Distinct circadian time structures characterize myeloid and erythroid progenitor and multipotential cell clonogenicity as well as marrow precursor proliferation dynamics.
Distinct circadian time structures characterize myeloid and erythroid progenitor and multipotential cell clonogenicity as well as marrow precursor proliferation dynamics.
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发表时间：
1998-06
影响因子：
2.6
通讯作者：
P. Wood;W. Hrushesky;R. Klevecz
中科院分区：
文献类型：
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作者：
P. Wood;W. Hrushesky;R. Klevecz
骨髓对辐射、骨髓毒性药物和生长因子的敏感性的昼夜节律差异表明，造血过程每天都有显著变化。一种可能导致在一天的不同时间从固定剂量的细胞毒性剂持续不同程度的骨髓损伤的机制是细胞周期事件的昼夜节律组织。以前的昼夜节律为导向的研究增殖使用普通骨髓报告似乎矛盾的高峰和低谷时间的一天。骨髓是由干细胞和造血祖细胞组成的异质群体，其增殖和分化受共同和独特因素的控制。因此，我们研究了谱系特异性的昼夜骨髓增殖动力学的证据，parasynchronous昼夜DNA合成。使用流式细胞术测定细胞周期时相，碘化丙啶染色和5-溴-2 '-脱氧尿苷（BrdU）掺入，同时基于细胞培养测定相同骨髓样品中的谱系特异性祖细胞数量。虽然没有明确的昼夜（24小时）节律的特点是未分级骨髓DNA合成，红细胞和骨髓富集亚群表现出不同的昼夜模式的百分比，细胞纳入BrdU，高达50%的差异，在每一天。有趣的是，红系和髓系祖细胞DNA合成中的这些昼夜节律彼此完全不同。进行DNA合成的细胞部分中的谱系特异性昼夜节律模式部分地被红细胞和髓细胞集落数量的高达8倍的昼夜节律差异掩盖。多能性菌落的数量在一天中也有变化，有自己独特的模式。每日节律的主要周期长度在殖民地数量和它们的振幅不同的功能的阶段的祖承诺。多能性和早期祖细胞集落数均表现出24小时节律，每天峰谷差异为3 - 5倍，而后期祖细胞集落数每天表现出两个峰（12小时节律），每天峰谷差异为2倍。体内促红细胞生成素（Epo）给药通过增加其振幅同时使其昼夜节律形状几乎不变来增强红细胞集落数量的每日节律。Epo给药后红系细胞集落数量的增量随给药日的时间变化高达16倍。总之，我们已经确定了骨髓祖细胞数量和增殖细胞明显不同的谱系依赖性昼夜节律模式。我们可以从这些数据中推断出，可以预期，对骨髓前体细胞的生物活性取决于其呈现的细胞周期阶段的物理，化学或生物制剂的给药的昼夜节律时间可以预测和显著地影响这种活性。这些结果可能有实际应用，在提高干细胞和祖细胞产量的最佳昼夜节律的生长因子管理和收获的时间。
Circadian differences in the susceptibility of the marrow to the effects of radiation, myelotoxic drugs, and growth factors suggest that hematopoietic processes vary significant throughout each day. One mechanism possibly responsible for the differing degrees of marrow damage sustained from a fixed dose of a cytotoxic agent at different times of day is the circadian organization of cell cycle events. Previous circadian rhythm-oriented studies of proliferation using unfractionated marrow have reported seemingly contradictory peak and nadir times of day. Marrow represents a heterogeneous population of stem cells and various hematopoietic progenitors whose proliferation and differentiation are controlled by both common and unique factors. Therefore, we examined lineage-specific circadian marrow proliferative dynamics for evidence of parasynchronous circadian DNA synthesis. Cell cycle phase was determined using flow cytometry with both propidium iodide staining and 5-bromo-2'-deoxyuridine (BrdU) incorporation concurrently with cell culture-based determinations of lineage-specific progenitor numbers in the same marrow samples. Although no clear circadian (24-hour) rhythm characterized unfractionated marrow DNA synthesis, both erythroid- and myeloid-enriched subpopulations demonstrated distinct circadian patterns with respect to the percentage of cells incorporating BrdU, with up to 50% differences throughout each day. Interestingly, these circadian rhythms in erythroid and myeloid progenitor cell DNA synthesis are entirely different from one another. The lineage-specific circadian patterns in the fraction of cells undergoing DNA synthesis are, in part, paralleled by up to eightfold larger circadian differences in erythroid and myeloid colony numbers. Multipotential colony numbers likewise vary throughout the day, with a unique pattern of their own. The predominant period length of daily rhythms in colony numbers and their amplitudes differ as a function of the stage of progenitor commitment. Multipotent and early progenitor colony numbers each exhibit 24-hour rhythms, with three- to fivefold daily peak-trough differences, whereas later progenitor colony numbers exhibit two peaks per day (12-hour rhythms) with twofold peak-trough differences throughout each day. In vivo erythropoietin (Epo) administration enhances daily rhythms in erythroid colony numbers by increasing their amplitudes while leaving their circadian shapes virtually unchanged. The increment in erythroid colony numbers after Epo administration varies up to 16-fold with the time of day of treatment. In summary, we have defined distinctly different lineage-dependent circadian patterns of marrow progenitor numbers and proliferating cells. We can infer from these data that the circadian timing of administration of physical, chemical, or biologic agents, whose bioactivity toward marrow precursors depends on the cell cycle phase of its presentation, can be expected to affect this activity predictably and significantly. These results may have practical applications in improving stem and progenitor cell yields by optimal circadian timing of growth factor administration and harvest.