Transforming growth factor beta 1 directly and reversibly inhibits the initial cell divisions of long-term repopulating hematopoietic stem cells.
Transforming growth factor beta 1 directly and reversibly inhibits the initial cell divisions of long-term repopulating hematopoietic stem cells.
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DOI：
10.1182/blood.v88.1.82.82
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发表时间：
1996-07
期刊：
影响因子：
20.3
通讯作者：
E. Sitnicka;F. Ruscetti;G. Priestley;N. Wolf;S. Bartelmez
中科院分区：
文献类型：
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作者：
E. Sitnicka;F. Ruscetti;G. Priestley;N. Wolf;S. Bartelmez
造血似乎部分受到细胞外正生长信号和负生长信号之间的平衡的调节。转化生长因子β-1（TGF-β1）已被证明是原始造血细胞的负调节因子。本研究在体外检验了 TGF-β1 对长期再生造血干细胞 (LTR-HSC) 增殖和分化的直接影响。我们之前报道了一种细胞分级分离方法，包括选择低 Hoescht 33342/低罗丹明 123 (低 Ho/Rh) 细胞级分，这些级分高度富集长期再生细胞 (LTR-HSC)，并且在干细胞因子 (SCF) + 白介素-3 (IL-3) + IL-6 存在的情况下克隆效率非常高：90% 至 100% 单独培养的低 Ho/Rh 细胞形成高增殖潜力的克隆。 LTR-HSC 富集细胞群的高克隆效率使增殖抑制研究更容易解释。在本报告中，我们表明，TGF-β1 的持续存在可直接抑制基本上所有低 Ho/Rh 细胞在体外第 0 至第 5 次细胞分裂期间的细胞分裂（以剂量依赖性方式）。因此，TGF-β1 必须直接抑制这些低 Ho/Rh 细胞内所含的 LTR-HSC 的增殖。在存在 TGF-β 1 的情况下，一些低 Ho/Rh 细胞在体外进行首次细胞分裂所需的时间也会延长。此外，当低 Ho/Rh 细胞在单克隆抗体中和 TGF-β 1 之前暴露于 TFG-β 1 不同时间时，在接触 TGF-β 1 约 4 天后，形成大克隆的能力显着下降。此外，与未添加 TGF-β 1 的培养物中 HPP-CFC 的损失相比，1 至 10 ng/mL 的 TGF-β 1 可在培养 8 天期间维持高增殖潜能集落形成细胞 (HPP-CFC)。 总之，本研究表明 TGF-β 1 直接抑制 LTR-HSC 增殖的初始阶段，并似乎减缓低 Ho/Rh 细胞的子细胞分化。
Hematopoiesis appears to be regulated, in part, by a balance between extracellular positive and negative growth signals. Transforming growth factor beta-1 (TGF-beta 1) has been shown to be a negative regulator of primitive hematopoietic cells. This study examined the direct effect of TGF-beta 1 on the proliferation and differentiation of long-term repopulating hematopoietic stem cells (LTR-HSC) in vitro. We previously reported a cell fractionation approach that includes the selection of low Hoescht 33342/low Rhodamine 123 (low Ho/Rh) cell fractions that are highly enriched for long-term repopulating cells (LTR-HSC) and also clone to a very high efficiency in the presence of stem cell factor (SCF) + interleukin-3 (IL-3) + IL-6: 90% to 100% of individually cultured low Ho/Rh cells formed high proliferative potential clones. This high cloning efficiency of an LTR-HSC enriched cell population enabled proliferation inhibition studies to be more easily interpreted. In this report, we show that the continuous presence of TGF-beta 1 directly inhibits the cell division of essentially all low Ho/Rh cells (in a dose-dependent manner) during their 0 to 5th cell division in vitro. Therefore, it follows that TGF-beta 1 must directly inhibit the proliferation of LTR-HSC contained within these low Ho/Rh cells. The time required for some low Ho/Rh cells to undergo their first cell division in vitro was also prolonged in the presence of TGF-beta 1. Furthermore, when low Ho/Rh cells were exposed to TFG-beta 1 for varying lengths of time before neutralization of the TGF-beta 1 by monoclonal antibody, the ability to form macroclones was markedly decreased after approximately 4 days of TGF-beta 1 exposure. In addition, 1 to 10 ng/mL of TGF-beta 1 resulted in a maintenance of high proliferative potential-colony-forming cell (HPP-CFC) during 8 days of culture compared with loss of HPP-CFC in cultures with no added TGF-beta 1. In conclusion, this study shows that TGF-beta 1 directly inhibits the initial stages of proliferation of LTR-HSC and appears to slow the differentiation of daughter cells of low Ho/Rh cells.