Adaptation to ex vivo culture drives human haematopoietic stem cell loss of repopulation capacity in a cell cycle independent manner
Adaptation to ex vivo culture drives human haematopoietic stem cell loss of repopulation capacity in a cell cycle independent manner
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.
Kaufmann Kerstin B、Drakopoulos Michael、Krivdova Gabriela、Calderbank Emily F、McLeod Jessica、Williams Matthew J、Basford Christina、Dick John E、Sinha Shubhankar、Belluschi Serena、Laurenti Elisa、Lau Winnie、Gottgens Bertie、Johnson Carys S、Francis Natalie、Howe Steven J、Mende Nicole、Green Anthony R、Grey-Wilson Charlotte、Wang Xiaonan、Mantica Giovanna、Wilson Nicola K、Diamanti Evangelia、Sham Kendig
基础医学细胞生物学分子生物学
Kaufmann Kerstin B,Drakopoulos Michael,Krivdova Gabriela,Calderbank Emily F,McLeod Jessica,Williams Matthew J,Basford Christina,Dick John E,Sinha Shubhankar,Belluschi Serena,Laurenti Elisa,Lau Winnie,Gottgens Bertie,Johnson Carys S,Francis Natalie,Howe Steven J,Mende Nicole,Green Anthony R,Grey-Wilson Charlotte,Wang Xiaonan,Mantica Giovanna,Wilson Nicola K,Diamanti Evangelia,Sham Kendig.Adaptation to ex vivo culture drives human haematopoietic stem cell loss of repopulation capacity in a cell cycle independent manner[EB/OL].(2025-03-28)[2025-05-13].https://www.biorxiv.org/content/10.1101/2022.11.17.516906.点此复制
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