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Fundamental properties of unperturbed haematopoiesis from stem cells in vivo

机译：体内干细胞不受干扰的造血作用的基本特性

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摘要

我们所了解到的关于造血干细胞(HSCs)性质的大部分内容都是从一个耗尽的血液和免疫系统的移植和重建获得的。对于HSCs在生理条件下的行为如何相对来说知之甚少。最近曾有人报告说,成年个体的正常造血作用是由数以千计的长寿命祖细胞而不是经典HSCs驱动的。Hans-Reimer Rodewald及同事利用一个小鼠模型中原始HSCs的"可诱导基因标记"结合数学模拟显示,虽然HSCs参与了早期生命中血液系统的建立,但稳定状态的造血作用主要取决于能够自我更新、但也从长期HSCs接受"罕见输入"(rareinput)的祖细胞。这种输入在生理条件有挑战性之后会增加。%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. Chromosomal marking, viral integration 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 Tie2~+ 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 polyclonal 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 oligoclonal 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.
机译：我们所了解到的关于造血干细胞(HSCs)性质的大部分内容都是从一个耗尽的血液和免疫系统的移植和重建获得的。对于HSCs在生理条件下的行为如何相对来说知之甚少。最近曾有人报告说,成年个体的正常造血作用是由数以千计的长寿命祖细胞而不是经典HSCs驱动的。Hans-Reimer Rodewald及同事利用一个小鼠模型中原始HSCs的"可诱导基因标记"结合数学模拟显示,虽然HSCs参与了早期生命中血液系统的建立,但稳定状态的造血作用主要取决于能够自我更新、但也从长期HSCs接受"罕见输入"(rareinput)的祖细胞。这种输入在生理条件有挑战性之后会增加。%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. Chromosomal marking, viral integration 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 Tie2~+ 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 polyclonal 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 oligoclonal 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.

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  • 来源
    《Nature》 |2015年第7540期|542-546a5|共6页
  • 作者

    Katrin Busch; Kay Klapproth; Melania Barile; Michael Flossdorf; Tim Holland-Letz; Susan M. Schlenner; Michael Reth; Thomas Hoefer; Hans-Reimer Rodewald;

  • 作者单位

    Division of Cellular Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany;

    Division of Cellular Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany;

    Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany;

    Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany;

    Division of Biostatistics, German Canxer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany;

    Department of Microbiology and Immunology, University of Leuven, B-3000 Leuven, Belgium, Autoimmune Genetics Laboratory, VIB, B-3000 Leuven, Belgium;

    BIOSS, Centre For Biological Signaling Studies, University of Freiburg, Schaenzlestrasse 18, D-79104 Freiburg, Germany, Department of Molecular Immunology, Biolll, Faculty of Biology, University of Freiburg, and Max-Planck Institute of Immunobiology and Epigenetics, Stuebeweg 51, D-79108 Freiburg, Germany;

    Division of Theoretical Systems Biology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany;

    Division of Cellular Immunology, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, D-69120 Heidelberg, Germany;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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