Role of epigenetic reprogramming in hematopoietic stem cell function.

Abstract

Epigenetic regulatory networks determine the fate of dividing hematopoietic stem cells (HSCs). Prior attempts at the ex-vivo expansion of transplantable human HSCs have led to the depletion or at best maintenance of the numbers of HSCs because of the epigenetic events that silence the HSC gene-expression pattern. The purpose of this review is to outline the recent efforts to use small molecules to reprogram cultured CD34 cells so as to expand their numbers. Chromatin-modifying agents (CMAs) reactivate the gene-expression patterns of HSCs that have been silenced as they divide ex vivo. Increasing evidence indicates that CMAs act not only by promoting HSC symmetrical self-renewal divisions, but also by reprogramming progenitor cells, resulting in greater numbers of HSCs. The use of such CMAs for these purposes has not resulted in malignant transformation of the ex-vivo treated cell product. The silencing of the gene-expression program that determines HSC function after ex-vivo culture can be reversed by reprogramming the progeny of dividing HSCs with transient exposure to CMAs. The successful implementation of this approach provides a strategy which might lead to the development of a clinically relevant means of manufacturing increased numbers of HSCs.