Chromatin-modifying agents permit human hematopoietic stem cells to undergo multiple cell divisions while retaining their repopulating potential

Hiroto Araki, Kazumi Yoshinaga, Piernicola Boccuni, Yan Zhao, Ronald Hoffman, Nadim Mahmud

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

Abstract

Human hematopoietic stem cells (HSCs) exposed to cytokines in vitro rapidly divide and lose their characteristic functional properties presumably due to the alteration of a genetic program that determines the properties of an HSC. We have attempted to reverse the silencing of this HSC genetic program by the sequential treatment of human cord blood CD34+ cells with the chromatin-modifying agents, 5-aza-2′-deoxycytidine (5azaD) and trichostatin A (TSA). We determined that all CD34+CD90+ cells treated with 5azaD/TSA and cytokines after 9 days of incubation divide, but to a lesser degree than cells exposed to only cytokines. When CD34 +CD90+ cells that have undergone extensive number of cell divisions (5-10) in the presence of cytokines alone were transplanted into immunodeficient mice, donor cell chimerism was not detectable. By contrast, 5azaD/TSA-treated cells that have undergone similar numbers of cell divisions retained their marrow repopulating potential. The expression of several genes and their products previously implicated in HSC self-renewal were up-regulated in the cells treated with 5azaD/TSA as compared to cells exposed to cytokines alone. These data indicate that HSC treated with chromatin-modifying agents are capable of undergoing repeated cell divisions in vitro while retaining their marrow-repopulating potential.

Original languageEnglish
Pages (from-to)3570-3578
Number of pages9
JournalBlood
Volume109
Issue number8
DOIs
StatePublished - 15 Apr 2007
Externally publishedYes

Fingerprint

Dive into the research topics of 'Chromatin-modifying agents permit human hematopoietic stem cells to undergo multiple cell divisions while retaining their repopulating potential'. Together they form a unique fingerprint.

Cite this