Patel Bhakti, Zhou Yifan, Babcock Rachel L, Ma Feiyang, Zal Malgorzata A, Kumar Dhiraj, Medik Yusra B, Kahn Laura M, Pineda Josué E, Park Elizabeth M, Tang Ximing, Raso Maria Gabriela, Zal Tomasz, Clise-Dwyer Karen, Giancotti Filippo G, Colla Simona, Watowich Stephanie S
Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, Houston, TX, USA.
bioRxiv. 2023 Feb 11:2023.02.10.528069. doi: 10.1101/2023.02.10.528069.
STAT3 function in hematopoietic stem and progenitor cells (HSPCs) has been difficult to discern as deficiency in the hematopoietic system induces systemic inflammation, which can impact HSPC activity. To address this, we established mixed bone marrow (BM) chimeric mice with CreER-mediated deletion in 20% of the hematopoietic compartment. -deficient HSPCs had impaired hematopoietic activity and failed to undergo expansion in BM in contrast to -sufficient (CreER) controls. Single-cell RNA sequencing of LinckitSca1 BM cells revealed altered transcriptional responses in -deficient hematopoietic stem cells (HSCs) and multipotent progenitors, including intrinsic activation of cell cycle, stress response, and interferon signaling pathways. Consistent with their deregulation, -deficient LinckitSca1 cells accumulated γH2AX over time. Following secondary BM transplantation, -deficient HSPCs failed to reconstitute peripheral blood effectively, indicating a severe functional defect in the HSC compartment. Our results reveal essential roles for STAT3 in HSCs and suggest the potential for using targeted synthetic lethal approaches with STAT3 inhibition to remove defective or diseased HSPCs.
由于造血系统缺陷会引发全身性炎症，进而影响造血干细胞和祖细胞（HSPCs）的活性，因此一直难以明确信号转导和转录激活因子3（STAT3）在其中的作用。为了解决这一问题，我们构建了混合骨髓（BM）嵌合小鼠，通过CreER介导在20%的造血区室中进行缺失。与STAT3充足（CreER）的对照组相比，STAT3缺陷的HSPCs造血活性受损，无法在骨髓中进行扩增。对Lin⁻ckit⁺Sca1⁺骨髓细胞进行单细胞RNA测序，结果显示STAT3缺陷的造血干细胞（HSCs）和多能祖细胞的转录反应发生改变，包括细胞周期、应激反应和干扰素信号通路的内在激活。与其失调一致，STAT3缺陷的Lin⁻ckit⁺Sca1⁺细胞随着时间的推移积累了γH2AX。二次骨髓移植后，STAT3缺陷的HSPCs无法有效重建外周血，表明造血干细胞区室存在严重的功能缺陷。我们的研究结果揭示了STAT3在造血干细胞中的重要作用，并表明利用靶向合成致死方法抑制STAT3以清除有缺陷或患病的HSPCs具有潜在可能性。
