Ex vivo human HSC expansion requires coordination of cellular reprogramming with mitochondrial remodeling and p53 activation.
Blood Adv
; 2(20): 2766-2779, 2018 10 23.
Article
em En
| MEDLINE
| ID: mdl-30348672
ABSTRACT
The limited number of hematopoietic stem cells (HSCs) in umbilical cord blood (UCB) units restricts their use for stem cell transplantation. Ex vivo treatment of UCB-CD34+ cells with valproic acid (VPA) increases the number of transplantable HSCs. In this study, we demonstrate that HSC expansion is not merely a result of proliferation of the existing stem cells but, rather, a result of a rapid reprogramming of CD34+CD90- cells into CD34+CD90+ cells, which is accompanied by limited numbers of cell divisions. Beyond this phenotypic switch, the treated cells acquire and retain a transcriptomic and mitochondrial profile, reminiscent of primary HSCs. Single and bulk RNA-seq revealed a signature highly enriched for transcripts characteristic of primary HSCs. The acquisition of this HSC signature is linked to mitochondrial remodeling accompanied by a reduced activity and enhanced glycolytic potential. These events act in concert with a modest upregulation of p53 activity to limit the levels of reactive oxygen species (ROS). Inhibition of either glycolysis or p53 activity impairs HSC expansion. This study indicates that a complex interplay of events is required for effective ex vivo expansion of UCB-HSCs.
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Base de dados:
MEDLINE
Assunto principal:
Células-Tronco Hematopoéticas
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Proteína Supressora de Tumor p53
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Reprogramação Celular
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Mitocôndrias
Idioma:
En
Ano de publicação:
2018
Tipo de documento:
Article