Fundamental properties of unperturbed haematopoiesis from stem cells in vivo
Fundamental properties of unperturbed haematopoiesis from stem cells in vivo
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DOI：
10.1038/nature14242
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发表时间：
2015-02-26
期刊：
影响因子：
64.8
通讯作者：
Rodewald, Hans-Reimer
中科院分区：
文献类型：
--
作者：
Busch, Katrin;Klapproth, Kay;Rodewald, Hans-Reimer
造血干细胞（HSC）通过将HSC移植到免疫和血细胞耗竭的受体中而被广泛研究。单个HSC可以在移植后重建系统（1-5）。移植的HSC的“染色体标记”、“病毒整合”（7-9）和“条形码化”表明非常低数量的HSC使分化细胞的连续流永久化。然而，在正常造血过程中生产性HSC的数量，以及分化后代的流量仍然未知。在这里，我们设计了一种小鼠模型，允许骨髓中最原始的Tie（2+）HSC的诱导性遗传标记，并通过有限稀释分析和数据驱动建模来量化标记进展沿着造血发育。在造血系统的维持期间，在标记诱导后，成年小鼠中至少30%或5，000个HSC是生产性的。然而，在标记的HSC和它们的后代之间达到平衡的时间令人惊讶地长，这一时间尺度将超过小鼠的寿命。事实上，我们发现成人造血主要是由先前指定的HSC下游的“短期”干细胞维持的，这些干细胞几乎完全自我更新，并接受罕见但多源的HSC输入。相比之下，在胎儿和出生后早期，HSC被迅速用于建立免疫和血液系统。在成年小鼠中，5-氟尿嘧啶诱导的白细胞减少症增强了HSC和下游隔室的输出，从而加速了造血通量。标记追踪还发现成年小鼠存在强烈的谱系偏好，骨髓输出比淋巴输出大几百倍，并且随着年龄的增长而稍微加剧。最后，我们表明，移植对HSC植入施加了严格的限制，与以前观察到的寡核苷酸HSC在这些条件下的活性一致。因此，我们揭示了造血系统的正常维持、通过攻击调节和移植后重建之间的根本差异。HSC命运映射及其相关建模为原位研究健康和疾病中造血调控提供了定量框架。
Haematopoietic stem cells (HSCs) are widely studied by HSC transplantation into immune- and blood-cell-depleted recipients. Single HSCs can rebuild the system after transplantation(1-5). Chromosomal marking', viral integration(7-9) and barcoding' of transplanted HSCs suggest that very low numbers of HSCs perpetuate a continuous stream of differentiating cells. However, the numbers of productive HSCs during normal haematopoiesis, and the flux of differentiating progeny remain unknown. Here we devise a mouse model allowing inducible genetic labelling of the most primitive Tie(2+) HSCs in bone marrow, and quantify label progression along haematopoietic development by limiting dilution analysis and data-driven modelling. During maintenance of the haematopoietic system, at least 30% or 5,000 HSCs are productive in the adult mouse after label induction. However, the time to approach equilibrium between labelled HSCs and their progeny is surprisingly long, a time scale that would exceed the mouse's life. Indeed, we find that adult haematopoiesis is largely 'sustained by previously designated 'short-term' stem cells downstream of HSCs that nearly fully self-renew, and receive rare but polydonal HSC input. By contrast, in fetal and early postnatal life, HSCs are rapidly used to establish the immune and blood system. In the adult mouse, 5-fluoruracil-induced leukopenia enhances the output of HSCs and of downstream compartments, thus accelerating haematopoietic flux. Label tracing also identifies a strong lineage bias in adult mice, with several-hundred-fold larger myeloid than lymphoid output, which is only marginally accentuated with age. Finally, we show that transplantation imposes severe constraints on HSC engraftment, consistent with the previously observed oligodonal HSC activity under these conditions. Thus, we uncover fundamental differences between the normal maintenance of the haematopoietic system, its regulation by challenge, and its re-establishment after transplantation. HSC fate mapping and its linked modelling provide a quantitative framework for studying in situ the regulation of haematopoiesis in health and disease.