Major age-related changes of mouse hematopoietic stem/progenitor cells
Major age-related changes of mouse hematopoietic stem/progenitor cells
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DOI：
10.1111/j.1749-6632.2003.tb03247.x
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发表时间：
2003-01-01
期刊：
影响因子：
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通讯作者：
Spangrude, GJ
中科院分区：
文献类型：
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作者：
Kim, M;Moon, HM;Spangrude, GJ
为了研究小鼠骨髓（BM）细胞和造血干细胞（HSCs）的年龄相关性变化，我们从老年小鼠骨髓中分离出罗丹明-123（low）（Rh-low）Thy1.1（low）Lin（-）Sca-1（+）（TLS）HSCs，并将其功能特性与从年轻小鼠中分离的相同表型的细胞进行比较。我们观察到受损的恢复B淋巴细胞和减少自我更新的老Rh低细胞相比，年轻的Rh低细胞的受体。使用维拉帕米阻断Rh外排改善了富集HSC的淋巴重建，并且基于荧光多药耐药（MDR）底物（Bodipy-Verapamil）外排的老化HSC的分离导致了与用Rh获得的HSC活性相当的富集。这些观察结果表明，在衰老过程中MDR活性和HSC功能之间存在复杂的关系。为了解决年轻和老年供体之间的差异是HSC区室固有的还是由于HSC表型的转变，我们共移植了来自年轻或老年供体的正常BM，并在相同的受体动物中同时进行再增殖。在平行实验中，我们将从老年供体纯化的HSC与来自年轻供体的BM共移植。在这两个实验中，年轻和老年接受者都接受了移植。结果显示，无论受者的年龄如何，来自老年供体的BM或HSC的B细胞植入都存在明显缺陷。相比之下，骨髓移植主要来自老年供体的BM或HSC，同样与受体年龄无关。这些数据表明B细胞免疫衰老和老年人髓细胞白血病发病率增加的干细胞基础。
To study age-related changes of mouse bone marrow (BM) cells and hematopoietic stem cells (HSCs), we isolated rhodamine-123(low) (Rh-low) Thy1.1(low)Lin(-)Sca-1(+) (TLS) HSCs from the BM of old mice and compared their functional characteristics to cells of the same phenotype isolated from young mice. We observed impaired recovery of B lymphocytes and decreased self-renewal in recipients of old Rh-low cells compared to young Rh-low cells. Blockade of Rh efflux using verapamil improved lymphoid reconstitution by enriched HSCs, and isolation of aged HSCs based on efflux of a fluorescent multi-drug resistance (MDR) substrate (Bodipy-verapamil) resulted in enrichment of HSC activity equivalent to that obtained with Rh. These observations suggest a complex relationship between MDR activity and HSC function during aging. To address whether the difference between young and aged donors was intrinsic to the HSC compartment or was due to a shift in HSC phenotype, we co-transplanted normal BM derived from young or old donors and followed repopulation simultaneously in the same recipient animals. In a parallel experiment, we co-transplanted HSCs purified from old donors with BM derived from young donors. In both experiments, transplants were given to both young and old recipients. The results show a clear defect in B-cell engraftment from either BM or HSCs of old donors, irrespective of the age of the recipient. In contrast, myeloid engraftment was predominantly derived from BM or HSCs derived from aged donors, again irrespective of recipient age. These data suggest a stem cell basis for B-cell immuno-senescence and the increased incidence of myelocytic leukemia in elderly people.