Impaired hematopoietic stem cell functioning after serial transplantation and during normal aging
Impaired hematopoietic stem cell functioning after serial transplantation and during normal aging
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DOI：
10.1634/stemcells.2004-0066
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发表时间：
2005-01-01
期刊：
影响因子：
5.2
通讯作者：
De Haan, G
中科院分区：
文献类型：
--
作者：
Kamminga, LM;Van Os, R;De Haan, G
成体干细胞具有广泛的自我更新能力，因为它们的主要作用是补充衰老和功能受损的组织。我们之前已经表明，与长寿的 C57BL/6 (136) 小鼠相比，短命 DBA/2 (D2) 小鼠的干细胞池在衰老过程中会减少。这表明干细胞中存在由基因决定的有丝分裂时钟，这可能限制机体衰老。在此报告的研究中，将未分级的骨髓 (BM) 细胞或高度纯化的 Lin(-)Sca-1(+)c-kit(+) (LSK) 细胞连续移植到经致死辐射的 D2 和 B6 小鼠体内。在这两种菌株中，连续移植导致干细胞活性大幅丧失。然而，据我们估计，在 B6 小鼠中，原始细胞群体倍增的最大数量约为 30，而在 D2 小鼠中，这一数字仅为 20 左右，导致扩增潜力相差 1,000 倍，无论移植的是全骨髓还是纯化的造血干细胞 (HSC)。有趣的是，用连续移植的骨髓细胞重建的受体能够接受新鲜分离的移植物，而无需任何进一步的调理。最后，我们表明，虽然将 BM 细胞移植到健康、非条件化、年轻的 B6 受体中不会导致植入，但年轻的 BM 细胞确实会植入并在未受辐射的老年小鼠中提供多谱系重建。我们的数据清楚地确定了与衰老过程中干细胞功能受损相关的内在遗传控制程序的相关性。
Adult somatic stem cells possess extensive self-renewal capacity, as their primary role is to replenish aged and functionally impaired tissues. We have previously shown that the stem cell pool in short-lived DBA/2 (D2) mice is reduced during aging, in contrast to long-lived C57BL/6 (136) mice. This suggests the existence of a genetically determined mitotic clock operating in stem cells, which possibly limits organismal aging. In the study reported here, unfractionated bone marrow (BM) cells or highly purified Lin(-)Sca-1(+)c-kit(+) (LSK) cells were serially transplanted in lethally irradiated D2 and B6 mice. In both strains, serial transplantation resulted in a substantial loss of stem cell activity. However, as we estimate that in B6 mice, the maximum number of population doublings of primitive cells is approximately 30, in D2 mice this is only approximately 20, resulting in a 1,000-fold difference in expansion potential, irrespective of whether whole bone marrow or purified hematopoietic stem cells (HSCs) were transplanted. Interestingly, recipients reconstituted with serially transplanted BM cells were able to accept a freshly isolated graft without any further conditioning. Finally, we show that whereas transplantation of BM cells into healthy, nonconditioned, young B6 recipients does not lead to engraftment, young BM cells do engraft and provide multilineage reconstitution in nonirradiated aged mice. Our data clearly establish the relevance of an intrinsic, genetically controlled program associated with impaired stem cell functioning during aging.