美国加州大学洛杉矶分校Hanna K. A. Mikkola等研究人员合作发现，MYCT1控制人类造血干细胞的环境感应。2024年6月5日，国际知名学术期刊《自然》在线发表了这一成果。

研究人员发现MYC靶标1（MYCT1，又称MTLC）是一种重要的人类人类造血干细胞（HSC）调控因子，可调节HSC的内吞和环境感应。MYCT1在未分化的人类造血干细胞和祖细胞（HSPC）以及内皮细胞中选择性表达，但在HSC培养过程中会明显下调。慢病毒介导的MYCT1基因敲低阻止了人胎儿肝脏和脐带血（CB）HSPC的扩增和移植。

相比之下，恢复MYCT1的表达能改善培养的CB HSPC的扩增和移植。对敲低或过表达MYCT1的人CB HSPC进行单细胞RNA测序发现，MYCT1控制着造血干细胞干性所必需的重要调节程序和细胞特性，如ETS因子表达和低线粒体活性。MYCT1定位于造血干细胞的内体膜，并与囊泡贩运调节因子和信号机制相互作用。HSPC中MYCT1的缺失会导致过度内吞和信号反应亢进，而恢复MYCT1的表达则能平衡培养诱导的内吞和失调信号。

此外，根据最低内吞率对培养的CB HSPC进行分类，可识别出保留MYCT1表达的HSPC和MYCT1调控的HSC干性程序。该工作确定了MYCT1调节的内吞和环境感应是保持人类HSC干性所需的重要调节机制。这些数据还指出，MYCT1的沉默是细胞培养诱导的脆弱性，会损害人类HSC的扩增。

据了解，人类HSC自我更新和移植的过程鲜为人知，在培养中重现这些过程以可靠地扩增功能性造血干细胞具有挑战性。

附：英文原文

Title: MYCT1 controls environmental sensing in human haematopoietic stem cells

Author: Aguad-Gorgori, Jlia, Jami-Alahmadi, Yasaman, Calvanese, Vincenzo, Kardouh, Maya, Fares, Iman, Johnson, Haley, Rezek, Valerie, Ma, Feiyang, Magnusson, Mattias, Wang, Yanling, Shin, Juliana E., Nance, Karina J., Goodridge, Helen S., Liebscher, Simone, Schenke-Layland, Katja, Crooks, Gay M., Wohlschlegel, James A., Mikkola, Hanna K. A.

Issue&Volume: 2024-06-05

Abstract: The processes that govern human haematopoietic stem cell (HSC) self-renewal and engraftment are poorly understood and challenging to recapitulate in culture to reliably expand functional HSCs1,2,3. Here we identify MYC target1 (MYCT1; also known as MTLC) as a crucial human HSC regulator that moderates endocytosis and environmental sensing in HSCs. MYCT1 is selectively expressed in undifferentiated human haematopoietic stem and progenitor cells (HSPCs) and endothelial cells but becomes markedly downregulated during HSC culture. Lentivirus-mediated knockdown of MYCT1 prevented human fetal liver and cord blood (CB) HSPC expansion and engraftment. By contrast, restoring MYCT1 expression improved the expansion and engraftment of cultured CB HSPCs. Single-cell RNA sequencing of human CB HSPCs in which MYCT1 was knocked down or overexpressed revealed that MYCT1 governs important regulatory programmes and cellular properties essential for HSC stemness, such as ETS factor expression and low mitochondrial activity. MYCT1 is localized in the endosomal membrane in HSPCs and interacts with vesicle trafficking regulators and signalling machinery. MYCT1 loss in HSPCs led to excessive endocytosis and hyperactive signalling responses, whereas restoring MYCT1 expression balanced culture-induced endocytosis and dysregulated signalling. Moreover, sorting cultured CB HSPCs on the basis of lowest endocytosis rate identified HSPCs with preserved MYCT1 expression and MYCT1-regulated HSC stemness programmes. Our work identifies MYCT1-moderated endocytosis and environmental sensing as essential regulatory mechanisms required to preserve human HSC stemness. Our data also pinpoint silencing of MYCT1 as a cell-culture-induced vulnerability that compromises human HSC expansion.

DOI: 10.1038/s41586-024-07478-x

Source: https://www.nature.com/articles/s41586-024-07478-x