MYCT1 controls environmental sensing in human haematopoietic stem cells

Júlia Aguadé-Gorgorió (), 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 and Hanna K. A. Mikkola ()
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Júlia Aguadé-Gorgorió: University of California Los Angeles
Yasaman Jami-Alahmadi: University of California Los Angeles
Vincenzo Calvanese: University of California Los Angeles
Maya Kardouh: University of California Los Angeles
Iman Fares: University of California Los Angeles
Haley Johnson: University of California Los Angeles
Valerie Rezek: University of California Los Angeles
Feiyang Ma: University of California Los Angeles
Mattias Magnusson: University of California Los Angeles
Yanling Wang: University of California Los Angeles
Juliana E. Shin: Cedars-Sinai Medical Center
Karina J. Nance: Cedars-Sinai Medical Center
Helen S. Goodridge: David Geffen School of Medicine at UCLA
Simone Liebscher: Eberhard Karls University
Katja Schenke-Layland: Eberhard Karls University
Gay M. Crooks: University of California Los Angeles
James A. Wohlschlegel: University of California Los Angeles
Hanna K. A. Mikkola: University of California Los Angeles

Nature, 2024, vol. 630, issue 8016, 412-420

Abstract: 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 HSCs1–3. 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.

Date: 2024
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DOI: 10.1038/s41586-024-07478-x

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