Kohutek Zachary A, Caslin Heather L, Fehrenbach Daniel J, Heimlich J Brett, Brown Jonathan D, Madhur Meena S, Ferrell P Brent, Doran Amanda C
Department of Radiation Oncology (Z.A.K.), Vanderbilt University Medical Center, Nashville, TN.
Department of Health and Human Performance, University of Houston, TX (H.L.C.).
Circ Res. 2025 Jan 31;136(3):325-353. doi: 10.1161/CIRCRESAHA.124.323778. Epub 2025 Jan 30.
Cardiovascular and cardiometabolic diseases are leading causes of morbidity and mortality worldwide, driven in part by chronic inflammation. Emerging research suggests that the bone marrow microenvironment, or marrow niche, plays a critical role in both immune system regulation and disease progression. The bone marrow niche is essential for maintaining hematopoietic stem cells (HSCs) and orchestrating hematopoiesis. Under normal conditions, this niche ensures a return to immune homeostasis after acute stress. However, in the setting of inflammatory conditions such as those seen in cardiometabolic diseases, it becomes dysregulated, leading to enhanced myelopoiesis and immune activation. This review explores the reciprocal relationship between the bone marrow niche and cardiometabolic diseases, highlighting how alterations in the niche contribute to disease development and progression. The niche regulates HSCs through complex interactions with stromal cells, endothelial cells, and signaling molecules. However, in the setting of chronic diseases such as hypertension, atherosclerosis, and diabetes, inflammatory signals disrupt the balance between HSC self-renewal and differentiation, promoting the excessive production of proinflammatory myeloid cells that exacerbate the disease. Key mechanisms discussed include the effects of hyperlipidemia, hyperglycemia, and sympathetic nervous system activation on HSC proliferation and differentiation. Furthermore, the review emphasizes the role of epigenetic modifications and metabolic reprogramming in creating trained immunity, a phenomenon whereby HSCs acquire long-term proinflammatory characteristics that sustain disease states. Finally, we explore therapeutic strategies aimed at targeting the bone marrow niche to mitigate chronic inflammation and its sequelae. Novel interventions that modulate hematopoiesis and restore niche homeostasis hold promise for the treatment of cardiometabolic diseases. By interrupting the vicious cycle of inflammation and marrow dysregulation, such therapies may offer new avenues for reducing cardiovascular risk and improving patient outcomes.
心血管疾病和心脏代谢疾病是全球发病和死亡的主要原因，部分原因是慢性炎症。新出现的研究表明，骨髓微环境或骨髓生态位在免疫系统调节和疾病进展中都起着关键作用。骨髓生态位对于维持造血干细胞（HSC）和协调造血过程至关重要。在正常情况下，这个生态位可确保在急性应激后恢复免疫稳态。然而，在诸如心脏代谢疾病中所见的炎症状态下，它会失调，导致髓系造血增强和免疫激活。本综述探讨了骨髓生态位与心脏代谢疾病之间的相互关系，强调了生态位的改变如何促进疾病的发展和进展。生态位通过与基质细胞、内皮细胞和信号分子的复杂相互作用来调节造血干细胞。然而，在高血压、动脉粥样硬化和糖尿病等慢性疾病的情况下，炎症信号会破坏造血干细胞自我更新和分化之间的平衡，促进促炎髓系细胞的过度产生，从而加剧疾病。讨论的关键机制包括高脂血症、高血糖和交感神经系统激活对造血干细胞增殖和分化的影响。此外，该综述强调了表观遗传修饰和代谢重编程在产生训练有素的免疫中的作用，这是一种造血干细胞获得长期促炎特征以维持疾病状态的现象。最后，我们探讨了旨在靶向骨髓生态位以减轻慢性炎症及其后遗症的治疗策略。调节造血并恢复生态位稳态的新型干预措施有望用于治疗心脏代谢疾病。通过中断炎症和骨髓失调的恶性循环，此类疗法可能为降低心血管风险和改善患者预后提供新途径。
