c-Myc Inhibitor 10074-G5 Induces Murine and Human Hematopoietic Stem and Progenitor Cell Expansion and HDR Modulator Rad51 Expression
c-Myc Inhibitor 10074-G5 Induces Murine and Human Hematopoietic Stem and Progenitor Cell Expansion and HDR Modulator Rad51 Expression
复制标题
DOI：
10.2174/1568009618666180905100608
复制
发表时间：
2019-01-01
影响因子：
3
通讯作者：
Kocabas, Fatih
中科院分区：
文献类型：
--
作者：
Aksoz, Merve;Albayrak, Esra;Kocabas, Fatih
背景资料：c-Myc在维持糖酵解代谢和造血干细胞（HSC）静止中起重要作用。目的：靶向HSC静止和代谢的调节剂可导致HSC细胞进入周期并伴随扩增。方法和结果：在此，我们显示c-Myc抑制剂10074-G5治疗7天后导致小鼠LSKCD 34（低）HSC隔室增加2倍。此外，c-Myc抑制增加了CD 34+和CD 133+人HSC数量。c-Myc抑制导致离体和体内糖酵解和细胞周期蛋白依赖性激酶抑制剂（CDKI）基因表达下调。此外，c-Myc抑制上调造血细胞中主要HDR调节剂Rad 51的表达。此外，c-Myc抑制不改变内皮细胞、成纤维细胞或脂肪来源的间充质干细胞的增殖动力学，然而，其限制骨髓来源的间充质干细胞增殖。我们进一步证明，c-Myc抑制剂10074-05沿着牛磺熊去氧胆酸（TUDCA）和i-NOS抑制剂L-NIL的混合物提供了稳健的HSC维持和离体扩增，如通过诱导所分析的所有干细胞抗原所证明的。有趣的是，c-Myc抑制剂10074-G5、TUDCA和L-NIL的混合物可提高HDR相关基因的表达。结论：这些发现为通过调节HSC糖酵解和HDR途径来改善离体HSC维持和扩增、自体HSC移植和基因编辑提供了工具。
Background: c-Myc plays a major role in the maintenance of glycolytic metabolism and hematopoietic stem cell (HSC) quiescence.Objective: Targeting modulators of HSC quiescence and metabolism could lead to HSC cell cycle entry with concomitant expansion.Methods and Results: Here we show that c-Myc inhibitor 10074-G5 treatment leads to 2-fold increase in murine LSKCD34(low) HSC compartment post 7 days. In addition, c-Myc inhibition increases CD34+ and CD133+ human HSC number. c-Myc inhibition leads to downregulation of glycolytic and cyclin-dependent kinase inhibitor (CDKI) gene expression ex vivo and in vivo. In addition, c-Myc inhibition upregulates major HDR modulator Rad51 expression in hematopoietic cells. Besides, c-Myc inhibition does not alter proliferation kinetics of endothelial cells, fibroblasts or adipose-derived mesenchymal stem cells, however, it limits bone marrow derived mesenchymal stem cell proliferation. We further demonstrate that a cocktail of c-Myc inhibitor 10074-05 along with tauroursodeoxycholic acid (TUDCA) and i-NOS inhibitor L-NIL provides a robust HSC maintenance and expansion ex vivo as evident by induction of all stem cell antigens analyzed. Intriguingly, the cocktail of c-Myc inhibitor 10074-G5, TUDCA and L-NIL, improves HDR related gene expression.Conclusion: These findings provide tools to improve ex vivo HSC maintenance and expansion, autologous HSC transplantation and gene editing through modulation of HSC glycolytic and HDR pathways.