Epigenetic reprogramming and blood development

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Date: Feb. 2015
From: Epigenomics(Vol. 7, Issue 1)
Publisher: Future Medicine Ltd.
Document Type: Abstract
Length: 2,202 words
Lexile Measure: 1520L

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Author(s): Maximilian Christopeit aff1

Epigenetic basis for pharmacological ex vivo expansion of hematopoietic stem cells. Evaluation of: Epigenetic reprogramming induces the expansion of cord blood stem cells. Chaurasia P, Gajzer DC, Schaniel C, D'Souza S, Hoffman R. J. Clin. Invest. 124(6), 2378-2395 (2014).

Bone marrow (BM), mobilized peripheral blood (PBSC) and umbilical cord blood (UCB) hematopoietic stem cells (HSC) are used to treat a variety of hematologic diseases with allogeneic hematopoietic stem cell transplantation. An increasing need for HSC grafts has been observed because conditioning procedures are becoming better tolerable and hematologic diseases are on the rise in aging societies. Beyond this, HSC numbers in single UCB grafts rarely suffice to stably engraft in adult humans. Thus, efforts to increase the numbers of available stem cell donors worldwide are paralleled by attempts to increase the capacity of a single graft to reconstitute hematopoiesis in the single recipient (i.e., to sustain long-term engraftment). Insights gained from expansion studies might additionally yield novel insights into the self-reconstituting nature of stem cells and cancer. Prior attempts to expand HSC, for example, by the co-cultivation of mesenchymal stem cells [ 1 ] or other means have shown some success [2 ]. A frequent obstacle is an increase in the number of short-term but not that of long-term repopulating HSC. Chaurasia et al . recently published in the Journal of Clinical Investigation that treatment with the histone deacetylase inhibitor (HDACi), valproic acid (VPA) increases the regenerative potential of human UCB grafts [3 ]. Earlier work of the Hoffman group succeeded in achieving increased numbers of HSC but largely at the expense of their long-term repopulating potential [ 4-7 ]. Now, treatment consisted of different HDACi (VPA, scriptaid [SCR], trichostatin A [TSA], suberoylanilide hydroxamic acid [SAHA], CAY10433, CAY10398, CAY10603). Expansion was either attempted in media containing serum or in serum free media. Intriguingly, treatment with either VPA, SCR or CAY10433 lead to an enormous increase of CD34+CD90+ HSC. Remarkably, this increase of CD34+CD90+ HSC was far more prominent in serum free (20,202-fold increase of CD34+CD90+ HSC with VPA) as compared with serum containing media (89-fold). Markers reflecting the phenotypic but even more so the functional status of a primitive stem cell such as increased aldehyde dehydrogenase (ALDH) activity [8 ] increased after treatment with VPA. In line with an increased expression of CD49f (integrin [alpha]6) and CD184 (CXCR4), migration toward SDF1 in vitro and homing in non-obese diabetes severe combined immunodeficiency IL2R -[gamma]-chain knockout (NSG) mice was increased after stimulation with VPA. Transplantation of NSG mice with VPA stimulated HSC resulted in a greater proportion of cells in the marrow of respective mice, and a higher number of cells expressing CD184 (CXCR4). Additionally, the pattern of regeneration qualitatively differed significantly from the pattern observed in control animals. That is, a higher number of CD41+ cells, CD19+ cells and GPA+ cells was seen in the marrow of mice transplanted with VPA treated cells. Secondary transplantation was successful after this treatment, too. Teratomas were not seen after HDACi stimulation, and the upregulation in...

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Gale Document Number: GALE|A409374835