Graduate Program in Immunology, Baylor College of Medicine, Houston, United States.
Department of Pediatrics, Division of Infectious Diseases, Baylor College of Medicine, Houston, United States.
Elife. 2022 Feb 15;11:e74561. doi: 10.7554/eLife.74561.
New therapeutic strategies to reduce sepsis-related mortality are urgently needed, as sepsis accounts for one in five deaths worldwide. Since hematopoietic stem and progenitor cells (HSPCs) are responsible for producing blood and immune cells, including in response to immunological stress, we explored their potential for treating sepsis. In a mouse model of Group A (GAS)-induced sepsis, severe immunological stress was associated with significant depletion of bone marrow HSPCs and mortality within approximately 5-7 days. We hypothesized that the inflammatory environment of GAS infection drives rapid HSPC differentiation and depletion that can be rescued by infusion of donor HSPCs. Indeed, infusion of 10,000 naïve HSPCs into GAS-infected mice resulted in rapid myelopoiesis and a 50-60% increase in overall survival. Surprisingly, mice receiving donor HSPCs displayed a similar pathogen load compared to untreated mice. Flow cytometric analysis revealed a significantly increased number of myeloid-derived suppressor cells in HSPC-infused mice, which correlated with reduced inflammatory cytokine levels and restored HSPC levels. These findings suggest that HSPCs play an essential immunomodulatory role that may translate into new therapeutic strategies for sepsis.
急需新的治疗策略来降低与败血症相关的死亡率，因为败血症占全球每五例死亡中的一例。由于造血干细胞和祖细胞（HSPCs）负责产生血液和免疫细胞，包括对免疫应激的反应，因此我们探讨了它们治疗败血症的潜力。在 GAS 诱导的败血症的小鼠模型中，严重的免疫应激与骨髓 HSPCs 的大量消耗以及大约 5-7 天内的死亡率有关。我们假设 GAS 感染的炎症环境驱动 HSPC 的快速分化和耗竭，而输注供体 HSPCs 可以挽救这种情况。事实上，将 10000 个幼稚的 HSPC 输注到 GAS 感染的小鼠中会导致快速的骨髓生成，总生存率提高 50-60%。令人惊讶的是，与未治疗的小鼠相比，接受供体 HSPC 的小鼠显示出相似的病原体负荷。流式细胞术分析显示，在输注 HSPC 的小鼠中，髓源性抑制细胞的数量显著增加，这与炎症细胞因子水平降低和 HSPC 水平恢复有关。这些发现表明 HSPCs 发挥着重要的免疫调节作用，可能转化为败血症的新治疗策略。
