MYCT1 controls environmental sensing in human haematopoietic stem cells.

Autor: Aguadé-Gorgorió J; Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA. julia.aguade@gmail.com.; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. julia.aguade@gmail.com., Jami-Alahmadi Y; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA.; Pfizer, Cambridge, MA, USA., Calvanese V; Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA.; Laboratory for Molecular Cell Biology, University College London, London, UK.; Josep Carreras Leukaemia Research Institute, Barcelona, Spain., Kardouh M; Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.; Oakland University William Beaumont School of Medicine, Rochester, MI, USA., Fares I; Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.; Kite Pharma, Santa Monica, CA, USA., Johnson H; Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.; Department of Laboratory Medicine, University of California San Francisco, San Francisco, CA, USA., Rezek V; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA.; David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.; UCLA AIDS Institute, University of California Los Angeles, Los Angeles, CA, USA., Ma F; Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.; Institute for Genomics and Proteomics, University of California Los Angeles, Los Angeles, CA, USA.; Amgen, Thousand Oaks, CA, USA., Magnusson M; Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA.; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA.; Division of Molecular Medicine and Gene Therapy, Lund Stem Cell Center, Lund University, Lund, Sweden., Wang Y; Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA., Shin JE; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA.; David Geffen School of Medicine at UCLA, Los Angeles, CA, USA., Nance KJ; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Goodridge HS; David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.; Board of Governors Regenerative Medicine Institute, Cedars-Sinai Medical Center, Los Angeles, CA, USA., Liebscher S; Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University, Tübingen, Germany., Schenke-Layland K; Institute of Biomedical Engineering, Department for Medical Technologies and Regenerative Medicine, Eberhard Karls University, Tübingen, Germany.; NMI Natural and Medical Sciences Institute at the University Tübingen, Reutlingen, Germany., Crooks GM; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA.; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA.; Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA., Wohlschlegel JA; Department of Biological Chemistry, University of California Los Angeles, Los Angeles, CA, USA., Mikkola HKA; Department of Molecular, Cell and Developmental Biology, University of California Los Angeles, Los Angeles, CA, USA. hmikkola@mcdb.ucla.edu.; Eli and Edythe Broad Center for Regenerative Medicine and Stem Cell Research, University of California Los Angeles, Los Angeles, CA, USA. hmikkola@mcdb.ucla.edu.; Jonsson Comprehensive Cancer Center, University of California Los Angeles, Los Angeles, CA, USA. hmikkola@mcdb.ucla.edu.; Molecular Biology Institute, University of California Los Angeles, Los Angeles, CA, USA. hmikkola@mcdb.ucla.edu.
Jazyk: angličtina
Zdroj: Nature [Nature] 2024 Jun; Vol. 630 (8016), pp. 412-420. Date of Electronic Publication: 2024 Jun 05.
DOI: 10.1038/s41586-024-07478-x
Abstrakt: 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.
(© 2024. The Author(s).)
Databáze: MEDLINE
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