Singh Apeksha, Chia Jennifer J, Rao Dinesh S, Hoffmann Alexander
Signaling Systems Laboratory, Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles, CA.
Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA.
Blood. 2025 Mar 20;145(12):1293-1308. doi: 10.1182/blood.2024025598.
Aging and chronic inflammation are associated with overabundant myeloid-primed multipotent progenitors (MPPs) among hematopoietic stem and progenitor cells (HSPCs). Although hematopoietic stem cell (HSC) differentiation bias has been considered a primary cause of myeloid bias, whether it is sufficient has not been quantitatively evaluated. Here, we analyzed bone marrow data from the IκB- (Nfkbia+/-Nfkbib-/-Nfkbie-/-) mouse model of inflammation with elevated NFκB activity, which reveals increased myeloid-biased MPPs. We interpreted these data with differential equation models of population dynamics to identify alterations of HSPC proliferation and differentiation rates. This analysis revealed that short-term HSC differentiation bias alone is likely insufficient to account for the increase in myeloid-biased MPPs. To explore additional mechanisms, we used single-cell RNA sequencing (scRNA-seq) measurements of IκB- and wild-type HSPCs to track the continuous differentiation trajectories from HSCs to erythrocyte/megakaryocyte, myeloid, and lymphoid primed progenitors. Fitting a partial differential equations model of population dynamics to these data revealed not only less lymphoid-fate specification among HSCs but also increased expansion of early myeloid-primed progenitors. Differentially expressed genes along the differentiation trajectories supported increased proliferation among these progenitors. These findings were conserved when wild-type HSPCs were transplanted into IκB- recipients, indicating that an inflamed bone marrow microenvironment is a sufficient driver. We then applied our analysis pipeline to scRNA-seq measurements of HSPCs isolated from aged mice and human patients with myeloid neoplasms. These analyses identified the same myeloid-primed progenitor expansion as in the IκB- models, suggesting that it is a common feature across different settings of myeloid bias.
衰老和慢性炎症与造血干细胞和祖细胞（HSPCs）中髓系启动的多能祖细胞（MPPs）过多有关。尽管造血干细胞（HSC）分化偏向被认为是髓系偏向的主要原因，但其是否充分尚未得到定量评估。在这里，我们分析了来自IκB-（Nfkbia+/-Nfkbib-/-Nfkbie-/-）小鼠炎症模型的骨髓数据，该模型中NFκB活性升高，显示出髓系偏向的MPPs增加。我们用群体动力学的微分方程模型来解释这些数据，以确定HSPC增殖和分化率的变化。该分析表明，仅短期HSC分化偏向可能不足以解释髓系偏向的MPPs增加。为了探索其他机制，我们使用IκB-和野生型HSPCs的单细胞RNA测序（scRNA-seq）测量来追踪从HSCs到红细胞/巨核细胞、髓系和淋巴系启动祖细胞的连续分化轨迹。将群体动力学的偏微分方程模型拟合到这些数据中，不仅揭示了HSCs中淋巴系命运特化减少，而且早期髓系启动祖细胞的扩增增加。沿着分化轨迹差异表达的基因支持了这些祖细胞的增殖增加。当将野生型HSPCs移植到IκB-受体中时，这些发现是一致的，表明炎症的骨髓微环境是一个充分的驱动因素。然后，我们将我们的分析流程应用于从老年小鼠和患有髓系肿瘤的人类患者中分离出的HSPCs的scRNA-seq测量。这些分析确定了与IκB-模型中相同的髓系启动祖细胞扩增，表明这是不同髓系偏向环境中的一个共同特征。
