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HOXA4 provides stronger engraftment potential to short-term repopulating cells than HOXB4.

ABSTRACT: Genes of the HOX4 paralog group have been shown to expand hematopoietic stem cells (HSCs). Endogenous expression of HOXA4 is 10-fold higher than HOXB4 in embryonic primitive hematopoietic cells undergoing self-renewal suggesting a more potent capacity of HOXA4 to expand HSC. In this study, we provide evidence by direct competitive bone marrow cultures that HOXA4 and HOXB4 induce self-renewal of primitive hematopoietic cells with identical kinetics. Transplantation assays show that short-term repopulation by HOXA4-overexpressing multilineage progenitors was significantly greater than HOXB4-overexpressing progenitors in vivo, indicating differences in the sensitivity of the cells to external signals. Small array gene expression analysis showed an increase in multiple Notch and Wnt signaling -associated genes, including receptors and ligands, as well as pluripotency genes, for both HOXA4- and HOXB4-overexpressing cells, which was more pronounced for HOXA4, suggesting that both HOX proteins may assert their affects through intrinsic and extrinsic pathways to induce self-renewal of primitive hematopoietic cells. Thus, HOXA4 increases short-term repopulation to higher levels than HOXB4, which may involve Notch signaling.

SUBMITTER: Fournier M

PROVIDER: S-EPMC4598939 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Differential effects of HOXB4 on nonhuman primate short- and long-term repopulating cells.

Project description:BackgroundHematopoietic stem cells (HSCs) or repopulating cells are able to self-renew and differentiate into cells of all hematopoietic lineages, and they can be enriched using the CD34 cell surface marker. Because of this unique property, HSCs have been used for HSC transplantation and gene therapy applications. However, the inability to expand HSCs has been a significant limitation for clinical applications. Here we examine, in a clinically relevant nonhuman primate model, the ability of HOXB4 to expand HSCs to potentially overcome this limitation.Methods and findingsUsing a competitive repopulation assay, we directly compared in six animals engraftment of HOXB4GFP (HOXB4 green fluorescent protein) and control (yellow fluorescent protein [YFP])-transduced and expanded CD34+ cells. In three animals, cells were infused after a 3-d transduction culture, while in three other animals cells were infused after an additional 6-9 d of ex vivo expansion. We demonstrate that HOXB4 overexpression resulted in superior engraftment in all animals. The most dramatic effect of HOXB4 was observed early after transplantation, resulting in an up to 56-fold higher engraftment compared to the control cells. At 6 mo after transplantation, the proportion of marker gene-expressing cells in peripheral blood was still up to 5-fold higher for HOXB4GFP compared to YFP-transduced cells.ConclusionsThese data demonstrate that HOXB4 overexpression in CD34+ cells has a dramatic effect on expansion and engraftment of short-term repopulating cells and a significant, but less pronounced, effect on long-term repopulating cells. These data should have important implications for the expansion and transplantation of HSCs, in particular for cord blood transplantations where often only suboptimal numbers of HSCs are available.

| S-EPMC1450018 | biostudies-literature

Increased Engraftment of Human Short Term Repopulating Hematopoietic Cells in NOD/SCID/IL2rγnull Mice by Lentiviral Expression of NUP98-HOXA10HD.

Project description:Techniques to expand human hematopoietic stem cells ex-vivo could be beneficial to the fields of clinical hematopoietic stem cell transplantation and gene therapy targeted at hematopoietic stem cells. NUP98-HOXA10HD is a relatively newly discovered fusion gene that in mouse transplant experiments has been shown to increase numbers of hematopoietic stem cells. We evaluated whether this fusion gene could be used to expand engrafting human primitive CD34+ cells in an immunodeficient mouse model. Gene transfer was achieved using a lentiviral based vector. The engraftment of mobilized peripheral blood human CD34+ cells grown in culture for one week after gene transfer was evaluated 3-4 months after transplant and found to be 2-3 fold higher in the NUP98-HOXA10HD groups as compared to controls. These data suggest an expansive effect at least at the short term human repopulating cell level. Further evaluation in long term repopulating models and investment in a NUP98-HOXA10HD protein seems worthy of consideration. Additionally, the results here provide strong impetus to utilize NUP98-HOXA10HD as a tool to search for underlying genes and pathways involved in hematopoietic stem cell expansion that can be enhanced and have an even more potent expansive effect.

| S-EPMC4711970 | biostudies-literature

Short-term immunosuppression promotes engraftment of embryonic and induced pluripotent stem cells.

Project description:Embryonic stem cells (ESCs) are an attractive source for tissue regeneration and repair therapies because they can be differentiated into virtually any cell type in the adult body. However, for this approach to succeed, the transplanted ESCs must survive long enough to generate a therapeutic benefit. A major obstacle facing the engraftment of ESCs is transplant rejection by the immune system. Here we show that blocking leukocyte costimulatory molecules permits ESC engraftment. We demonstrate the success of this immunosuppressive therapy for mouse ESCs, human ESCs, mouse induced pluripotent stem cells (iPSCs), human induced pluripotent stem cells, and more differentiated ESC/(iPSCs) derivatives. Additionally, we provide evidence describing the mechanism by which inhibition of costimulatory molecules suppresses T cell activation. This report describes a short-term immunosuppressive approach capable of inducing engraftment of transplanted ESCs and iPSCs, providing a significant improvement in our mechanistic understanding of the critical role costimulatory molecules play in leukocyte activation.

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Notch2 governs the rate of generation of mouse long- and short-term repopulating stem cells.

Project description:HSCs either self-renew or differentiate to give rise to multipotent cells whose progeny provide blood cell precursors. However, surprisingly little is known about the factors that regulate this choice of self-renewal versus differentiation. One candidate is the Notch signaling pathway, with ex vivo studies suggesting that Notch regulates HSC differentiation, although a functional role for Notch in HSC self-renewal in vivo remains controversial. Here, we have shown that Notch2, and not Notch1, inhibits myeloid differentiation and enhances generation of primitive Sca-1(+)c-kit(+) progenitors following in vitro culture of enriched HSCs with purified Notch ligands. In mice, Notch2 enhanced the rate of formation of short-term repopulating multipotential progenitor cells (MPPs) as well as long-term repopulating HSCs, while delaying myeloid differentiation in BM following injury. However, consistent with previous reports, once homeostasis was achieved, neither Notch1 nor Notch2 affected repopulating cell self-renewal. These data indicate a Notch2-dependent role in assuring orderly repopulation by HSCs, MPPs, myeloid cells, and lymphoid cells during BM regeneration.

| S-EPMC3049401 | biostudies-literature

Effect of intravenous coadministration of human stroma cell lines on engraftment of long-term repopulating clonal myelodysplastic syndrome cells in immunodeficient mice.

Project description:Engraftment of clonal hematopoietic precursor cells from patients with myelodysplastic syndrome (MDS) in immunodeficient mice has been difficult to achieve by intravenous (i.v.) injection. We used i.v. coadministration of the human marrow stroma cell line HS27a with CD34+ MDS cells in Nod.cg-Prkdc(scid) Il2rg(tm1wjll) (NSG) mice to provide signals that would facilitate engraftment. Hematopoietic cells from 24 MDS patients were transplanted. Cells from all patients were engrafted, and engraftment was documented in 44 of 46 evaluable mice (95%). Immunohistochemistry revealed human HS27a stroma colocalizing with human hematopoietic cells in mouse spleens. Human CD34+ precursors harvested from marrow and spleen of primary murine recipients, when combined with HS27a cells, were also engrafted successfully in secondary NSG recipients, showing persistence of the original clonal characteristics. This observation supports the concept that clonal markers were present in long-term repopulating cells. We suggest that HS27a stroma cells 'traveled' in direct contact with hematopoietic precursors and enabled their propagation. An essential signal for engraftment appears to be CD146, which is prominently expressed on HS27a cells. This xenotransplantation model will allow to further dissect signals that control engraftment of MDS cells and should be amenable to in vivo treatment studies.

| S-EPMC3641319 | biostudies-literature

Umbilical cord blood expansion with nicotinamide provides long-term multilineage engraftment.

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| S-EPMC4071379 | biostudies-literature

Engraftment and lineage potential of adult hematopoietic stem and progenitor cells is compromised following short-term culture in the presence of an aryl hydrocarbon receptor antagonist.

Project description:Hematopoietic stem cell gene therapy for HIV/AIDS is a promising alternative to lifelong antiretroviral therapy. One of the limitations of this approach is the number and quality of stem cells available for transplant following in vitro manipulations associated with stem cell isolation and genetic modification. The development of methods to increase the number of autologous, gene-modified stem cells available for transplantation would overcome this barrier. Hematopoietic stem and progenitor cells (HSPC) from adult growth factor-mobilized peripheral blood were cultured in the presence of an aryl hydrocarbon receptor antagonist (AhRA) previously shown to expand HSPC from umbilical cord blood. Qualitative and quantitative assessment of the hematopoietic potential of minimally cultured (MC-HSPC) or expanded HSPC (Exp-HSPC) was performed using an immunodeficient mouse model of transplantation. Our results demonstrate robust, multilineage engraftment of both MC-HSPC and Exp-HSPC although estimates of expansion based on stem cell phenotype were not supported by a corresponding increase in in vivo engrafting units. Bone marrow of animals transplanted with either MC-HSPC or Exp-HSPC contained secondary engrafting cells verifying the presence of primitive stem cells in both populations. However, the frequency of in vivo engrafting units among the more primitive CD34+/CD90+ HSPC population was significantly lower in Exp-HSPC compared with MC-HSPC. Exp-HSPC also produced fewer lymphoid progeny and more myeloid progeny than MC-HSPC. These results reveal that in vitro culture of adult HSPC in AhRA maintains but does not increase the number of in vivo engrafting cells and that HSPC expanded in vitro contain defects in lymphopoiesis as assessed in this model system. Further investigation is required before implementation of this approach in the clinical setting.

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CD133 is a marker for long-term repopulating murine epidermal stem cells.

Project description:Maintenance, repair, and renewal of the epidermis are thought to depend on a pool of dedicated epidermal stem cells (EpiSCs). Like for many somatic tissues, isolation of a nearly pure population of stem cells is a primary goal in cutaneous biology. We used a quantitative transplantation assay, using injection of keratinocytes into subcutis combined with limiting dilution analysis, to assess the long-term repopulating ability of putative murine EpiSC populations. Putative EpiSC populations were isolated by FACS sorting. The CD133(+) population and the subpopulation of CD133(+) cells that exhibits high mitochondrial membrane potential (D?m(hi)) were enriched for long-term repopulating EpiSCs versus unfractionated cells (3.9- and 5.2-fold, respectively). Evidence for self-renewal capacity was obtained by serial transplantation of long-term epidermal repopulating units derived from CD133(+) and CD133(+)??m(hi) keratinocytes. CD133(+) keratinocytes were multipotent and produced significantly more hair follicles than CD133(-) cells. CD133(+) cells were a subset of the previously described integrin ?6(+)CD34(+) bulge cell population, and 28.9±8.6% were label-retaining cells. Thus, murine keratinocytes within the CD133(+) and CD133(+)??m(hi) populations contain EpiSCs that regenerate the epidermis for the long term, are self-renewing, multipotent, and label-retaining cells.

| S-EPMC3997791 | biostudies-literature

Glucose oxidase induces mobilization of long-term repopulating hematopoietic cells in mice.

Project description:Hematopoietic stem progenitor cells (HSPCs) mobilized to peripheral blood, rather than those remaining in the bone marrow (BM), are commonly used as stem cell source in the clinic. As reactive oxygen species (ROS) are suggested as mediator of HSPC mobilization, we examined the impacts of glucose oxidase (GO) on peripheral mobilization of BM HSPCs and the associated mechanisms. Intravenous injection of GO induced HSPC mobilization even by single treatment, and the GO-mobilized cells maintained their long-term reconstituting and differentiating potentials in conditioned recipients. GO-injected mice lived a normal life without adverse effects such as stem cell senescence, hematopoietic disorders, and blood parameter alteration. The mobilization effect of GO was even evident in animal models showing poor mobilization, such as old, 5-fluorouracil-treated, or alendronate-treated mice. Importantly, combined injection of GO with granulocyte colony-stimulating factor (G-CSF) and/or AMD3100 enhanced more greatly HSPC mobilization than did G-CSF, AMD3100, or both. The GO-stimulated HSPC mobilization was almost completely attenuated by N-acetyl-L-cysteine treatment. Collectively, our results not only highlight the potential role of GO in HSPC mobilization via ROS signaling, but also provide a GO-based new strategy to improve HSPC mobilization in poorly mobilizing allogeneic or autologous donors via combination with G-CSF and/or AMD3100.

| S-EPMC8459634 | biostudies-literature

CD133-targeted gene transfer into long-term repopulating hematopoietic stem cells.

Project description:Gene therapy for hematological disorders relies on the genetic modification of CD34(+) cells, a heterogeneous cell population containing about 0.01% long-term repopulating cells. Here, we show that the lentiviral vector CD133-LV, which uses a surface marker on human primitive hematopoietic stem cells (HSCs) as entry receptor, transfers genes preferentially into cells with high engraftment capability. Transduction of unstimulated CD34(+) cells with CD133-LV resulted in gene marking of cells with competitive proliferative advantage in vitro and in immunodeficient mice. The CD133-LV-transduced population contained significantly more cells with repopulating capacity than cells transduced with vesicular stomatitis virus (VSV)-LV, a lentiviral vector pseudotyped with the vesicular stomatitis virus G protein. Upon transfer of a barcode library, CD133-LV-transduced cells sustained gene marking in vivo for a prolonged period of time with a 6.7-fold higher recovery of barcodes compared to transduced control cells. Moreover, CD133-LV-transduced cells were capable of repopulating secondary recipients. Lastly, we show that this targeting strategy can be used for transfer of a therapeutic gene into CD34(+) cells obtained from patients suffering of X-linked chronic granulomatous disease. In conclusion, direct gene transfer into CD133(+) cells allows for sustained long-term engraftment of gene corrected cells.

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