Inhibitors of histone deacetylases promote hematopoietic stem cell self-renewal

Young, Judy; Wu, Spencer; Hansteen, Gun; Du, Changsheng; Sambucetti, Lidia; Remiszewski, Stacy; O’Farrell, Anne-Marie; Hill, Beth; Lavau, Catherine; Murray, Lesley J.

doi:10.1080/14653240410004899

Cited by 64 publications

(48 citation statements)

References 46 publications

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“…The supplementation of human cord blood CD34 + cells in culture with the HDAC inhibitor valproic acid for 7 d upregulated expression of stemness genes, elevated aldehyde dehydrogenase activity, and stimulated a 36-fold increase of SCIDrepopulating cells [180]. Another HDAC inhibitor chlamydocin also induced expansion of HSCs in culture [181]. G9a and G9a-like protein (GLP) are methyltransferases that dimethylate histone H3 Lys 9 (H3K9me1/2).…”

Section: Epigenetic Modifiersmentioning

confidence: 99%

Ex vivo expansion of hematopoietic stem cells

Xie

Zhang

2015

Sci. China Life Sci.

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Ex vivo expansion of hematopoietic stem cells (HSCs) would benefit clinical applications in several aspects, to improve patient survival, utilize cord blood stem cells for adult applications, and selectively propagate stem cell populations after genetic manipulation. In this review we summarize and discuss recent advances in the culture systems of mouse and human HSCs, which include stroma/HSC co-culture, continuous perfusion and fed-batch cultures, and those supplemented with extrinsic ligands, membrane transportable transcription factors, complement components, protein modification enzymes, metabolites, or small molecule chemicals. Some of the expansion systems have been tested in clinical trials. The optimal condition for ex vivo expansion of the primitive and functional human HSCs is still under development. An improved understanding of the mechanisms for HSC cell fate determination and the HSC culture characteristics will guide development of new strategies to overcome difficulties. In the future, development of a combination treatment regimen with agents that enhance self-renewal, block differentiation, and improve homing will be critical. Methods to enhance yields and lower cost during collection and processing should be employed. The employment of an efficient system for ex vivo expansion of HSCs will facilitate the further development of novel strategies for cell and gene therapies including genome editing. ex vivo expansion, hematopoietic stem cells, niche, signal transduction, cord blood, transplantation, SCID-repopulating cell, genome editing, CRISPR/Cas9 Citation:Xie JJ, Zhang CC. Ex vivo expansion of hematopoietic stem cells.

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Section: Epigenetic Modifiersmentioning

confidence: 99%

Ex vivo expansion of hematopoietic stem cells

Xie

Zhang

2015

Sci. China Life Sci.

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“…62 In vitro, HSCs require both hematopoietic cytokines and adhesion molecules, provided in vivo by bone marrow-derived mesenchymal stem cells (MSCs), to proliferate and differentiate. The addition of DNA methylation modifiers (5 aza-cytadine) or HDAC inhibitors (trichostatin A) directly to HSCs promoted their expansion in culture [63][64][65][66] however, this has been associated with apoptosis. 67 In contrast, when these agents were added to cocultures of HSCs and MSCs together, the CD34+ HSC population was enhanced, suggesting that MSCs may provide survival factors that balance the apoptotic effects of the epigenetic agents.…”

Section: A Hematopoietic Stem Cells (Hscs)mentioning

confidence: 99%

The Epigenetics of Adult (Somatic) Stem Cells

Eilertsen

Floyd

Gimble

2008

Crit Rev Eukar Gene Expr

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While genetic studies have provided a wealth of information about health and disease, there is a growing awareness that individual characteristics are also determined by factors other than genetic sequences. These "epigenetic" changes broadly encompass the influence of the environment on gene regulation and expression and in a more narrow sense, describe the mechanisms controlling DNA methylation, histone modification and genetic imprinting. In this review, we focus on the epigenetic mechanisms that regulate adult (somatic) stem cell differentiation, beginning with the metabolic pathways and factors regulating chromatin structure and DNA methylation and the molecular biological tools that are currently available to study these processes. The role of these epigenetic mechanisms in manipulating adult stem cells is followed by a discussion of the challenges and opportunities facing this emerging field.

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“…Further modifications to this liquid ex vivo expansion technique have included attempts to further optimize ex vivo culture conditions; 46,48,[52][53][54][55]58 the development of serum-free culture systems; 52,56,59 the use of tetraethylenepentamine, a copper chelator thought to modulate the proliferation and differentiation of primitive hematopoietic progenitors; [60][61][62] the use of histone deacetylases, thought to promote HSC self-renewal; 63 and the use of glycogen synthase kinase-3 inhibitors reported to maintain the pluripotency of stem cells. 64 A phase I/II trial was conducted by de Lima et al 27 to analyze the potential therapeutic efficacy of tetraethylenepentamine added in liquid UCB expansion.…”

Section: Liquid Suspension Culturementioning

confidence: 99%

Ex Vivo Expansion of Cord Blood

McNiece¹,

Shpall²

2008

Frontiers of Cord Blood Science

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A marked increase in the utilization of umbilical cord blood (UCB) transplantation has been observed in recent years; however, the use of UCB as a hematopoietic stem cell (HSC) source is limited primarily by the number of progenitor cells contained in the graft. Graft failure, delayed engraftment and profound delay in immune reconstitution lead to significant morbidity and mortality in adults. The lack of cells available for post transplant therapies, such as donor lymphocyte infusions, has also been considered to be a disadvantage of UCB. To improve outcomes and extend applicability of UCB transplantation, one potential solution is ex vivo expansion of UCB. Investigators have used several methods, including liquid suspension culture with various cytokines and expansion factors, co-culture with stromal elements and continuous perfusion systems. Techniques combining ex vivo expanded and unmanipulated UCB are being explored to optimize the initial engraftment kinetics as well as the long-term durability. The optimal expansion conditions are still not known; however, recent studies suggest that expanded UCB is safe. It is hoped that by ex vivo expansion of UCB, a resulting decrease in the morbidity and mortality of UCB transplantation will be observed, and that the availability of additional cells may allow adoptive immunotherapy or gene transfer therapies in the UCB setting.

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Inhibitors of histone deacetylases promote hematopoietic stem cell self-renewal

Cited by 64 publications

References 46 publications

Ex vivo expansion of hematopoietic stem cells

Ex vivo expansion of hematopoietic stem cells

The Epigenetics of Adult (Somatic) Stem Cells

Ex Vivo Expansion of Cord Blood

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