Biomedical subjects

W Dragowska

Publications and source records attributed to W Dragowska.

At least 19 recordsLinked to original sources

PubMed2006

Development and assessment of conventional and targeted drug combinations for use in the treatment of aggressive breast cancers.

Combination chemotherapy has been at the forefront of cancer treatment for over 40 years. However, the rationale for selecting drug combinations and the process used to demonstrate clinical effectiveness has primarily followed trial and error methodology. Typically, the selection and assessment of combined drug therapies has been based on the effectiveness of each agent as monotherapy in treating the neoplasm and avoiding overlapping toxicities, followed by clinical trials to establish dose scheduling, toxicity, and efficacy. Unfortunately, this scheme is inefficient in terms of the time required to complete and revise these clinical trials based on the outcome to optimize the drug combination. A more rational approach for the development of combination oncology products should consider (i) in vitro assays for assessing therapeutic effects of drug combinations (antagonistic, additive or synergistic interactions) when added simultaneously; (ii) methods for measuring these interactions in vivo; (iii) the importance of understanding pharmacokinetic and biodistribution parameters when using drug combinations; (iv) the need to assess pathways known to contribute to cancer cell survival as well as metastasis; and (iv) the need to assess the fate of different cell populations (cancer and stroma) contributing to the development of cancer. Therefore, the goal of this article is to provide a road map for the preclinical development of drug combination products that will have improved therapeutic activity and a high likelihood of providing beneficial therapeutic outcomes in patients with aggressive cancers with a specific focus on patients with breast cancer.

Animals↗

PubMed1999

Asymmetric cell divisions in hematopoietic stem cells.

In order to study cell kinetics involved in long-term hematopoiesis, we studied single sorted candidate hematopoietic stem cells (HSC) from fetal liver cultured in the presence of a mixture of stimulatory cytokines. After 8-10 days in culture, the number of cells varied from less than a hundred to more than ten thousand cells. Single cells in slowly growing colonies were recloned upon reaching a 100-200-cell stage. Strikingly, the number of cells in subclones varied widely again. These results are indicative of asymmetric divisions in primitive hematopoietic cells in which the proliferative potential and cell cycle properties are unevenly distributed among daughter cells. The continuous generation of heterogeneity in cell cycle properties among the clonal progeny of HSC appears a relevant mechanism to maintain long-term maintenance of hematopoiesis in vitro and in vivo.

Adult↗

PubMed1998

Asymmetric cell divisions sustain long-term hematopoiesis from single-sorted human fetal liver cells.

Hematopoietic stem cells (HSCs) in adult marrow are believed to be derived from fetal liver precursors. To study cell kinetics involved in long-term hematopoiesis, we studied single-sorted candidate HSCs from fetal liver that were cultured in the presence of a mixture of stimulatory cytokines. After 8-10 d, the number of cells in primary cultures varied from <100 to >10,000 cells. Single cells in slow growing colonies were recloned upon reaching a 100-200 cell stage. Strikingly, the number of cells in subclones varied widely again. These results are indicative of asymmetric divisions in primitive hematopoietic cells in which proliferative potential and cell cycle properties are unevenly distributed among daughter cells. The continuous generation of functional heterogeneity among the clonal progeny of HSCs is in support of intrinsic control of stem cell fate and provides a model for the long-term maintenance of hematopoiesis in vitro and in vivo.

ADP-ribosyl Cyclase↗

PubMed1998

Telomere length dynamics in human lymphocyte subpopulations measured by flow cytometry.

To measure the average length of telomere repeats at chromosome ends in individual cells we developed a flow cytometry method using fluorescence in situ hybridization (flow FISH) with labeled peptide nucleic acid (PNA) probes. Results of flow FISH measurements correlated with results of conventional telomere length measurements by Southern blot analysis (R = 0.9). Consistent differences in telomere length in CD8+ T-cell subsets were identified. Naive and memory CD4+ T lymphocytes in normal adults differed by around 2.5 kb in telomere length, in agreement with known replicative shortening of telomeres in lymphocytes in vivo. T-cell clones grown in vitro showed stabilization of telomere length after an initial decline and rare clones capable of growing beyond 100 population doublings showed variable telomere length. These results show that flow FISH can be used to measure specific nucleotide repeat sequences in single cells and indicate that the very large replicative potential of lymphocytes is only indirectly related to telomere length.

Adult↗

PubMed1998

Short telomeres on human chromosome 17p.

Human chromosomes terminate in a series of T2AG3 repeats, which, together with associated proteins, are essential for chromosome stability. In somatic cells, these sequences are known to be gradually lost through successive cells divisions; however, information about changes on specific chromosomes is not available. Individual telomeres could mediate important biological effects as was shown in yeast, in which loss of a single telomere results in cell-cycle arrest and chromosome loss. We now demonstrate by quantitative fluorescence in situ hybridization (Q-FISH; ref. 7) that the number of T2AG3 repeats on specific chromosome arms is very similar in different tissues from the same donor and varies only to some extent between donors. In all sixteen individuals studied, telomeres on chromosome 17p were shorter than the median telomere length--a finding confirmed by analysis of terminal restriction fragments from sorted chromosomes. These observations provide evidence of chromosome-specific factors regulating the number of T2AG3 repeats in individual telomeres and raise the possibility that the relatively short telomeres on chromosome 17p contribute to the frequent loss of 17p alleles in human cancers.

Adult↗

PubMed1997

Overexpression of HOXA10 in murine hematopoietic cells perturbs both myeloid and lymphoid differentiation and leads to acute myeloid leukemia.

Multiple members of the A, B, and C clusters of Hox genes are expressed in hematopoietic cells. Several of these Hox genes have been found to display distinctive expression patterns, with genes located at the 3' side of the clusters being expressed at their highest levels in the most primitive subpopulation of human CD34+ bone marrow cells and genes located at the 5' end having a broader range of expression, with downregulation at later stages of hematopoietic differentiation. To explore if these patterns reflect different functional activities, we have retrovirally engineered the overexpression of a 5'-located gene, HOXA10, in murine bone marrow cells and demonstrate effects strikingly different from those induced by overexpression of a 3'-located gene, HOXB4. In contrast to HOXB4, which causes selective expansion of primitive hematopoietic cells without altering their differentiation, overexpression of HOXA10 profoundly perturbed myeloid and B-lymphoid differentiation. The bone marrow of mice reconstituted with HOXA10-transduced bone marrow cells contained in high frequency a unique progenitor cell with megakaryocytic colony-forming ability and was virtually devoid of unilineage macrophage and pre-B-lymphoid progenitor cells derived from the transduced cells. Moreover, and again in contrast to HOXB4, a significant proportion of HOXA10 mice developed a transplantable acute myeloid leukemia with a latency of 19 to 50 weeks. These results thus add to recognition of Hox genes as important regulators of hematopoiesis and provide important new evidence of Hox gene-specific functions that may correlate with their normal expression pattern.

Acute Disease↗

PubMed1996

Production of interleukin 1beta by human hematopoietic progenitor cells.

The production of interleukin 1beta (IL-1beta) by human hematopoietic stem/progenitor cells was studied to explore the concept that these cells are not merely responders to stimuli from their microenvironment, but can themselves produce a powerful biomodulator. Cells with a CD34+ CD45RA(lo) CD71(lo) phenotype were purified from human umbilical cord blood and cultured one per well in serum-free medium with a mixture of cytokines. Cells that had divided over 2-5 d to form doublets were identified and the daughter cells were studied individually. 91% (460/506) of daughter cells had clonogenic potential. Analysis of these individual daughter cells by reverse transcription-polymerase chain reaction showed that 29% of them (14/48) were positive for IL-1beta mRNA. One of the cells that was strongly positive for IL-1beta mRNA had a sibling that generated 366,000 cells of multiple lineages after 14 d. IL-1beta converting enzyme mRNA, which is necessary to produce IL-1beta, was also detected by reverse transcription-polymerase chain reaction at the single-cell level. Moreover, enzyme immunoassay for mature secreted IL-1beta in culture supernatants demonstrated the production of IL-1beta protein by these cells. This was confirmed by fluorescent immunostaining of the cells for human IL-1beta which showed a significant portion of positive cells. Taken together, the results demonstrate the capacity of early hematopoietic cells to synthesize IL-1beta. The capacity of human hematopoietic stem/progenitor cells to produce IL-1beta may be involved in regulation of their proliferation and differentiation under certain circumstances and dysregulation of this process may be modified in leukemogenesis.

Actins↗

PubMed1996

Differential expression of telomerase activity in hematopoietic progenitors from adult human bone marrow.

The loss of telomeric DNA may serve as a mitotic clock which signals cell senescence and exit from cell cycle. Telomerase, and enzyme which synthesizes telomeric repeats de novo, is required to maintain telomere lengths. In humans, significant telomerase activity has been found in cells with essentially unlimited replicative potential such as reproductive cells in ovaries and testes, immortal cell lines and cancer tissues, but not in most normal somatic cells or tissues. We have now examined telomerase expression in subpopulations of hematopoietic cells from adult human bone marrow using a sensitive polymerase chain reaction-based telomeric repeat amplification protocol. Telomerase activity was found at low levels in the highly enriched primitive hematopoietic cells (CD34+CD71loCD45RAlo) and was increased transiently when these cells were cultured in the presence of a mixture of cytokines. In contrast, the early progenitors (CD34+CD71+) expressed telomerase activity at a higher level which was subsequently downregulated in response to cytokines. Telomerase activity remained low in the more mature CD34-cells upon exposure to cytokines. Taken together, our results suggest that telomerase is expressed at a basal level in all hematopoietic cell populations examined, is induced in a primitive subset of hematopoietic progenitor cells and is downregulated upon further proliferation and differentiation of these cells. We have previously observed telomere shortening in cytokine-stimulated primitive hematopoietic cells. The low and transient activation of telomerase activity described here thus appears insufficient to maintain telomere lengths in cultured hematopoietic cells.

Adolescent↗

PubMed1995

Differential effects of the hematopoietic inhibitors MIP-1 alpha, TGF-beta, and TNF-alpha on cytokine-induced proliferation of subpopulations of CD34+ cells purified from cord blood and fetal liver.

We have previously characterized the proliferative response of primitive CD34+ cells, purified from adult bone marrow, umbilical cord blood, and fetal liver, to a mixture of hematopoietic stimulators (steel factor [SF], interleukin-3 [IL-3], IL-6, and erythropoietin [Epo]) in serum-free liquid cultures. In the present study, we assessed the effects of the hematopoietic inhibitors, macrophage inflammatory protein-1 alpha (MIP-1 alpha), transforming growth factor-beta (TGF-beta), and tumor necrosis factor-alpha (TNF-alpha), on the cytokine-induced proliferation of three different CD34+ cell subpopulations derived from cord blood and on total CD34+ cells derived from fetal liver. In cultures of cord blood cells, addition of MIP-1 alpha inhibited the numerical expansion of primitive CD34+ cells (CD34+ CD45RAlow CD71low cells) without inhibiting the proliferation of more mature subpopulations enriched for myeloid (CD34+ CD45RA+ CD71low cells) or erythroid (CD34+ CD45RAlow CD71+ cells) progenitors. TGF-beta significantly reduced the proliferation of all three subpopulations, although its effects were more pronounced on cells of the erythroid lineage, particularly immature erythroid progenitors. Similarly, TNF-alpha preferentially inhibited total nucleated and CD34+ cell production in the subpopulation enriched for erythroid cells. However, in contrast to TGF-beta, TNF-alpha preferentially inhibited the proliferation of more mature erythroid progenitors. In a separate set of experiments, MIP-1 alpha, TGF-beta, and TNF-alpha were added to cultures of total CD34+ cells purified from fetal liver. In keeping with the fact that the majority of the progenitors contained in these cells were erythroid progenitors, the inhibitory effects of the three cytokines were similar to those observed in cultures of CD34+ CD45RAlow CD71+ cord blood cells. The results of the present study demonstrate that MIP-1 alpha, TGF-beta, and TNF-alpha have the capacity to modulate cytokine-induced proliferation of cord blood and fetal liver progenitors. The differential effects of these three cytokines confirm their pleiotropic nature as regulators of hematopoiesis.

Antigens, CD↗

PubMed1994

Evidence for a mitotic clock in human hematopoietic stem cells: loss of telomeric DNA with age.

The proliferative life-span of the stem cells that sustain hematopoiesis throughout life is not known. It has been proposed that the sequential loss of telomeric DNA from the ends of human chromosomes with each somatic cell division eventually reaches a critical point that triggers cellular senescence. We now show that candidate human stem cells with a CD34+CD38lo phenotype that were purified from adult bone marrow have shorter telomeres than cells from fetal liver or umbilical cord blood. We also found that cells produced in cytokine-supplemented cultures of purified precursor cells show a proliferation-associated loss of telomeric DNA. These findings strongly suggest that the proliferative potential of most, if not all, hematopoietic stem cells is limited and decreases with age, a concept that has widespread implications for models of normal and abnormal hematopoiesis as well as gene therapy.

Adolescent↗

PubMed1994

Transforming growth factor beta 1 is an inducer of erythroid differentiation.

Normal human bone marrow cells, highly enriched for burst-forming units-erythroid (BFU-E), were cultured in serum-free medium, in the presence and absence of various factors, to investigate the mechanisms involved in regulating erythroid differentiation. In cultures containing interleukin 3 (IL-3), Steel factor (SF), and erythropoietin (Ep), benzidine-positive erythroblasts first became detectable on day 6. Their numbers then rapidly increased until, by day 16, > 99% of the cells, which were 20,000-fold amplified over input numbers, were benzidine-positive. It is interesting to note that omission of either SF or Ep from this assay markedly enhanced the rate of differentiation and reduced total cell numbers, whereas omission of IL-3 had no effect on the rate of differentiation and only slightly reduced cell numbers. Of various agents tested, the most potent erythroid differentiation inducer (and inhibitor of cell proliferation) was found to be transforming growth factor beta 1 (TGF-beta 1). This cytokine stimulated both the rapid appearance of hemoglobin-positive cells and an early cessation of cell proliferation. Using fluorescently tagged antibodies to glycophorin A and fluorescence-activated cell sorter (FACS) analysis, this phenomenon was shown to be due to an early induction of erythroid differentiation rather than an aberrant production of hemoglobin. Methylcellulose assays indicated that the well-documented reduction of BFU-E colony numbers observed with TGF-beta 1 may actually be due to a TGF-beta 1-induced "conversion" of BFU-E into colony-forming units-erythroid (CFU-E). Thus, in vivo, TGF-beta 1 might serve, in part, to decrease the number of mature erythrocytes by stimulating BFU-E to skip a number of cell divisions and differentiate early.

Animals↗

PubMed1994

Expression of interleukin-1 beta gene in candidate human hematopoietic stem cells.

Reverse transcription-polymerase chain reaction (RT-PCR) was used to detect interleukin-1 beta (IL-1 beta) mRNA in candidate human hematopoietic stem cells. The cells, obtained from adult bone marrow (BM) or umbilical cord blood, had a CD34+ CD45RAlo CD71lo phenotype and were further fractionated into CD38+ and CD38- or Thy-1+ and Thy-1- subpopulations. The purity of these fractions was always more than 99%. IL-1 beta and CD34 mRNA were detected in pools of 30 BM-derived CD34+ CD45RAlo CD71lo cells. To further exclude any contribution by contaminating cells, individual cells were analyzed for CD34 and IL-1 beta mRNA. Positive results were obtained with 2 of 5 individual BM-derived CD34+ CD45RAlo CD71lo CD38+ cells isolated by micromanipulation after overnight culture in serum-free medium without any exogenous cytokines, and 1 of 10 individual CD34+ CD45RAlo CD71lo CD38- cells isolated immediately after sorting. Moreover, of 10 pools of three BM-derived CD34+ CD45RAlo CD71lo cells cultured overnight in the presence of a mixture of various cytokines (Steel factor, IL-3, IL-6, macrophage colony-stimulating factor [M-CSF], erythropoietin, and IL-3/granulocyte-macrophage colony-stimulating factor [GM-CSF] fusion protein), 5 were positive for IL-1 beta mRNA. This result was compatible with more than 20% (95% confidence limit 0.06-0.61) of the BM cells with the CD34+ CD45RAlo CD71lo phenotype expressing IL-1 beta mRNA. IL-1 beta expression was also consistently observed from day 0 to day 9 in liquid cultures of cord-blood-derived CD34+ CD45RAlo CD71lo Thy-1+ or Thy-1- cells. The cultures contained the same combination of cytokines and resulted in an expansion of cell numbers of up to 400-fold. GM-CSF mRNA was not detected in the equivalent of 75 cells at any day, even though it could be detected with high sensitivity in control stromal cells. Because IL-1 beta is a powerful and pleiotropic biomodulator of cytokines and adhesion molecules, our observations suggest that at least some primitive hematopoietic cells do not merely respond passively to signals from their environment, but may themselves regulate the paracrine production of cytokines from neighboring stromal cells.(ABSTRACT TRUNCATED AT 400 WORDS)

Antigens, CD↗

PubMed1994

Amplification of Sca-1+ Lin- WGA+ cells in serum-free cultures containing steel factor, interleukin-6, and erythropoietin with maintenance of cells with long-term in vivo reconstituting potential.

Normal murine bone marrow (BM) cells were sorted on the basis of low forward and orthogonal light scatter properties, Sca-1 expression (Sca-1+), lack of staining with a cocktail of mature hematopoietic lineage markers (Lin-), and binding of wheat germ agglutinin (WGA+). This approach allowed the reproducible isolation of a very small subpopulation (0.037% +/- 0.023% of all nucleated BM cells) that was approximately 400-fold enriched in cells capable of reconstituting both lymphoid and myeloid lineages in lethally irradiated recipients. Transplantation of 30 or 10 of these Sca-1+Lin-WGA+ cells resulted in > or = to 20% donor-derived nucleated peripheral blood cells 3 months posttransplantation in 100% and 22% of the recipients, respectively. When Sca-1+Lin-WGA+ cells were cultured in serum-free medium supplemented with Steel factor, interleukin-6 (IL-6), and erythropoietin (with or without IL-3), a large increase in total cell number, including cells with an Sca-1+Lin-WGA+ phenotype was observed. Single cell cultures showed that 90% to 95% of the input cells underwent at least one division during the first 2 weeks and the remainder died. Interestingly, this proliferative response was not accompanied by a parallel increase in the number of cells with both lymphoid and myeloid repopulating potential in vivo, as quantitation of these by limiting dilution analysis showed they had decreased slightly (1.3-fold) but not significantly below the number initially present. These results demonstrate that Sca-1+Lin-WGA+ cells with long-term repopulating potential can be maintained for 2 weeks in a serum- and stroma cell-free culture, providing a simple in vitro system to study their behavior under well-defined conditions. The observed expansion of Sca-1+Lin-WGA+ cells in vitro without a concomitant increase in reconstituting cells also shows that extensive functional heterogeneity exists within populations of cells with this surface phenotype.

Animals↗

PubMed1994

CD45 isoform expression on human haemopoietic cells at different stages of development.

Alternate splicing and glycosylation produce multiple CD45 isoforms which are selectively expressed on the surface of cells of the haemopoietic system. The expression of CD45RA, CD45RB and CD45RO on CD34+ and CD34- haemopoietic cells from umbilical cord blood, bone marrow and fetal liver were studied by flow cytometry. CD34+ subpopulations defined by CD45 isoform expression were sorted from bone marrow and tested in long-term culture assays. By combining results of functional studies with phenotypic data and previously published information, the following pattern of CD45 isoform expression on early haemopoietic cells was established. The most primitive CD34+ cells are CD45RO+ CD45RB+ and express low or undetectable levels of CD45RA. Upon erythroid differentiation, CD34+ cells remain CD45RO+ CD45RB+, whereas commitment into the myeloid and lymphoid lineages coincides with down-regulation of CD45RO and up-regulation of CD45RA. As a result, the majority of CD34+ cells can be divided into two mutually exclusive populations of cells which express either CD45RO or CD45RA. This notion was confirmed in this study by three-colour immunofluorescence. The alternative expression of various CD45 isoforms on functionally distinct haemopoietic cells suggests an important role for these molecules in the proliferation and differentiation of haemopoietic cells.

Alternative Splicing↗

PubMed1994

Age-related decline in proliferative potential of purified stem cell candidates.

Recent studies in our laboratory have shown striking differences in the functional properties of candidate hematopoietic stem cells purified from fetal, neonatal, and adult human tissues. These differences include the ability to produce CD34+ cells, the turnover rate, and the fraction of cells that respond to a mixture of cytokines. All these parameters decrease with the age of the cell donor, and some of these observations are summarized here. Extensive qualitative changes in hematopoietic cells from various stages of development should be taken into account in the design of novel therapeutic strategies.

Adult↗

PubMed1993

Characterization of functionally distinct subpopulations of CD34+ cord blood cells in serum-free long-term cultures supplemented with hematopoietic cytokines.

We have previously identified, based on the expression of the CD45RA and CD71 antigens, three major subpopulations of CD34+ cells derived from human umbilical cord blood: CD34+ CD45RAloCD71lo cells (up to 42% multipotent progenitors), CD34+ CD45RA+ CD71lo cells (90% myeloid progenitors), and CD34+ CD45RAloCD71+ cells (70% erythroid progenitors). In the present study, we have investigated the long-term proliferation and differentiation of these subpopulations in response to hematopoietic cytokines. Cells from each subpopulation were cultured for 38 days in serum- and stroma-free liquid cultures supplemented with cytokine combinations that favor either erythropoiesis or myelopoiesis. In keeping with their high content of primitive progenitors, CD34+ CD45RAloCD71lo cells showed the highest CD34+ cell expansion (up to 532-fold) throughout the culture period, followed by CD34+ CD45RA+ CD71lo (130-fold) and CD34+ CD45RAloCD71+ (28-fold) cells. Interestingly, the cytokine combination favoring myelopoiesis was always more efficient in inducing CD34+ cell expansion than the one favoring erythropoiesis. In all but one of the cultures, a predominance of myelopoiesis was observed after 2 weeks, even in those supplemented with the cytokine mixture that favors erythropoiesis. Only when CD34+ CD45RAloCD71+ cells were cultured in the presence of erythroid cytokine mixture, erythropoiesis was evident at all time points. However, such cultures could be sustained for only 29 days. The results of this study demonstrate that the cord blood-derived CD34+ cell compartment consists of functionally distinct cell subpopulations that possess different proliferative capacities in vitro. Our results also show that the cytokine combinations used here were able to modulate proliferation and, to a much lesser extent, differentiation of such subpopulations, probably by favoring the expansion of committed progenitors rather than by acting on uncommitted cells.

Antigens, CD↗

PubMed1993

Ontogeny-related changes in proliferative potential of human hematopoietic cells.

Blood cells originate from hematopoietic stem cells that are located at different sites during ontogeny. Production of human stem cells and their progeny in culture is expected to have important implications for experimental therapeutic strategies involving gene transfer and transplantation. Here we report striking differences between primitive hematopoietic cells purified from adult bone marrow, umbilical cord blood, and fetal liver in cytokine-supplemented, serum-free cultures. In such cultures both the fraction of responding cells and their ability to produce CD34+ progenitor cells decreased markedly with the age of the cell donor. These results document extensive, ontogeny-related functional differences between primitive hematopoietic cells.

Adult↗

PubMed1993

Cytokine-induced selective expansion and maturation of erythroid versus myeloid progenitors from purified cord blood precursor cells.

To study the role of different cytokine combinations on the proliferation and differentiation of highly purified primitive progenitor cells, a serum-free liquid culture system was used in combination with phenotypic and functional analysis of the cells produced in culture. CD34+ CD45RAlo CD71lo cells, purified from umbilical cord blood by flow cytometry and cell sorting, were selected for this study because of their high content of clonogenic cells (34%), particularly multipotent progenitors (CFU-MIX, 12% of all cells). Four cytokine combinations were tested: (1) mast cell growth factor (MGF; a c-kit ligand) and interleukin-6 (IL-6); (2) MGF, IL-6, IL-3, and erythropoietin (Epo); (3) MGF, IL-6, granulocyte-macrophage colony-stimulating factor (GM-CSF)/IL-3 fusion protein (FP), macrophage colony-stimulating factor (M-CSF), and granulocyte-CSF (G-CSF); and (4) MGF, IL-6, FP, M-CSF, G-CSF, and Epo. Maximum numbers of erythroid progenitors (BFU-E, up to 55-fold increase) and mature erythroid cells were observed in the presence of MGF, IL-6, IL-3, and Epo, whereas maximum levels of myeloid progenitors (CFU-C, up to 70-fold increase) and mature myeloid cells were found in cultures supplemented with MGF, IL-6, FP, M-CSF, and G-CSF. When MGF, IL-6, FP, M-CSF, G-CSF, and Epo were present, maximum levels of both erythroid and myeloid progenitors and their progeny were observed. These results indicate that specific cytokine combinations can act directly on primitive hematopoietic cells resulting in significant expansion of progenitor cell numbers and influencing their overall patterns of proliferation and differentiation. Furthermore, the observations presented in this study suggest that the cytokine combinations used were unable to bias lineage commitment of multipotent progenitors, but rather had a permissive effect on the development of lineage-restricted clonogenic cells.

Antigens, CD↗