Department of Immunology, Weizmann Institute of Science, Rehovot, Israel.
Division of Experimental Hematology and Cancer Biology, Cincinnati Children's Hospital Medical Center, Cincinnati, OH.
Blood. 2020 Dec 3;136(23):2607-2619. doi: 10.1182/blood.2020005399.
The fate of hematopoietic stem and progenitor cells (HSPC) is tightly regulated by their bone marrow (BM) microenvironment (ME). BM transplantation (BMT) frequently requires irradiation preconditioning to ablate endogenous hematopoietic cells. Whether the stromal ME is damaged and how it recovers after irradiation is unknown. We report that BM mesenchymal stromal cells (MSC) undergo massive damage to their mitochondrial function after irradiation. Donor healthy HSPC transfer functional mitochondria to the stromal ME, thus improving mitochondria activity in recipient MSC. Mitochondrial transfer to MSC is cell-contact dependent and mediated by HSPC connexin-43 (Cx43). Hematopoietic Cx43-deficient chimeric mice show reduced mitochondria transfer, which was rescued upon re-expression of Cx43 in HSPC or culture with isolated mitochondria from Cx43 deficient HSPCs. Increased intracellular adenosine triphosphate levels activate the purinergic receptor P2RX7 and lead to reduced activity of adenosine 5'-monophosphate-activated protein kinase (AMPK) in HSPC, dramatically increasing mitochondria transfer to BM MSC. Host stromal ME recovery and donor HSPC engraftment were augmented after mitochondria transfer. Deficiency of Cx43 delayed mesenchymal and osteogenic regeneration while in vivo AMPK inhibition increased stromal recovery. As a consequence, the hematopoietic compartment reconstitution was improved because of the recovery of the supportive stromal ME. Our findings demonstrate that healthy donor HSPC not only reconstitute the hematopoietic system after transplantation, but also support and induce the metabolic recovery of their irradiated, damaged ME via mitochondria transfer. Understanding the mechanisms regulating stromal recovery after myeloablative stress are of high clinical interest to optimize BMT procedures and underscore the importance of accessory, non-HSC to accelerate hematopoietic engraftment.
造血干细胞和祖细胞（HSPC）的命运受到其骨髓（BM）微环境（ME）的严格调节。BM 移植（BMT）通常需要照射预处理来清除内源性造血细胞。照射后基质 ME 是否受损以及如何恢复尚不清楚。我们报告说，BM 间充质基质细胞（MSC）在照射后其线粒体功能会受到严重破坏。供体健康的 HSPC 将功能性线粒体转移到基质 ME，从而提高受者 MSC 中的线粒体活性。MSC 的线粒体转移依赖于细胞接触，并由 HSPC 连接蛋白-43（Cx43）介导。造血 Cx43 缺陷嵌合小鼠显示出线粒体转移减少，而在 HSPC 中重新表达 Cx43 或在用 Cx43 缺陷 HSPC 的分离线粒体培养时可以挽救。细胞内三磷酸腺苷水平的增加激活嘌呤能受体 P2RX7，导致 HSPC 中 5'-单磷酸腺苷激活蛋白激酶（AMPK）活性降低，从而显著增加向 BM MSC 的线粒体转移。线粒体转移后，宿主基质 ME 的恢复和供体 HSPC 的植入增加。Cx43 缺乏延迟间充质和成骨再生，而体内 AMPK 抑制增加基质恢复。因此，由于支持性基质 ME 的恢复，造血部分的重建得到改善。我们的发现表明，健康的供体 HSPC 不仅在移植后重建造血系统，而且通过线粒体转移支持和诱导其照射损伤的 ME 的代谢恢复。了解调节骨髓清除应激后基质恢复的机制对于优化 BMT 程序具有重要的临床意义，并强调了非造血干细胞加速造血植入的辅助作用的重要性。
