دورية أكاديمية
MYCT1 controls environmental sensing in human haematopoietic stem cells.
| العنوان: | MYCT1 controls environmental sensing in human haematopoietic stem cells. |
|---|---|
| المؤلفون: | 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. |
| المصدر: | Nature [Nature] 2024 Jun; Vol. 630 (8016), pp. 412-420. Date of Electronic Publication: 2024 Jun 05. |
| نوع المنشور: | Journal Article |
| اللغة: | English |
| بيانات الدورية: | Publisher: Nature Publishing Group Country of Publication: England NLM ID: 0410462 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1476-4687 (Electronic) Linking ISSN: 00280836 NLM ISO Abbreviation: Nature Subsets: MEDLINE |
| أسماء مطبوعة: | Publication: Basingstoke : Nature Publishing Group Original Publication: London, Macmillan Journals ltd. |
| مواضيع طبية MeSH: | Cell Self Renewal* , Hematopoietic Stem Cells*/cytology , Hematopoietic Stem Cells*/metabolism , Nuclear Proteins*/metabolism, Animals ; Female ; Humans ; Male ; Mice ; Cells, Cultured ; Endocytosis ; Endosomes/metabolism ; Endothelial Cells/cytology ; Endothelial Cells/metabolism ; Fetal Blood/cytology ; Gene Knockdown Techniques ; Liver/cytology ; Liver/metabolism ; Liver/embryology ; Mitochondria/metabolism ; Signal Transduction ; Proto-Oncogene Proteins c-ets/genetics ; Proto-Oncogene Proteins c-ets/metabolism ; Single-Cell Gene Expression Analysis |
| مستخلص: | 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).) |
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| معلومات مُعتمدة: | P30 CA016042 United States CA NCI NIH HHS; T32 HL086345 United States HL NHLBI NIH HHS; United Kingdom WT_ Wellcome Trust; R01 HL162408 United States HL NHLBI NIH HHS; P30 AI152501 United States AI NIAID NIH HHS; R01 DK125097 United States DK NIDDK NIH HHS; R01 DK121557 United States DK NIDDK NIH HHS; R01 DK100959 United States DK NIDDK NIH HHS; R35 GM153408 United States GM NIGMS NIH HHS |
| المشرفين على المادة: | 0 (MYCT1 protein, human) 0 (Nuclear Proteins) 0 (Proto-Oncogene Proteins c-ets) |
| تواريخ الأحداث: | Date Created: 20240605 Date Completed: 20240612 Latest Revision: 20240622 |
| رمز التحديث: | 20240623 |
| مُعرف محوري في PubMed: | PMC11168926 |
| DOI: | 10.1038/s41586-024-07478-x |
| PMID: | 38839950 |
| قاعدة البيانات: | MEDLINE |
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| DOI: | 10.1038/s41586-024-07478-x |