Fares Iman, Rivest-Khan Laura, Cohen Sandra, Sauvageau Guy
aMolecular Genetics of Stem Cells Laboratory, Institute for Research in Immunology and Cancer (IRIC), University of Montreal bDivision of Hematology, Maisonneuve-Rosemont Hospital cDepartment of Medicine, Faculty of Medicine, University of Montreal, Montreal, QC, Canada.
Curr Opin Hematol. 2015 Jul;22(4):309-16. doi: 10.1097/MOH.0000000000000151.
Hematopoietic stem and progenitor cell (HSPC) transplantation is frequently used in the treatment of hematological diseases. The outcome of the procedure is strongly influenced by the quantity of injected cells, especially if low cell numbers are infused as frequently encountered with cord blood transplants. Ex-vivo expansion of cord blood HSPCs would increase cell numbers, thus accelerating engraftment and reducing infectious complications and transplant-related mortality. In addition, expansion would maximize accessibility to better HLA-matched units, further improving patients' outcome. Similarly, in-vitro maintenance or expansion of leukemic stem cells (LSCs) would enable research into the much awaited targeted therapies that spare normal hematopoietic stem cells (HSCs). Here, we review recent findings on small molecules (excluding biologicals) regulating the activity of normal and leukemic stem cells and provide insights into basic science and clinical implications.
High-throughput screening of small molecules active on primary hematopoietic cells has led to the identification of two potent series of chemical compounds, best exemplified by StemRegenin1 and UM171, that both expand HSPCs. Current data suggest that the aryl hydrocarbon receptor antagonist StemRegenin1 is most active on primitive normal hematopoietic progenitors and LSCs and that UM171 expands long-term normal HSCs.
Small molecules are clinically useful and powerful tools for expanding HSPCs. They are also of potential value for dissecting the still elusive regulatory networks that govern self-renewal of human HSCs.
造血干细胞和祖细胞（HSPC）移植常用于治疗血液系统疾病。该手术的结果受注入细胞数量的强烈影响，特别是当注入细胞数量较少时，如脐血移植中经常遇到的情况。脐血HSPC的体外扩增将增加细胞数量，从而加速植入并减少感染并发症和移植相关死亡率。此外，扩增将最大限度地提高获得更好HLA匹配单位的机会，进一步改善患者的预后。同样，白血病干细胞（LSC）的体外维持或扩增将有助于研究备受期待的靶向疗法，这些疗法可使正常造血干细胞（HSC）免受影响。在此，我们综述了调节正常和白血病干细胞活性的小分子（不包括生物制剂）的最新研究结果，并深入探讨了其基础科学和临床意义。
对原代造血细胞有活性的小分子的高通量筛选已导致鉴定出两类有效的化合物系列，最典型的是StemRegenin1和UM171，它们都能扩增HSPC。目前的数据表明，芳烃受体拮抗剂StemRegenin1对原始正常造血祖细胞和LSC最具活性，而UM171能扩增长期正常HSC。
小分子是临床上用于扩增HSPC的有用且强大的工具。它们对于剖析仍难以捉摸的调控人类HSC自我更新的网络也具有潜在价值。
