2025年2月25日，安萨里干细胞研究所Shahin Rafii团队在《自然—免疫学》杂志发表论文，他们揭示了通过微环境感知再生造血的转录激活。

研究团队发现，在小鼠再生造血过程中，Fli-1的活性是必不可少的。Fli-1在启动细胞感觉和输出机制的同时指导激活程序，通过小生境衍生的血管分泌Notch1信号的传播，使HSPCs与受刺激的血管生态位共同适应。在缺乏Fli-1的情况下，组成性诱导的Notch1信号足以恢复功能性造血干细胞损伤，而不会发生白血病转化。将FLI-1瞬时修饰的mrna转导到潜在的成人动员的HSPCs中，使其具有小生境介导的扩展和优越的植入能力。因此，干细胞激活程序的解密为免疫再生医学提供了有价值的见解。

据悉，造血干细胞和祖细胞（HSPCs）在激活和静止状态之间的过渡受到细胞内在手段和微环境共同适应的严格控制。尽管这种平衡是终身造血和免疫的基础，但其潜在的分子机制仍不清楚。多模态分析揭示了不同HSPC状态之间的转录活性差异，表明在活化的造血干细胞中存在Fli-1转录因子结合基序。

附：英文原文

Title: Transcriptional activation of regenerative hematopoiesis via microenvironmental sensing

Author: Itkin, Tomer, Houghton, Sean, Schreiner, Ryan, Lin, Yang, Badwe, Chaitanya R., Voisin, Veronique, Murison, Alex, Seyedhassantehrani, Negar, Kaufmann, Kerstin B., Garcia-Prat, Laura, Booth, Gregory T., Geng, Fuqiang, Liu, Ying, Gomez-Salinero, Jesus M., Shieh, Jae-Hung, Redmond, David, Xiang, Jenny Z., Josefowicz, Steven Z., Trapnell, Cole, Pietras, Eric M., Spencer, Joel A., Levine, Ross, Xiao, Wenbin, Zangi, Lior, Hadland, Brandon, Dick, John E., Xie, Stephanie Z., Rafii, Shahin

Issue&Volume: 2025-02-25

Abstract: Transition between activation and quiescence states in hematopoietic stem and progenitor cells (HSPCs) is tightly governed by cell-intrinsic means and microenvironmental co-adaptation. Although this balance is fundamental for lifelong hematopoiesis and immunity, the underlying molecular mechanisms remain poorly defined. Multimodal analysis divulging differential transcriptional activity between distinct HSPC states indicates the presence of Fli-1 transcription factor binding motif in activated hematopoietic stem cells. We reveal that Fli-1 activity is essential during regenerative hematopoiesis in mice. Fli-1 directs activation programs while priming cellular sensory and output machineries, enabling HSPCs co-adoptability with a stimulated vascular niche through propagation of niche-derived angiocrine Notch1 signaling. Constitutively induced Notch1 signaling is sufficient to recuperate functional hematopoietic stem cells impairments in the absence of Fli-1, without leukemic transformation. Applying FLI-1 transient modified-mRNA transduction into latent adult human mobilized HSPCs, enables their niche-mediated expansion and superior engraftment capacities. Thus, decryption of stem cell activation programs offers valuable insights for immunological regenerative medicine.

DOI: 10.1038/s41590-025-02087-w

Source: https://www.nature.com/articles/s41590-025-02087-w