Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, 980 West Walnut St, Indianapolis, IN, 46202, USA.
Center for Computational Biology and Bioinformatics, Indiana University School of Medicine, Indianapolis, IN, 46202, USA.
Stem Cell Rev Rep. 2021 Oct;17(5):1840-1854. doi: 10.1007/s12015-021-10177-z. Epub 2021 May 11.
Aging of hematopoiesis is associated with increased frequency and clonality of hematopoietic stem cells (HSCs), along with functional compromise and myeloid bias, with donor age being a significant variable in survival after HSC transplantation. No clinical methods currently exist to enhance aged HSC function, and little is known regarding how aging affects molecular responses of HSCs to biological stimuli. Exposure of HSCs from young fish, mice, nonhuman primates, and humans to 16,16-dimethyl prostaglandin E (dmPGE) enhances transplantation, but the effect of dmPGE on aged HSCs is unknown. Here we show that ex vivo pulse of bone marrow cells from young adult (3 mo) and aged (25 mo) mice with dmPGE prior to serial competitive transplantation significantly enhanced long-term repopulation from aged grafts in primary and secondary transplantation (27 % increase in chimerism) to a similar degree as young grafts (21 % increase in chimerism; both p < 0.05). RNA sequencing of phenotypically-isolated HSCs indicated that the molecular responses to dmPGE are similar in young and old, including CREB1 activation and increased cell survival and homeostasis. Common genes within these pathways identified likely key mediators of HSC enhancement by dmPGE and age-related signaling differences. HSC expression of the PGE receptor EP4, implicated in HSC function, increased with age in both mRNA and surface protein. This work suggests that aging does not alter the major dmPGE response pathways in HSCs which mediate enhancement of both young and old HSC function, with significant implications for expanding the therapeutic potential of elderly HSC transplantation.
造血衰老与造血干细胞 (HSCs) 的频率和克隆性增加有关，同时伴随着功能障碍和骨髓偏向，供体年龄是 HSC 移植后存活的重要变量。目前尚无临床方法可增强衰老 HSC 的功能，并且对于衰老如何影响 HSC 对生物刺激的分子反应知之甚少。年轻鱼类、小鼠、非人灵长类动物和人类的 HSCs 暴露于 16,16-二甲基前列腺素 E (dmPGE) 中可增强移植效果，但 dmPGE 对衰老 HSCs 的影响尚不清楚。在这里，我们展示了在进行连续竞争移植之前，用 dmPGE 对年轻成年（3 个月）和老年（25 个月）小鼠的骨髓细胞进行离体脉冲处理，可显著增强老年移植物在原发性和继发性移植中的长期重建造血作用（嵌合率增加 27%），与年轻移植物的效果相似（嵌合率增加 21%；均 p<0.05）。对表型分离的 HSCs 进行 RNA 测序表明，dmPGE 诱导的分子反应在年轻和年老时相似，包括 CREB1 激活以及细胞存活和稳态增加。这些途径中的共同基因可能是 dmPGE 和与年龄相关的信号转导差异增强 HSC 的关键介质。与 HSC 功能相关的 PGE 受体 EP4 在 HSC 中的表达在 mRNA 和表面蛋白水平上均随年龄增长而增加。这项工作表明，衰老不会改变 HSCs 中 dmPGE 主要反应途径，这些途径介导了年轻和年老 HSC 功能的增强，这对扩大老年 HSC 移植的治疗潜力具有重要意义。
