SERIAL DEPLETION AND REGENERATION OF THE MURINE HEMATOPOIETIC SYSTEM - IMPLICATIONS FOR HEMATOPOIETIC ORGANIZATION AND THE STUDY OF CELLULAR AGING
SERIAL DEPLETION AND REGENERATION OF THE MURINE HEMATOPOIETIC SYSTEM - IMPLICATIONS FOR HEMATOPOIETIC ORGANIZATION AND THE STUDY OF CELLULAR AGING
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DOI：
10.1084/jem.155.2.432
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发表时间：
1982-01-01
影响因子：
15.3
通讯作者：
MICKLEM, HS
中科院分区：
文献类型：
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作者：
ROSS, EAM;ANDERSON, N;MICKLEM, HS
小鼠的造血系统经历了反复耗尽和再生，要么是通过致死性照射的受者连续移植骨髓细胞，要么是通过循环活性药物羟基脲(HU)重复治疗。每隔一段时间用两种方法检测存活干细胞的增殖和自我更新能力：脾集落法和用染色体标记检测受者的竞争性再扩增能力，并以正常骨髓细胞为内对照。在HU治疗期间，在连续骨髓移植过程中发生的干细胞功能进行性下降和单次移植后已经开始的干细胞功能的进行性下降在HU治疗期间没有出现；超过1年的多达25对HU注射对最后一次注射后3周出现的干细胞数量或其自我更新能力没有明显影响。在HU暴露后2天内，存活干细胞的平均自我更新能力增强。显然，这种药物选择性地消除了自我更新能力差的干细胞；这些干细胞比具有高自我复制潜力的干细胞更容易进入周期。然而，注射时处于周期这一事实本身并不影响自我更新。骨髓连续移植不是研究克隆衰老现象的有效方法，因为它不能满足此类研究所基于的假设。在HU诱导的耗竭后，没有证据表明骨髓群体重复再生的能力有任何内在的限制。然而，这并不一定意味着单个造血克隆能够无限扩张，因为造血可能(正如高度自我复制的干细胞对有丝分裂信号的相对抵抗力所表明的)可能在克隆继承的基础上进行。
The mouse hematopoietic system was subjected to repeated depletion and regeneration either by serial transfer of bone marrow cells through lethally irradiated recipients or by repeated treatment with the cycle-active drug hydroxyurea (HU). The capacity of surviving stem cells to proliferate and self-renew was assayed at intervals by 2 methods: the spleen colony method; and competitive repopulation of irradiated recipients using chromosome markers, with normal bone marrow cells as an internal control. The progressive decline in stem cell function that occurred during serial transfer of bone marrow and that had already begun after a single transfer was not seen during HU treatment; up to 25 pairs of HU injections given over more than 1 yr had no discernible effect on the number of stem cells present 3 wk after the final injection or on their capacity to self-renew. Within 2 days after exposure to HU, the average self-renewal capacity of surviving stem cells was enhanced. Apparently, the drug selectively eliminates poorly self-renewing stem cells; these enter cycle more readily than stem cells with a high self-replicative potential. However, the fact of being in cycle at the time of injection did not of itself affect self-renewal. Serial transfer of bone marrow is not a valid method for studying clonal aging phenomena because it does not fulfill the assumptions on which such studies are based. No evidence was obtained for any intrinsic limitation in the capacity of bone marrow populations for repeated regeneration after HU-induced depletion. However, this does not necessarily imply that individual hematopoietic clones are capable of indefinite expansion because hematopoiesis may (as suggested by the relative resistance of highly self-replicative stem cells to mitogenic signals) proceed on the basis of clonal succession.