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Adaptation to ex vivo culture reduces human hematopoietic stem cell activity independently of cell cycle.
Johnson, Carys S; Williams, Matthew J; Sham, Kendig; Belluschi, Serena; Ma, Wenjuan; Wang, Xiaonan; Lau, Winnie Wy; Kaufmann, Kerstin; Krivdova, Gabriela; Calderbank, Emily Francesca; Mende, Nicole; McLeod, Jessica; Mantica, Giovanna; Li, Juan; Grey-Wilson, Charlotte; Drakopoulos, Michael; Basheer, Shaaezmeen; Sinha, Shubhankar; Diamanti, Evangelia; Basford, Christina; Wilson, Nicola K; Howe, Steven J; Dick, John E; Gottgens, Berthold; Green, Anthony R; Francis, Natalie; Laurenti, Elisa.
Afiliación
  • Johnson CS; University of Cambridge, Cambridge, United Kingdom.
  • Williams MJ; University of Cambridge, Cambridge, United Kingdom.
  • Sham K; University of Edinburgh, Edinburgh, United Kingdom.
  • Belluschi S; University of Cambridge, Cambridge, United Kingdom.
  • Ma W; University of Cambridge, Cambridge, United Kingdom.
  • Wang X; University of Cambridge, United Kingdom.
  • Lau WW; University of Cambridge, Cambridge, United Kingdom.
  • Kaufmann K; University Health Network, Toronto, Ontario, Canada.
  • Krivdova G; University Health Network, Canada.
  • Calderbank EF; University of Cambridge, Cambridge, United Kingdom.
  • Mende N; University of Cambridge, Cambridge, United Kingdom.
  • McLeod J; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
  • Mantica G; University of Cambridge, Cambridge, United Kingdom.
  • Li J; University of Cambridge, Cambridge, United Kingdom.
  • Grey-Wilson C; University of Cambridge, Cambridge, United Kingdom.
  • Drakopoulos M; University of Cambridge, Cambridge, United Kingdom.
  • Basheer S; University of Cambridge, Horsham, United Kingdom.
  • Sinha S; University of Cambridge, Cambridge, United Kingdom.
  • Diamanti E; University of Cambridge, Cambridge, United Kingdom.
  • Basford C; GlaxoSmithKline, Stevenage, United Kingdom.
  • Wilson NK; University of Cambridge, Cambridge, United Kingdom.
  • Howe SJ; GlaxoSmithKline, Stevenage, United Kingdom.
  • Dick JE; University Health Network, Toronto, Ontario, Canada.
  • Gottgens B; University of Cambridge, Cambridge, United Kingdom.
  • Green AR; University of Cambridge, Cambridge, United Kingdom.
  • Francis N; GlaxoSmithKline, United Kingdom.
  • Laurenti E; University of Cambridge, Cambridge, United Kingdom.
Blood ; 2024 May 28.
Article en En | MEDLINE | ID: mdl-38805639
ABSTRACT
Loss of long-term hematopoietic stem cell (LT-HSC) function ex vivo hampers the success of clinical protocols reliant on culture. However, the kinetics and 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 the sharpest loss of LT-HSC repopulation capacity happens early on, between 6 and 24 hours of culture, before LT-HSCs commit to cell cycle progression. During this time window, LT-HSCs adapt to the culture environment, limiting global variability in gene expression and transiently upregulating gene networks involved in signaling and stress responses. From 24 hours, LT-HSC progression past early G1 contributes to the establishment of differentiation programmes in culture. However, contrary to current assumptions, we demonstrate that loss of HSC function ex vivo is independent of cell cycle progression. Finally, we show that targeting LT-HSC adaptation to culture by inhibiting early activation of JAK/STAT signaling improves HSC long-term repopulating function ex vivo. Collectively, our study demonstrates that controlling early LT-HSC adaptation to ex vivo culture, for example via JAK inhibition, is of critical importance to improve HSC gene therapy and expansion protocols.

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: Blood Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido

Texto completo: 1 Colección: 01-internacional Banco de datos: MEDLINE Idioma: En Revista: Blood Año: 2024 Tipo del documento: Article País de afiliación: Reino Unido