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HDAC Inhibitor Treatment Boosts Adult HSC Culture

Review of “Expansion and Preservation of the Functional Activity of Adult Hematopoietic Stem Cells Cultured Ex Vivo with a Histone Deacetylase Inhibitor” from STEM CELLS Translational Medicine by Stuart P. Atkinson

The general rarity of CD34-positive human hematopoietic stem cells (HSCs) requires ex vivo expansion to generate numbers relevant for the timely hematopoietic repopulation of patients with refractory hematological malignancies or genetic disorders involving blood cells. Unfortunately, extended periods of culture time under sub-optimal conditions can lead to a loss of stem cell function and hence therapeutic potential.

As a remedy to this vexing problem, previous research from the laboratory of Eran Zimran (Hadassah University Center, Jerusalem, Israel) described how the serum-free culture of HSCs derived from the umbilical cord blood in the presence of a cytokine cocktail and a histone deacetylase (HDAC) inhibitor led to a significant increase in the number of cells that maintained their long‐term engraftment abilities in immunodeficient mice [1, 2]. The success of this protocol led to the preclinical development of umbilical cord blood HSCs for allogeneic transplantation in patients with hematological malignancies [3] and the beginning of a clinical trial.

In their new STEM CELLS Translational Medicine study [4], the authors now report on the extension of their HDAC inhibitor-mediated expansion protocol to HSCs derived from cytokine-mobilized peripheral blood and bone marrow of healthy adult donors. Excitingly, their results support the implementation of HDAC inhibitor treatment for the ex vivo expansion of adult HSCs, an approach that would provide a boost to gene modification strategies and the development of safe and effective treatments for a range of hematological conditions. 

Briefly, the authors first primed peripheral blood- and bone marrow-derived HSCs with a cytokine cocktail for 16 hours, and then cultured HSCs in the presence of cytokines and the HDAC inhibitor valproic acid for seven days. Encouragingly, this process led to a significant increase in HSC number and an improvement in functional markers of HSCs, which included an increase in aldehyde dehydrogenase activity and a decrease in mitochondrial membrane potential. The effects of the HDAC inhibitor became apparent as early as three days in culture, a time point relevant to gene modification protocols aiming at correcting disease-associated mutations.

Importantly, HSCs derived from HDAC inhibitor-treated cultures displayed long‐term multilineage hematopoietic engraftment abilities in sublethally-irradiated immunodeficient mice and generated cellular progeny from each hematopoietic lineage, including both myeloid and lymphoid lineages, at a similar proportion to unmanipulated HSCs. Finally, a comparison of data from previous experiments suggested that HDAC inhibitor treatment affected HSCs derived from the peripheral blood and bone marrow similarly to those derived from umbilical cord blood, suggesting the adequacy of this strategy for both neonatal and adult HSCs.

For more on how enhanced HSC culture mediated by treatment with an HDAC inhibitor may foster the development of safe and effective treatments for a range of hematological conditions, stay tuned to the Stem Cells Portal.

References

  1. Chaurasia P, Gajzer DC, Schaniel C, et al., Epigenetic reprogramming induces the expansion of cord blood stem cells. Journal of Clinical Investigation 2014;124:2378-2395.
  2. Iancu-Rubin C and Hoffman R, Role of epigenetic reprogramming in hematopoietic stem cell function. Current Opinion in Hematology 2015;22.
  3. Iancu-Rubin C, Fong H, Mosoyan G, et al., Preclinical Development of a Cord Blood (CB)-Derived Hematopoietic Stem Cell (HSC) Product for Allogeneic Transplantation in Patients with Hematological Malignancies. Blood 2016;128:818-818.
  4. Zimran E, Papa L, Djedaini M, et al., Expansion and preservation of the functional activity of adult hematopoietic stem cells cultured ex vivo with a histone deacetylase inhibitor. STEM CELLS Translational Medicine 2020;9:531-542.