All-trans retinoic acid delays the differentiation of primitive hematopoietic precursors (lin-c-kit+Sca-1+) while enhancing the terminal maturation of committed granulocyte monocyte progenitors
All-trans retinoic acid delays the differentiation of primitive hematopoietic precursors (lin-c-kit+Sca-1+) while enhancing the terminal maturation of committed granulocyte monocyte progenitors
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DOI：
10.1182/blood.v94.2.483.414k12_483_495
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发表时间：
1999-07-15
期刊：
影响因子：
20.3
通讯作者：
Collins, SJ
中科院分区：
文献类型：
--
作者：
Purton, LE;Bernstein, ID;Collins, SJ
全反式维甲酸(ATRA)是一种有效的恶性早幼粒细胞终末分化诱导剂，但其对原始造血祖细胞和干细胞的作用尚不清楚。本研究观察了全反式维甲酸(ATRA)对液体悬浮培养28天的高浓缩小鼠造血祖细胞(LIN(-)、c-kit(+)、Sca-1(+))的影响。全反式维甲酸最初减缓了这些造血祖细胞的生长，但与未加ATRA培养的造血祖细胞相比，它们的集落形成细胞产量延长并显著增强。培养7天和14天，加入全反式维甲酸的细胞不表达谱系相关抗原(7天和14天分别为55.4%和68.6%)，并保留了SCA-1的表达(7天和14天分别为44.7%和79.9%)，而与未加全反式维甲酸培养的细胞(LIN(-)细胞：7天和14天分别为31.5%和4%；SCA-1(+)：7天和14天分别为10.4%和0.7%)相比，差异显著(P<0.05)。与全反式维甲酸共同孵育14天后，可明显抑制粒细胞的生成，显著延长和促进可移植细胞集落形成单位--S的生成。与其对原始LIN(-)、c-Kit(+)、SCA-1(+)造血祖细胞的作用不同，全反式维甲酸对LIN(-)、c-Kit(+)、SCA-1(-)造血祖细胞没有同样的作用。此外，在原始造血祖细胞培养中加入全反式维甲酸后(培养开始后7天)，这些原始造血祖细胞的集落形成细胞产量显著减少，这与促进粒细胞分化有关。这些观察表明，ATRA对造血细胞有不同的影响，取决于它们的成熟状态，防止和/或延迟原始造血祖细胞的分化，同时促进承诺的粒/单核细胞前体的终末分化，(C)1999，美国血液学学会。
All-trans retinoic acid (ATRA) is a potent inducer of terminal differentiation of malignant promyelocytes, but its effects on more primitive hematopoietic progenitors and stem cells are less clear. In this study, we investigated the effect of ATRA on highly enriched murine hematopoietic precursor cells (lin(-)c-kit(+)Sca-1(+)) grown in liquid suspension culture for 28 days. ATRA initially slowed the growth of these hematopoietic precursors but prolonged and markedly enhanced their colony-forming cell production compared with the hematopoietic precursors cultured in its absence. At 7 and 14 days of culture, a substantially greater percentage of cells cultured with ATRA did not express lineage-associated antigens (55.4% at day 7 and 68.6% at day 14) and retained expression of Sca-1 (44.7% at day 7 and 79.9% at day 14) compared with cells grown in its absence (lin(-) cells: 31.5% at day 7 and 4% at day 14; Sca-1(+): 10.4% at day 7 and 0.7% at day 14). Moreover, a marked inhibition of granulocyte production was observed in cultures continuously incubated with ATRA, Significantly, ATRA markedly prolonged and enhanced the production of transplantable colony-forming unit-spleen (CFU-S) during 14 days of liquid suspension culture. In contrast with its effects on primitive lin(-)c-kit(+)Sca-1(+) hematopoietic precursors, ATRA did not exert the same effects on the more committed lin(-)c-kit(+)Sca-1(-) progenitor cells. Moreover, the late addition of ATRA (7 days post-culture initiation) to cultures of primitive hematopoietic precursors resulted in a marked decrease in colony-forming cell production in these cultures, which was associated with enhanced granulocyte differentiation. These observations indicate that ATRA has different effects on hematopoietic cells depending on their maturational state, preventing and/or delaying the differentiation of primitive hematopoietic precursors while enhancing the terminal differentiation of committed granulocyte/monocyte progenitors, (C) 1999 by The American Society of Hematology.