Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans
Dynamics of genetically engineered hematopoietic stem and progenitor cells after autologous transplantation in humans
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DOI：
10.1038/s41591-018-0195-3
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发表时间：
2018-11-01
期刊：
影响因子：
82.9
通讯作者：
Biasco, Luca
中科院分区：
文献类型：
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作者：
Scala, Serena;Basso-Ricci, Luca;Biasco, Luca
造血干细胞和祖细胞（HSPC）被赋予产生和维持终身的极其多样化的血细胞池的作用（1）。在临床上，从同种异体健康供体移植人HSPC或输注自体基因校正的HSPC可以有效地补充由先天性或获得性疾病引起的有缺陷的血细胞产生（2-9）。然而，由于方法学和伦理学限制，人HSPC的研究主要限于体外试验（10）或异种移植模型（11，12），迄今为止，HSPC的体内活性在人体中仍相对未探索（13-16）。在这里，我们报告了一项关于人类7种HSPC亚型的频率、动力学和输出的综合研究，该研究通过跟踪6名使用自体HSPC移植接受慢病毒基因治疗的患者的148，093个个体克隆进行，并随访长达5年。我们发现，原始多能祖细胞和造血干细胞（HSC）群体在移植后的初始重建过程中，与随后的稳态阶段相比，具有不同的作用。此外，我们发现一部分体外活化的HSC是有弹性的，并在移植后经历一个确定的延迟活化期。最后，我们的数据支持这样的概念，即早期淋巴偏向的祖细胞可能能够长期存活，这样它们可以独立于HSC的连续生产而维持。总体而言，本研究提供了人体自体移植和基因治疗后HSPC动力学的全面数据。
Hematopoietic stem and progenitor cells (HSPC) are endowed with the role of generating and maintaining lifelong the extremely diverse pool of blood cells(1). Clinically, transplantation of human HSPC from an allogeneic healthy donor or infusion of autologous gene-corrected HSPC can effectively replenish defective blood cell production caused by congenital or acquired disorders(2-9). However, due to methodological and ethical constraints that have limited the study of human HSPC primarily to in vitro assays(10) or xenotransplantation models(11,12), the in vivo activity of HSPC has to date remained relatively unexplored in humans(13-16). Here we report a comprehensive study of the frequencies, dynamics and output of seven HSPC subtypes in humans that was performed by tracking 148,093 individual clones in six patients treated with lentiviral gene therapy using autologous HSPC transplantation and followed for up to 5 years. We discovered that primitive multipotent progenitor and hematopoietic stem cell (HSC) populations have distinct roles during the initial reconstitution after transplant, compared with subsequent steady-state phases. Furthermore, we showed that a fraction of in vitro-activated HSC are resilient and undergo a defined delayed activation period upon transplant. Finally, our data support the concept that early lymphoid-biased progenitors might be capable of long-term survival, such that they can be maintained independently of their continuous production from HSC. Overall, this study provides comprehensive data on HSPC dynamics after autologous transplantation and gene therapy in humans.