Identification of unique microRNA expression patterns in bone marrow hematopoietic stem and progenitor cells after hemorrhagic shock and multiple injuries in young and old adult mice.
Identification of unique microRNA expression patterns in bone marrow hematopoietic stem and progenitor cells after hemorrhagic shock and multiple injuries in young and old adult mice.
复制标题
DOI：
10.1097/ta.0000000000003350
复制
发表时间：
2021-10-01
期刊：
影响因子：
--
通讯作者：
Efron PA
中科院分区：
文献类型：
--
作者：
Darden DB;Mira JC;Lopez MC;Stortz JA;Fenner BP;Kelly LS;Nacionales DC;Budharaju A;Loftus TJ;Baker HV;Moore FA;Brakenridge SC;Moldawer LL;Mohr AM;Efron PA
在严重创伤后，老年宿主经历更多的骨髓（BM）造血干细胞和祖细胞（HSPC）的造血功能障碍，以及循环髓样细胞向有效的先天免疫细胞的分化功能障碍。我们的主要目的是在严重创伤和休克的临床相关模型中比较老年和年轻小鼠的BM HSPC miR应答。年龄为8-12周（年轻）和18-24个月（年老）的C57 BL/6成年雄性小鼠经历多发性创伤和出血性休克（PT），其产生等同于重大创伤（损伤严重性评分>15）。PT后24小时，在一些年轻和年老的成年小鼠中诱导肺炎假单胞菌（PNA）。分别在损伤后24小时和48小时从PT和PT+PNA小鼠分离的谱系阴性富集的BM HSPC中确定miR表达模式。还对来自两个小鼠队列的支气管肺泡灌洗（BAL）白细胞进行了全基因组表达和途径分析。miR表达在所有实验条件中显著不同（p<0.05），除了老年未处理与老年损伤（PT或PT+PNA）小鼠，表明老年小鼠不能对严重休克和损伤产生稳健的早期miR应答。此外，与老年小鼠相比，年轻成年小鼠从其BAL中获得的白细胞显著更多，并且多形核细胞数量更多（59.8% vs 2.2%，p=0.0069）。尽管基因表达变化增加，但老年小鼠的BAL白细胞对PT+PNA的转录组反应比年轻成年小鼠BAL白细胞功能障碍更严重，这反映在预测的上游功能途径分析中。PT（+/−PNA）后BM HSPC中的miR表达模式在老年小鼠与年轻成年小鼠中不同。在急性损伤后阶段，老年成年小鼠无法产生稳健的miR HSPC应答。老年PT小鼠中的HSPC miR表达反映了髓样细胞的功能状态减弱以及终末分化能力减弱。基础科学。实验鼠模型。
After severe trauma, the older host experiences more dysfunctional hematopoiesis of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs), and dysfunctional differentiation of circulating myeloid cells into effective innate immune cells. Our main objective was to compare BM HSPC miR responses of old and young mice in a clinically relevant model of severe trauma and shock. C57BL/6 adult male mice aged 8–12 weeks (young) and 18–24 months (old) underwent polytrauma and hemorrhagic shock (PT) that engenders the equivalent of major trauma (injury severity score >15). Pseudomonas pneumonia (PNA) was induced in some young and old adult mice 24 hours after PT. miR expression patterns were determined from lineage-negative enriched BM HSPCs isolated from PT and PT+PNA mice at 24- and 48-hours post-injury, respectively. Genome-wide expression and pathway analyses were also performed on bronchoalveolar lavage (BAL) leukocytes from both mouse cohorts. miR expression significantly differed among all experimental conditions (p<0.05), except for old-naïve vs old-injured (PT or PT+PNA) mice, suggesting an inability of old mice to mount a robust early miR response to severe shock and injury. In addition, young adult mice had significantly more leukocytes obtained from their BAL, and there were greater numbers of polymorphonuclear cells compared with old mice (59.8% vs 2.2%, p=0.0069). Despite increased gene expression changes, BAL leukocytes from old mice demonstrated a more dysfunctional transcriptomic response to PT+PNA than young adult murine BAL leukocytes, as reflected in predicted upstream functional pathway analysis. The miR expression pattern in BM HSPCs after PT(+/−PNA) is dissimilar in old versus young adult mice. In the acute post-injury phase, old adult mice are unable to mount a robust miR HSPC response. HSPC miR expression in old PT mice reflects a diminished functional status as well as a blunted capacity for terminal differentiation of myeloid cells. Basic Science. Experimental murine model.