MYCT1 controls environmental sensing in human haematopoietic stem cells

• 成果类型: Article
• 署名作者: Aguade-Gorgorio, Julia; 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.
• 署名单位: University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of London; University College London; Institut de Recerca Contra la Leucemia Josep Carreras (IJC); University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; Lund University; Cedars Sinai Medical Center; Eberhard Karls University of Tubingen; Eberhard Karls University of Tubingen; UCLA Jonsson Comprehensive Cancer Center; University of California System; University of California Los Angeles; University of California System; University of California Los Angeles; University of California Los Angeles Medical Center; David Geffen School of Medicine at UCLA; University of California System; University of California Los Angeles; Pfizer; Pfizer USA; Oakland University; University of California System; University of California San Francisco; Amgen
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4393
• DOI: 10.1038/s41586-024-07478-x
• 发表日期: 2024-06-13
• 页码: 412-+
• 关键词: cord blood stem; web-based tool; enrichment analysis; c-myc; expansion; target; transplantation; endocytosis; regulators; platform

摘要

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 HSCs1-3. 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.