Genetic regulation of primitive hematopoietic stem cell senescence
Genetic regulation of primitive hematopoietic stem cell senescence
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DOI：
10.1016/s0301-472x(99)00157-5
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发表时间：
2000-04-01
影响因子：
2.6
通讯作者：
Harrison, DE
中科院分区：
文献类型：
--
作者：
Chen, JC;Astle, CM;Harrison, DE
目标。确定菌株对体内PHSC（原始造血干细胞）衰老（随着年龄的增长功能下降）的影响，并绘制调节PHSC衰老的位点。材料与方法。采用竞争再生和体内连续移植的方法，比较了BALB/cBy （BALB）、DBA/2 （D2）和C57BL/6 （B6）三种小鼠骨髓细胞（BMC）的长期功能和自我更新。来自每个老年或年轻供者的BMC与标准剂量的同源、遗传标记的BMC混合，并移植到致命的受体中。受体中供体型红细胞和淋巴细胞的百分比决定了供体PHSC相对于标准的功能能力，供体BMC的一个再填充单位（RU）等于100,000个标准竞争对手BMC的再填充能力。使用类似的技术，比较了12株BALB和B6衍生的重组自交系（RI）供体在nk缺失的BALBxB6 Fl受体中的再生能力，以绘制一个在PHSC衰老中起主要作用的位点。BALB和D2 BR IC的PHSC功能随年龄增长而下降约2倍，B6 BMC的PHSC功能随年龄增长而增加2倍以上，且老幼品系差异均显著（p < 0.01）。连续移植10个月后，青年B6、BALB、D2 PHSC自我更新率分别为老年的1.6倍、4.2倍、3.2倍，其中BALB、D2老年/青年差异p < 0.01。年轻的B6 PHSC的自我更新能力是年轻的BALB和D2 PHSC的1.9倍和2.9倍。12株CS - RI菌株的PHSC衰老表型（老/年轻RU比）提示与12号染色体上的D12Nyul7有遗传连锁。PHSC衰老受基因调控，与BALE和D2菌株相比，B6菌株的PHSC衰老延迟得多。12号染色体上的莲花可能调节物理细胞衰老。(C) 2000国际实验血液学学会。Elsevier Science Inc.出版。
Objective. To define effects of strain on PHSC (primitive hematopoietic stem cells) senescence (decline in function with age) in vivo, and to map a locus that regulates PHSC senescence.Materials and Methods. Long-term function and self-renewal were compared in bone marrow cells (BMC) from old and young mice of three strains: BALB/cBy (BALB), DBA/2 (D2) and C57BL/6 (B6), using competitive repopulation and serial transplantation in vivo. BMC from each old or young donor were mixed with standard doses of congenic, genetically marked BMC and transplanted into Lethally recipients. Percentages of donor-type erythrocytes and lymphocytes in the recipients determined the functional ability of donor PHSC relative to the standard, where one repopulating unit (RU) of donor BMC equals the repopulating ability of 100,000 standard competitor BMC. Using similar techniques, repopulating abilities of old and young recombinant inbred (RI) donors of 12 strains derived from BALB and B6 were compared in NK-depleted BALBxB6 Fl recipients to map a locus that appears to have a major role in PHSC senescence,Results. PHSC function declined about 2 fold with age in BALB and D2 BR IC, and increased more than 2-fold with age in B6 BMC, with all old/young strain differences significant, p < .01. Ten months after serial transplantation, young B6, BALB, and D2 PHSC had self-renewed 1.6-, 4.2-, and 3.2-fold better than old, with BALB and D2 old/young differences p < .01. Young B6 PHSC self-renewed 1.9- and 2.9-fold better than young BALB and D2 PHSC. The PHSC senescence phenotypes (old/young RU ratios) for 12 CS RI strains suggested a genetic linkage to D12Nyul7 on Chromosome 12,Conclusion. PHSC senescence is genetically regulated, and is much delayed in the B6 strain compared to the BALE and D2 strains. A Lotus on Chromosome 12 may regulate PHSC senescence. (C) 2000 International Society for Experimental Hematology. Published by Elsevier Science Inc.