Hematopoietic stem cells expand during serial transplantation in vivo without apparent exhaustion
Hematopoietic stem cells expand during serial transplantation in vivo without apparent exhaustion
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DOI：
10.1016/s0960-9822(06)00341-1
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发表时间：
1997-10-01
期刊：
影响因子：
9.2
通讯作者：
Nawa, K
中科院分区：
文献类型：
--
作者：
Iscove, NN;Nawa, K
造血干细胞是否可以无限制地增殖，或者它们的再生能力是否会随着重复分裂而下降，这已经争论了几十年。流行的观点倾向于内在的“衰退”，这一观点基于小鼠骨髓可以连续移植的有限程度[1，2]，脾集落形成细胞（CFU-s）的自我更新受到重复传代的削弱[1]，以及干细胞在甚至单次移植后不能再生到正常水平[3，4]。然而，系列转移实验并没有专门监测长寿命干细胞（长期重建细胞，LTRC）的输入和输出，从而使竞争性解释无法解决。我们通过在连续移植期间定量7-12个月的LTRCs重新研究了这个问题。虽然这些细胞在初次骨髓移植后仅恢复到正常水平的4%，但在每次传代时，它们相对于移植量增加约10倍，在四次转移后，估计累积扩增超过原始输入8400倍。扩增受到骨髓细胞特别是LRTC数量增加的转移的限制，这表明干细胞生长的上限非常确定。相反，通过施用干细胞因子（SCF，c-kit配体）和白细胞介素-11在体内增强扩增。结果挑战了传代干细胞的扩增受耗竭限制的观点，并表明移植后的扩增受外在机制的限制，其作用通过进一步将干细胞转移到受照射的宿主中或通过施用外源性细胞因子是可逆的。(C)Current Biology Ltd ISSN 0960-9822。
Whether hematopoietic stem cells can proliferate without limit, or whether their regenerative capacity declines with repeated division, has been debated for decades. prevailing opinion favours an intrinsic 'decline', a view based on the finite degree to which murine bone marrow can be serially transplanted [1,2], the diminished self-renewal of spleen colony-forming cells (CFU-s) subjected to repeated passage [1], and the failure of stem cells to regenerate to normal levels after even a single transplantation [3,4]. However, serial transfer experiments did not specifically monitor input and output of long-lived stem cells (long-term reconstituting cells, LTRCs), leaving competing interpretations unresolved. We have re-examined the issue by quantitating 7-12 month LTRCs during sequential transplantations. Although these cells recovered to only 4% of normal levels after primary bone marrow transplantation, at each passage they increased around 10-fold relative to the amount transplanted, attaining an estimated cumulative expansion of 8400-fold over the original input after four transfers. Expansion was limited by transfer of increasing numbers of marrow cells and specifically of LRTCs, suggesting an extrinsically determined ceiling to stem cell growth. Conversely, expansion was enhanced in vivo by administration of stem cell factor (SCF, c-kit ligand) and interleukin-11. The results challenge the view that expansion of passaged stem cells is limited by exhaustion, and indicate that augmentation after transplant is limited by extrinsic mechanisms whose effects are reversible either by further tra nsf er of the stem cells into irradiated hosts or by administration of exogenous cytokines. (C) Current Biology Ltd ISSN 0960-9822.