Abstract
The identification of small molecules that either increase the number and/or enhance the activity of human hematopoietic stem and progenitor cells (hHSPCs) during ex vivo expansion remains challenging. We used an unbiased in vivo chemical screen in a transgenic (c-myb:EGFP) zebrafish embryo model and identified histone deacetylase inhibitors (HDACIs), particularly valproic acid (VPA), as significant enhancers of the number of phenotypic HSPCs, both in vivo and during ex vivo expansion. The long-term functionality of these expanded hHSPCs was verified in a xenotransplantation model with NSG mice. Interestingly, VPA increased CD34+ cell adhesion to primary mesenchymal stromal cells and reduced their in vitro chemokine-mediated migration capacity. In line with this, VPA-treated human CD34+ cells showed reduced homing and early engraftment in a xenograft transplant model, but retained their long-term engraftment potential in vivo, and maintained their differentiation ability both in vitro and in vivo. In summary, our data demonstrate that certain HDACIs lead to a net expansion of hHSPCs with retained long-term engraftment potential and could be further explored as candidate compounds to amplify ex-vivo engineered peripheral blood stem cells.
Highlights
In the clinical setting[1]
Long-term HSCs occur in the aorta-gonad-mesonephros (AGM) at approximately 30 hours post fertilization and migrate to the caudal hematopoietic tissue (CHT) region, colonize the thymus, and translocate to the kidney marrow, which is the equivalent of mammalian bone marrow[19] (Fig. 1a). c-myb is expressed in the cells of the AGM and CHT regions in zebrafish during hematopoiesis[20,21]
A transgenic zebrafish model was used to screen for molecules capable of expanding the hematopoietic stem and progenitor cells (HSPC) pool in vivo, and several Histone deacetylase inhibitors (HDACIs) were included in the screen, only valproic acid (VPA), resminostat, and entinostat increased the number of c-myb+ HSPCs, suggesting that HSPC expansion is specific to these three drugs rather than a general group effect of HDACIs
Summary
In the clinical setting[1]. issues regarding the yield of transplantable HSCs still prevail, especially in the context of UCB transplantation[2], despite the recent increase in the number of suitable donors and the success of haploidentical HSCT3. While certain procedures for ex vivo expansion have been shown to retain HSC function and clinical trials have attested to the feasibility of this approach[15], successful hematopoietic recovery after HSC transplantation relies on self-renewal and differentiation capacity and on homing to the bone marrow and subsequent lodging in hematopoietic stem cell niches[16]. Such migration and lodging of HSCs in specific niches are tightly regulated processes that are controlled by the expression and function of various molecules, including integrins (VLA-4, VLA-5, and LFA-1), selectins (P- and E-selectin), and certain chemokines (SDF-1)[17]. These results imply that HDACIs, VPA, can be used for the in vitro expansion of G-CSF mobilized hHSPCs, but their use in clinical transplantation protocols should consider impaired homing and lower short-term-engraftment
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