MYCT1 controls environmental sensing in human haematopoietic stem cells.

Return to Grants

Publication Year:
2024
Authors:
Julia Aguade-Gorgorio, Yasaman Jami-Alahmadi, Vincenzo Calvanese, Maya Kardouh, Iman Fares, Haley Johnson, Valerie Rezek, Feiyang Ma, Mattias Magnusson, Yanling Wang, Juliana E Shin, Karina J Nance, Helen S Goodridge, Simone Liebscher, Katja Schenke-Layland, Gay M Crooks, James A Wohlschlegel, Hanna K A Mikkola
PubMed ID:
38839950
Funding Grants:
Public Summary:
Blood stem cells are special cells that can make all types of blood cells and also copy themselves. Scientists would like to grow more of these cells in the lab for treatments, but it’s been hard to do this without the cells losing their important “stem cell” abilities. In this study, researchers found that a gene called MYCT1 plays a key role in keeping these blood stem cells healthy and functional. This gene is active in early-stage blood stem cells, but its activity drops when the cells are grown in the lab. When researchers reduced MYCT1 levels, the stem cells couldn’t grow well or successfully take hold when transplanted. But when they restored MYCT1, the cells grew better and worked more effectively. The study showed that MYCT1 helps control how stem cells take in signals from their environment. Without it, the cells become overstimulated and behave abnormally. With proper MYCT1 levels, the cells maintain a balanced state that preserves their stem cell properties. The researchers also found a way to identify the healthiest stem cells in culture—those that take in fewer external signals—and these cells tend to have higher MYCT1 activity. Overall, the study suggests that maintaining MYCT1 activity is crucial for successfully growing useful blood stem cells in the lab, which could improve future therapies like bone marrow transplants.
Scientific 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 HSCs(1-3). Here we identify MYC target 1 (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.