Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden.
Division of Physiological Chemistry I, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden; and.
Blood. 2020 Nov 5;136(19):2151-2161. doi: 10.1182/blood.2020005827.
Culture conditions in which hematopoietic stem cells (HSCs) can be expanded for clinical benefit are highly sought after. Here, we report that inhibition of the epigenetic regulator lysine-specific histone demethylase 1A (LSD1) induces a rapid expansion of human cord blood-derived CD34+ cells and promotes in vitro propagation of long-term repopulating HSCs by preventing differentiation. The phenotype and molecular characteristics of cells treated with LSD1 inhibitors were highly similar to cells treated with UM171, an agent promoting expansion of HSCs through undefined mechanisms and currently being tested in clinical trials. Strikingly, we found that LSD1, as well as other members of the LSD1-containing chromatin remodeling complex CoREST, is rapidly polyubiquitinated and degraded upon UM171 treatment. CRISPR (clustered regularly interspaced short palindromic repeats)/Cas9 depletion of the CoREST core member, RCOR1, resulted in expansion of CD34+ cells similar to LSD1 inhibition and UM171. Taken together, LSD1 and CoREST restrict HSC expansion and are principal targets of UM171, forming a mechanistic basis for the HSC-promoting activity of UM171.
人们迫切需要能够扩增造血干细胞（HSCs）以带来临床获益的培养条件。在此，我们报告称，抑制表观遗传调节剂赖氨酸特异性组蛋白去甲基酶 1A（LSD1）可通过阻止分化来快速扩增人脐血来源的 CD34+细胞，并促进长期重建造血干细胞的体外扩增。用 LSD1 抑制剂处理的细胞的表型和分子特征与用 UM171 处理的细胞高度相似，UM171 是一种通过未知机制促进 HSCs 扩增的药物，目前正在临床试验中进行测试。令人惊讶的是，我们发现 LSD1 以及 LSD1 包含的染色质重塑复合物 CoREST 的其他成员在 UM171 处理后会迅速被多泛素化和降解。使用 CRISPR（成簇规律间隔短回文重复）/Cas9 敲除 CoREST 的核心成员 RCOR1，可导致 CD34+细胞扩增，类似于 LSD1 抑制和 UM171。总之，LSD1 和 CoREST 限制 HSC 扩增，是 UM171 的主要靶点，为 UM171 的 HSC 促进活性提供了机制基础。
