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Stem cells suitable for transplantation, their preparation and pharmaceutical compositions comprising themStem cells suitable for transplantation, their preparation and pharmaceutical compositions comprising them description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20080025957, Stem cells suitable for transplantation, their preparation and pharmaceutical compositions comprising them. Brief Patent Description - Full Patent Description - Patent Application Claims
FIELD OF THE INVENTION [0001]The present invention relates to stem cells suitable for transplantation and to methods for their preparation. BACKGROUND OF THE INVENTION [0002]Clinical and experimental hematopoietic stem cells (HSC) transplantation procedures mimic the physiological process of HSC migration from the circulation into the bone marrow (BM) occurring during late embryonic development and steady state hematopoiesis in adults throughout life.sup.1-3. Gene transfer into human HSC may serve as a promising tool in the correction of a wide variety of hematopoietic and genetic disorders. HSC transplantation can be used to durably deliver these genetically modified cells to the BM, which in turn will release mature cells with the corrected gene into the circulation throughout life. [0003]Enhanced efficacy of stem cell engraftment could improve the outcome of clinical transplantations as well as gene therapy protocols, and might be achieved by modulating the ability of stem cells to home to and repopulate the recipient BM. For this purpose, a better understanding of the mechanisms, which regulate these processes, is necessary. [0004]Interactions between the chemokine stromal-derived factor-1 (SDF-1) also referred to as CXCL12, and its receptor CXCR4 play an essential role in stem cell seeding of the BM during murine embryonic developments.sup.10,11. Previously, the present inventors were able to show, using immune deficient NOD/SCID mice as recipients, that both the short term in vivo migration (homing) and high-level multilineage repopulation of the murine bone marrow by human CD34.sup.+ enriched cells are dependent on SDF-1/CXCR4 interactions.sup.12-15. In support of these data, it has been shown that either high levels of CXCR4 expression on human CD34.sup.+ cells, or high SDF-1 induced directional motility in vitro, correlates with faster recovery in both allogeneic and autologous clinical transplantations with positive selection of CD34.sup.+ cells.sup.16,17. [0005]CXCR4 expression is a dynamic process, which is regulated by environmental factors such as cytokines, chemokines, stromal cells, adhesion molecules, and proteolytic enzymes.sup.18. In hematopoietic stem and progenitor cells of human origin, CXCR4 can be upregulated from intracellular pools by short term (.about.40 hr) in vitro cytokine culture.sup.13,19 or stimulation of cord blood (CB) CD34.sup.+ with proteolytic enzymes such as MMP-2 and MMP-9.sup.20.This subsequently enhances their in vitro migration towards an SDF-1 gradient.sup.13 as well as their in vivo homing and repopulation capacities in transplanted NOD/SCID and serially transplanted .beta.2 mnull NOD/SCID mice.sup.12,13, linking stem cell self renewal and development with motility. A recent report demonstrated that longer culture periods with a cytokine cocktail results in a decrease in cell surface CXCR4 expression on human CB CD34.sup.+ enriched cells.sup.22 and reduced repopulation was documented with human progenitors cultured in vitro for longer periods.sup.23. Recently, the present inventors showed that CB CD34.sup.+/CXCR4- sorted cells harbor low levels of intracellular CXCR4, which, following short term in vitro cytokine stimulation, can rapidly be functionally expressed on the cell surface to mediate SDF-1 dependent homing and repopulation of transplanted NOD/SCID mice In addition to their central role in mediating directional migration of human and murine stem cells.sup.24, SDF-1/CXCR4 interactions are also involved in other stem cell functions. Of importance, SDF-1/CXCR4 interactions are also involved in retention of stem and progenitor cells in the BM .sup.10,32,33. This hypothesis has also been confirmed by other studies which demonstrated the involvement of SDF-1/CXCR4 interactions in the anchorage of human HSC injected directly into the murine BM cavity.sup.34,35. Interference of these interactions induces release/mobilization of both human and murine progenitors from the BM into the circulation.sup.36-41. [0006]Transgenic mice overexpressing human CD4 and CXCR4 on their CD4.sup.+ T cells have increased levels of these cells in their BM and only very low levels in the circulation.sup.42. Therefore, overexpression of CXCR4 on human CD34.sup.+ progenitor cells may facilitate their homing and repopulation potential. [0007]Lentiviral vectors have been used to introduce transgenes into SCID repopulating cells (SRCs).sup.43-46, due to their unique ability to transduce non-dividing cells.sup.47. Furthermore, a significant clinical breakthrough in gene therapy was made in patients with human severe combined immunodeficiency (SCID)-X1 resulting in full correction of disease phenotype.sup.48,49, proving that gene therapy can work in practice. However, emerging evidence exists for impaired homing.sup.8 and low engraftment.sup.9 of retrovirally-transduced human CD34.sup.+ cells. [0008]It is well documented that low concentrations of SDF-1 in synergy with other early acting cytokines enhance proliferation of both human CD34.sup.+ cells and murine stem and progenitor cells, suggesting a role for this chemokine in progenitor cell survival.sup.25-29, while high levels of SDF-1 induce quiescence of proliferating human long term culture initiating cells (LTCIC) and primitive human fetal liver CD34.sup.+ stem cells capable of serial repopulation of transplanted NOD/SCID mice .sup.30,31. [0009]One of the disadvantages of BM transplantation is the long lasting reduced levels of immature progenitors, such as long-term culture initiating cells (LTCIC), (1 log reduction) in the BM of transplanted patients compared to healthy individuals.sup.4-7. [0010]Long-term culture-initiating cells (LTC-IC) are hematopoietic progenitors able to generate colony-forming unit-cells (CFU) after 5 to 8 weeks (35 to 60 days) of culture on bone marrow (BM) stroma and represent progenitors currently detectable in vitro. It has been reported that long-term cultures initiated with CD34+CD38 - cells from human BM or cord blood are able to continue generating CFU for at least 100 days, i.e., beyond the standard LTC-IC period. Single-cell cultures from cord blood were used to study whether the subpopulation of CD34+CD38 - cells is able to generate CFU beyond 60 days ("extended long-term culture-initiating cells" or ELTC-IC). In contrast, to LTC-IC cord blood, ELTC-IC proliferate later in culture and are a more quiescent progenitor population. ELTC-IC generates threefold to fourfold more progeny than did LTC-IC (P<0.002). This is a functional hierarchy of progenitors in long-term culture, which correlates with their level of quiescence. (Blood. 1996 Nov. 1; 88(9): 3306-13 Crooks G M et al. [0011]In view of the ever-expanding use of stem cell therapy, it is highly desirable to enhance the levels of CD34+CD38-cell in the population of stem cells to improve the efficiency and success rate of cell replacement therapy. SUMMARY OF THE INVENTION [0012]The invention relates to a method for preparing a population of cells comprising stem cells with a high amount of immature primitive progenitors, the method comprising collecting stem cells and introducing into the cells a DNA fragment comprising the sequence of CXCR4. [0013]In one embodiment of the invention, the population of cells exhibits improved CXCR4 signaling in response to low concentration of SDF-1. [0014]In another embodiment of the invention, the population of cells exhibits improved CXCR4 signaling in response to high concentration of SDF-1. [0015]In a further embodiment of the invention, the stem cells are hematopoietic stem cells, preferably, CD34+ enriched. [0016]In a further embodiment of the invention, the immature primitive progenitors are of the CD34+/CD38 -/low lineage. [0017]In a further embodiment of the invention, the collection of the stem cells is effected after a stem cell mobilization procedure; and/or after a surgical procedure. [0018]In a further embodiment of the invention, after collection, stem cells having CXCR4 levels above a predetermined threshold are isolated e.g. by FACS. [0019]In a further embodiment of the invention, the stem cells of the invention are capable of differentiating towards the myeloid and erythroid lineages. [0020]In a further embodiment of the invention, the amount of the immature primitive progenitors of the CD34+/CD38-/low lineage are about 1-5% of the population. [0021]In a further embodiment of the invention, the amount of immature primitive progenitors of the CD34+/CD38 -/low lineage are equal to or higher than about 3% of the stem cells. 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