However, individual organisms exhibit natural variation in the hematopoietic aging phenotypes and the molecular basis of this heterogeneity is poorly understood. Here, we generated individual single-cell transcriptomic profiles of hematopoietic and nonhematopoietic cell types in 5 young adult and 9 middle-aged C57BL/6J female mice, providing a web-accessible transcriptomic resource for the field. Among all assessed cell types, hematopoietic stem cells (HSCs) exhibited the greatest phenotypic variation in expansion among individual middle-aged mice. We computationally pooled samples to define modules representing the molecular signatures of middle-aged HSCs and interrogated, which extrinsic regulatory cell types and factors would predict the variance in these signatures between individual middle-aged mice. Decline in signaling mediated by ADIPOQ, KITL and IGF1 from mesenchymal stromal cells (MSCs) was predicted to have the greatest transcriptional impact on middle-aged HSCs, as opposed to signaling mediated by endothelial cells or mature hematopoietic cell types. In individual middle-aged mice, lower expression of and in MSCs was highly correlated with reduced lymphoid lineage commitment of HSCs and increased signatures of differentiation-inactive HSCs. These signatures were independent of expression of aging-associated proinflammatory cytokines including interleukin-1β (IL-1β), IL-6, tumor necrosis factor α and RANTES. In sum, we find that and expression are coregulated and variable between individual mice at the middle age and expression of these factors is predictive of HSC activation and lymphoid commitment independently of inflammation.

中文翻译：

---

中年时期间充质 KITL/SCF 和 IGF1 表达的变化是造血干细胞稳态衰老的基础

内在分子程序和外在因素（包括促炎分子）被认为可以调节造血衰老。这是基于使用遗传扰动来评估因果关系的基础研究。然而，个体生物体在造血衰老表型方面表现出自然变异，而这种异质性的分子基础却知之甚少。在这里，我们在 5 只年轻成年小鼠和 9 只中年 C57BL/6J 雌性小鼠中生成了造血和非造血细胞类型的个体单细胞转录组图谱，为该领域提供了可通过网络访问的转录组资源。在所有评估的细胞类型中，造血干细胞（HSC）在个体中年小鼠中表现出最大的扩增表型变异。我们通过计算汇集样本来定义代表中年 HSC 分子特征的模块，并询问哪些外在调节细胞类型和因素可以预测个体中年小鼠之间这些特征的差异。与内皮细胞或成熟造血细胞类型介导的信号传导相反，间充质基质细胞 (MSC) 介导的 ADIPOQ、KITL 和 IGF1 介导的信号传导下降预计会对中年 HSC 产生最大的转录影响。在中年小鼠个体中，MSC 和 MSC 中的较低表达与 HSC 淋巴谱系定型的减少和分化不活跃的 HSC 特征的增加高度相关。这些特征与衰老相关促炎细胞因子的表达无关，包括白细胞介素-1β (IL-1β)、IL-6、肿瘤坏死因子 α 和 RANTES。总之，我们发现 和 表达在中年个体小鼠之间是共同调节的和可变的，并且这些因子的表达可以预测 HSC 激活和淋巴样定型，与炎症无关。