Interleukin-3 supports expansion of long-term multilineage repopulating activity after multiple stem cell divisions in vitro
Interleukin-3 supports expansion of long-term multilineage repopulating activity after multiple stem cell divisions in vitro
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DOI：
10.1182/blood.v96.5.1748.h8001748_1748_1755
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发表时间：
2000-09-01
期刊：
影响因子：
20.3
通讯作者：
Jacobsen, SEW
中科院分区：
文献类型：
--
作者：
Bryder, D;Jacobsen, SEW
虽然长期再生的造血干细胞（HSC）在体内可以自我更新和广泛扩增，但大多数体外扩增HSC的努力都被证明是不成功的，并且经常导致损害而不是改善HSC移植物。这引发了对细胞因子的最佳组合的探索，以促进HSC的扩增。通过这些研究，c-kit配体（KL）、flt3配体（FL）、血小板生成素和il - 1可能是HSC自我更新的正调节因子。相比之下，许多研究表明IL-3具有独特而有效的负调控作用，表明不同细胞因子可能对引入HSC的命运有不同的调节。然而，由于不同细胞因子可能针对HSC室中不同的亚群，以及缺乏证据表明HSC进行自我更新，对这些发现的解释变得复杂。这里，在KL+FL+巨核细胞生长发育因子（MGDF）存在的情况下，IL-3和IL-ll显示出不可区分的进一步增强增殖的能力，该因子在无血清条件下招募几乎所有Lin(-)Sca-1(+)kit（+）骨髓细胞进入增殖并促进其自我更新。令人惊讶的是，与il - 1相似，IL-3支持KL+FL+ mgdf诱导的原发性和继发性受体多系长期重建活性的扩增。此外，高分辨率的细胞分裂跟踪表明，所有的HSC都经历了至少5次细胞分裂，这表明在多次细胞分裂后，IL-3刺激不会损害长期再生的HSC。与此形成鲜明对比的是，小鼠HSC在胎牛含血清培养基中的体外扩增导致重构活性的广泛丧失，而IL-3的存在进一步促进了这一作用。(C) 2000年由美国血液学会出版。
Although long-term repopulating hematopoietic stem cells (HSC) can self-renew and expand extensively in vivo, most efforts at expanding HSC in vitro have proved unsuccessful and have frequently resulted in compromised rather than improved HSC grafts. This has triggered the search for the optimal combination of cytokines for HSC expansion. Through such studies, c-kit ligand (KL), flt3 ligand (FL), thrombopoietin, and IL-ll have emerged as likely positive regulators of HSC self-renewal. In contrast, numerous studies have implicated a unique and potent negative regulatory role of IL-3, suggesting perhaps distinct regulation of Introduction HSC fate by different cytokines, However, the interpretations of these findings are complicated by the fact that different cytokines might target distinct subpopulations within the HSC compartment and by the lack of evidence for HSC undergoing self-renewal. Here, in the presence of KL+FL+megakaryocyte growth and development factor (MGDF), which recruits virtually all Lin(-)Sca-1(+)kit(+) bone marrow cells into proliferation and promotes their self-renewal under serum-free conditions, IL-3 and IL-ll revealed an indistinguishable ability to further enhance proliferation. Surprisingly, and similar to IL-ll, IL-3 supported KL+FL+MGDF-induced expansion of multilineage, long-term reconstituting activity in primary and secondary recipients. Furthermore, high-resolution cell division tracking demonstrated that all HSC underwent a minimum of 5 cell divisions, suggesting that long-term repopulating HSC are not compromised by IL-3 stimulation after multiple cell divisions. In striking contrast, the ex vivo expansion of murine HSC in fetal calf serum-containing medium resulted in extensive loss of reconstituting activity, an effect further facilitated by the presence of IL-3. (C) 2000 by The American Society of Hematology.