Adaptation to ex vivo culture drives human haematopoietic stem cell loss of repopulation capacity in a cell cycle independent manner
Johnson, C. S.; Sham, K.; Belluschi, S.; Wang, X.; Lau, W.; Kaufmann, K. B.; Krivdova, G.; Calderbank, E. F.; Mende, N.; McLeod, J.; Mantica, G.; Williams, M. J.; Grey-Wilson, C.; Drakopoulos, M.; Sinha, S.; Diamanti, E.; Basford, C.; Green, A. R.; Wilson, N. K.; Howe, S. J.; Dick, J. E.; Gottgens, B.; Francis, N.; Laurenti, E.
Show abstract
Loss of long-term haematopoietic stem cell function (LT-HSC) hampers the success of ex vivo HSC gene therapy and expansion procedures, but the kinetics and the mechanisms by which this occurs remain incompletely characterized. Here through time-resolved scRNA-Seq, matched in vivo functional analysis and the use of a reversible in vitro system of early G1 arrest, we define the sequence of transcriptional and functional events occurring during the first ex vivo division of human LT-HSCs. We demonstrate that contrary to current assumptions, loss of long-term repopulation capacity during culture is independent of cell cycle progression. Instead it is a rapid event that follows an early period of adaptation to culture, characterised by transient gene expression dynamics and constrained global variability in gene expression. Cell cycle progression however contributes to the establishment of differentiation programmes in culture. Our data have important implications for improving HSC gene therapy and expansion protocols.
Matching journals
The top 9 journals account for 50% of the predicted probability mass.
Similar papers in this journal
- Developmental regulation of endothelial-to-hematopoietic transition from induced pluripotent stem cells 96%
- Clonal analysis of fetal hematopoietic stem/progenitor cell subsets reveals how post-transplantation capabilities are distributed 96%
- Tropomyosin 1 deficiency facilitates cell state transitions and enhances hemogenic endothelial cell specification during hematopoiesis 95%
Similar papers in this journal
- Loss of Nupr1 promotes engraftment by tuning the quiescence threshold of hematopoietic stem cell repository via regulating p53-checkpoint pathway 96%
- ANKRD26 is a new regulator of type I cytokine receptor signaling in normal and pathological hematopoiesis 95%
- Allo-defensive, multiplex base-edited, anti-CD38 CAR T cells for "off-the-shelf" Immunotherapy 95%
Similar papers in this journal
- Inflammatory signals from fatty bone marrow supports the early stages of DNMT3a driven clonal hematopoiesis 96%
- Engineered niches support the development of human dendritic cells in humanized mice 96%
- Multi-Modal Profiling of Human Fetal Liver-Derived Hematopoietic Stem Cells Reveals the Molecular Signature of Engraftment Potential 96%
Similar papers in this journal
- Resolving fate and transcriptome of hematopoietic stem cell clones 97%
- Post-Transplant Administration of G-CSF Impedes Engraftment of Gene Edited Human Hematopoietic Stem Cells by Exacerbating the p53-Mediated DNA Damage Response 97%
- Hematopoietic stem cells fail to regenerate following inflammatory challenge. 95%
Similar papers in this journal
- CD99 Promotes Self-renewal in Hematopoietic Stem Cells and Leukemia Stem Cells by Regulating Protein Synthesis 96%
- Hematopoietic recovery after transplantation is primarily derived from the stochastic contribution of hematopoietic stem cells 96%
- HLF Expression Defines the Human Hematopoietic Stem Cell State 96%
"Similar papers" are the closest papers from that journal in the model's embedding space. They show what the match is built on, but the ranking comes mostly from a classifier over the whole training set, not from these examples alone.