Institute for Stem Cell Biology and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA 94305;
Department of Stem Cell Biology and Regenerative Medicine, Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033.
Proc Natl Acad Sci U S A. 2019 Jan 22;116(4):1447-1456. doi: 10.1073/pnas.1801480116. Epub 2019 Jan 8.
While the aggregate differentiation of the hematopoietic stem cell (HSC) population has been extensively studied, little is known about the lineage commitment process of individual HSC clones. Here, we provide lineage commitment maps of HSC clones under homeostasis and after perturbations of the endogenous hematopoietic system. Under homeostasis, all donor-derived HSC clones regenerate blood homogeneously throughout all measured stages and lineages of hematopoiesis. In contrast, after the hematopoietic system has been perturbed by irradiation or by an antagonistic anti-ckit antibody, only a small fraction of donor-derived HSC clones differentiate. Some of these clones dominantly expand and exhibit lineage bias. We identified the cellular origins of clonal dominance and lineage bias and uncovered the lineage commitment pathways that lead HSC clones to different levels of self-renewal and blood production under various transplantation conditions. This study reveals surprising alterations in HSC fate decisions directed by conditioning and identifies the key hematopoiesis stages that may be manipulated to control blood production and balance.
虽然造血干细胞（HSC）群体的总体分化已经得到了广泛研究，但对于单个 HSC 克隆的谱系分化过程知之甚少。在这里，我们提供了 HSC 克隆在体内平衡和内源性造血系统受到干扰后的谱系分化图谱。在体内平衡状态下，所有供体来源的 HSC 克隆在所有测量的造血阶段和谱系中均均匀地再生血液。相比之下，造血系统受到辐射或拮抗的抗 ckit 抗体的干扰后，只有一小部分供体来源的 HSC 克隆会分化。其中一些克隆会明显扩增并表现出谱系偏向。我们确定了克隆优势和谱系偏向的细胞起源，并揭示了在不同移植条件下导致 HSC 克隆在自我更新和血液生成水平上产生差异的谱系分化途径。这项研究揭示了由条件作用指导的 HSC 命运决定的惊人变化，并确定了可能被操纵以控制血液生成和平衡的关键造血阶段。
