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PubMed1995

Differential effects of polyunsaturated fatty acids on cell growth and differentiation of premonocytic U937 cells.

The effect of long chain polyunsaturated fatty acids (PUFA) on cell growth and differentiation was assessed in human premonocytic U937 cells. Addition of either 10 microM arachidonic acid (AA, 20:4n-6), eicosapentaenoic acid (EPA, 20:5n-3) or docosahexaenoic acid (DHA, 22:6n-3) resulted in the rapid incorporation of these fatty acids into cellular phospholipids. Their uptake was greatest in the first 2 h. AA and EPA reached steady-state levels after 8 h, while levels of DHA increased steadily over 72 h. In parallel, fatty acid metabolites derived from AA and EPA, 22:4n-6, 22:5n-6 and 22:5n-3, 22:6n-3, respectively, increased continuously indicating an active fatty acid elongation and desaturation. The effects of PUFA on monocytic differentiation were examined in cells which had been enriched with AA, EPA or DHA for 8 h and subsequently treated with retinoic acid (RA), 1,25-(OH)2-vitamin D3 (1,25-D3), interferon-gamma (IFN-gamma) or their combinations for 72 h. Growth of differentiating or non-differentiating U937 cells was not affected by enrichment with PUFA. However, in cells differentiated with 1,25-D3 plus IFN-gamma, prior enrichment with all three PUFA slightly but significantly (P < 0.05) increased the expression of the monocytic surface antigens CD11b and CD14 and generation of superoxide anion. The data indicate that although n-6 and n-3 PUFA are rapidly incorporated into phospholipids, they do not affect cell growth. However, enrichment with PUFA increases monocytic differentiation of U937 cells when induced most effectively with 1,25-D3 plus IFN-gamma.

Antigens, CD↗
PubMed2006

Derivation, characterization and differentiation of human embryonic stem cells: comparing serum-containing versus serum-free media and evidence of germ cell differentiation.

BACKGROUND: This study was designed to establish human embryonic stem cell (hESC) lines, to identify the differences when maintained in serum-containing versus serum-free medium and to test their potential of in vitro differentiation. METHODS: Procedures including immunosurgery were performed on 11 donated human blastocysts to establish hESC lines. The cell lines were characterized and maintained using either serum-free or serum-containing media to compare their morphology, Oct-4 expression, apoptosis and growth speed. Differentiation of these lines was evaluated by the morphology and the expression of genes belonging to the three embryonic germ layers and the germ cell lineage. RESULTS: Three hESC lines were established, and they grew at similar speed in both media (serum-containing or serum-free), but hESC cultured in serum-containing medium yielded significantly higher percentages of morphologically good colonies and cells expressing Oct-4. These cell lines differentiated spontaneously in vitro into cells expressing markers belonging to all three embryonic germ layers and germ cell markers, including c-Kit, STELLA, VASA and growth differentiation factor 9 (GDF9), in directly adherent culture. CONCLUSIONS: Three hESC lines with Taiwanese ancestry have been established, and they retain the in vitro differentiation potential with or without embryoid body (EB) formation. The data support that hESC may be capable of differentiation into germ cells although further confirmation is needed. It is also suggested that strategies such as stepwise adaptation will be needed before implementing a serum-free culture condition for hESC lines that have previously been derived in a medium containing serum.

Apoptosis↗
PubMed2000

Growth differentiation factor-9 stimulates proliferation but suppresses the follicle-stimulating hormone-induced differentiation of cultured granulosa cells from small antral and preovulatory rat follicles.

In addition to pituitary gonadotropins and paracrine factors, ovarian follicle development is also modulated by oocyte factors capable of stimulating granulosa cell proliferation but suppressing their differentiation. The nature of these oocyte factors is unclear. Because growth differentiation factor-9 (GDF-9) enhanced preantral follicle growth and was detected in the oocytes of early antral and preovulatory follicles, we hypothesized that this oocyte hormone could regulate the proliferation and differentiation of granulosa cells from these advanced follicles. Treatment with recombinant GDF-9, but not FSH, stimulated thymidine incorporation into cultured granulosa cells from both early antral and preovulatory follicles, accompanied by increases in granulosa cell number. Although GDF-9 treatment alone stimulated basal steroidogenesis in granulosa cells, cotreatment with GDF-9 suppressed FSH-stimulated progesterone and estradiol production. In addition, GDF-9 cotreatment attentuated FSH-induced LH receptor formation. The inhibitory effects of GDF-9 on FSH-induced granulosa cell differentiation were accompanied by decreases in the FSH-induced cAMP production. These data suggested that GDF-9 is a proliferation factor for granulosa cells from early antral and preovulatory follicles but suppresses FSH-induced differentiation of the same cells. Thus, oocyte-derived GDF-9 could account, at least partially, for the oocyte factor(s) previously reported to control cumulus and granulosa cell differentiation.

Animals↗
PubMed1980

Induction of morphological and functional differentiation of human promyelocytic leukemia cells (HL-60) by componuds which induce differentiation of murine leukemia cells.

Various compounds active in promoting in vitro differentiation of certain murine leukemia cell lines (Friend erythroleukemia cells and mouse myeloid leukemia cells) were tested for their capacity to induce differentiation of HL-60 cells, a human promyelocytic leukemia cell line capable of terminally differentiating in vitro to functionally mature granulocytes. Polar planar compounds including hexamethylene bisacetamide (HMBA), certain purines (particularly hypoxanthine), and actinomycin-D induced morphological and functional (as assessed by the capacity to reduce NBT dye) differentiation of HL-60. In contrast, hemin, ouabain, prostaglandin E1, X-irradiation, dexamethasone and some other anti-leukemic chemotherapeutic agents induced little if any significant differentiation of HL-60 cells. These results, together with previous observations with murine leukemia cells, suggest that the human HL-60 cells share common cellular target sites for the inducing action of polar planar compounds, hypoxanthine and actinomycin-D with some murine leukemic cells. In contrast, hemin, ouabain and prostaglandin E1 may be specific for mouse erythroleukemia cells, while X-irradiation and chemotherapeutic agents induce differentiation of both types (erythroid and myeloid) of mouse leukemic cells, but have little effect on HL-60 cells.

Animals↗
PubMed1984

Control of in vivo differentiation of myeloid leukemic cells. IV. Inhibition of leukemia development by myeloid differentiation-inducing protein.

It is shown that a 5-day schedule of two injections per day of the myeloid differentiation-inducing protein MGI-2 inhibited the in vivo development of leukemia in SL and SJL/J mice with different syngeneic MGI+D+ clones of myeloid leukemic cells. With this schedule of treatment high levels of MGI-2 were maintained in the serum for long periods. In contrast to these results with MGI-2, the same schedule of injections of the myeloid growth-inducing protein MGI-I did not affect the in vivo development of leukemia in mice with MGI+D+ myeloid leukemic cells, but stimulated normal myelopoiesis in the bone marrow. Different forms of MGI-I including MGI-IM and MGI-IG had different serum half-lives, and the form of MGI-I with the shortest serum half-life showed the smallest in vivo effect on normal myelopoiesis. MGI-2 injections did not inhibit the in vivo development of differentiation-defective WEHI-3B myelomonocytic leukemic cells or YAC lymphoma cells. The results indicate that the in vivo inhibitory effect of MGI-2 on the development of myeloid leukemia correlated with its differentiation-inducing potential on the leukemic cells. It is concluded that this approach of inhibiting leukemia development by inducing differentiation should also be applied to human leukemic patients, whose cells have been shown to be inducible for differentiation in culture by human MGI-2 or by other differentiation-inducing compounds.

Animals↗
PubMed1990

Differentiation-inducing and growth-inhibitory activities of erythroid differentiation factor (EDF/activin A) toward mouse erythroleukemic cells in vivo.

The in vivo differentiation-inducing activity of a purified human erythroid differentiation factor (EDF) toward mouse erythroleukemic cells (MEL cells) was examined. BDF1 mice with diffusion chambers implanted in the peritoneal cavity were treated with continuous i.p. administration of EDF. MEL cells within a diffusion chamber differentiated into hemoglobin-positive cells when treated with EDF, the percentage of the positive cells being 32.3 +/- 28.3 on day 5 as compared to 0.2 +/- 0.3 in the controls. The anti-tumor activity of EDF was also examined in a nude mouse MEL solid tumor model. Daily intra-tumor treatment with EDF for 10 days resulted in 73% suppression of tumor growth on day 25. A histological study revealed that EDF-treated solid tumor cells became hemoglobin-positive, indicating the anti-tumor activity of EDF through induction of differentiation in vivo. EDF could induce in vitro the differentiation of human erythroleukemic cell lines K562 and HEL, as well as the murine cell line. These results indicate the possibility of differentiation therapy for erythroleukemia using EDF.

Activins↗
PubMed2002

Differential expression of a WD protein during squamous differentiation of tracheal epithelial cells.

The lining of the trachea consists of a pseudostratified, mucociliary epithelium that under a variety of conditions, such as vitamin A deficiency, toxic and mechanical injury, becomes a stratified squamous epithelium. Several in vitro cell culture models have been established to study the process of differentiation of airway epithelium. Such studies have indicated that mucosecretory differentiation of tracheal epithelial cells can be modulated by substratum. This study was undertaken to understand molecular mechanisms of squamous differentiation in tracheal epithelia. Primary cultured tracheal cells grown on uncoated filters were differentiated to single layer of squamous cells, whereas cells were grown as stratified columnar cells on collagen-I coated filters. The responses to secretagogues were altered according to culture conditions. DD-PCR revealed that FAK and a WD protein expression was increased in squamous tracheal epithelia. Expression of a WD protein was changed by the treatment of retinoic acid in various epithelial cells. These results indicated that squamous differentiation of tracheal cells changes the expression of a variety of genes, and that the experimental model for this study can be employed to study molecular mechanisms of squamous differentiation in airway epithelial cells.

Animals↗
PubMed1975

Control of normal differentiation of myeloid leukemic cells. VIII. Induction of differentiation to mature granulocytes in mass culture.

There are three types of myeloid leukemic cells, IR+D, IR+D- and IR-D-. IR+D+ cells were induced to differentiate to granulocytes in mass culture in liquid medium by conditioned medium (CM) from cultures of lungs from mice injected with endotoxin. About 90% of the leukemic cells were induced to differentiate, 50% to mature granulocytes and 40% to intermediate stages. An efficient induction of granulocyte differentiation was also obtained with CM from primary cultures of rat embryo or human spleen and there was a lower activity with CM from various other sources. IR+D- cells were induced to differentiate to about 20% cells with intermediate stages but not to mature granulocytes; IR-D- cells could not be induced to differentiate to intermediate or mature stages. IR+D+ cells were induced to form intermediate stages of granulocyte differentiation, to phagocytose and to attach to the surface of the Petri dish, three days after incubation with CM. Optimum induction of mature granulocytes required six more days incubation with CM. Mature granulocytes induced from leukemic cells showed cytochemical properties and a morphology in the electron microscope similar to that of normal mature granulocytes. These induced granulocytes did not form leukemiac in animals or colonies in agar. The granulocytes induced from the myeloid leukemic cells, therefore, behaved like normal mature granulocytes.

Acid Phosphatase↗
PubMed1976

Control of normal differentiation of myeloid leukemic cells. XI. Induction of a specific requirement for cell viability and growth during the differentiation of myeloid leukemic cells.

Normal hematopoetic cells require the presence of a protein (MGI) in the appropriate conditioned medium (CM) for cell viability and growth and for differentiation to mature macrophages and granulocytes. Clones of myeloid leukemic cells have been established in culture (D+ clones) which require CM with this protein for differentiation, but not for cell viability and growth. It has been shown that these leukemic cells can be induced by CM to again require, like normal cells, the presence of CM for cell viability and growth. Induction of this requirement, which will be referred to as RVG, occurred before the D+ cells differentiated to mature granulocytes. Clones of myeloid leukemic cells (D- clones) that could not be induced to differentiate to mature cells, did not show the induction of RVG. The steroid hormones prednisolone and dexamethasone can induce some, but not all the changes associated with differentiation of D+ cells, Incubation with these steroids did not result in the induction of a requirement for these steroids for cell growth and viability. Studies with CM from different sources have shown, that all batches that induced RVG also induced differentiation of D+ cells and that both activities were inhibited after treating the CM with trypsin. It is suggested that the same protein (MGI) may be involved in both activities. Incubation of D+ cells with CM resulted in an increase in agglutinability by concanavalin A and this increase was maintained even in the absence of CM. This suggests, that the induction of RVG in D+ myeloid leukemic cells is associated with a change in the cell surface membrane.

Agglutination↗
PubMed2006

Regulator of G-protein signaling (RGS) proteins differentially control chondrocyte differentiation.

Control of chondrocyte differentiation is attained, in part, through G-protein signaling, but the functions of the RGS family of genes, well known to control G-protein signaling at the Galpha subunit, have not been studied extensively in chondrogenesis. Recently, we have identified the Rgs2 gene as a regulator of chondrocyte differentiation. Here we extend these studies to additional Rgs genes. We demonstrate that the Rgs4, Rgs5, Rgs7, and Rgs10 genes are differentially regulated during chondrogenic differentiation in vitro and in vivo. To investigate the roles of RGS proteins during cartilage development, we overexpressed RGS4, RGS5, RGS7, and RGS10 in the chondrogenic cell line ATDC5. We found unique and overlapping effects of individual Rgs genes on numerous parameters of chondrocyte differentiation. In particular, RGS5, RGS7, and RGS10 promote and RGS4 inhibits chondrogenic differentiation. The identification of Rgs genes as novel regulators of chondrogenesis will contribute to a better understanding of both normal cartilage development and the etiology of chondrodysplasias and osteoarthritis.

Animals↗
PubMed1994

3,5,3'-Triiodo-L-thyronine induces cardiac myocyte differentiation but not neuronal differentiation in P19 teratocarcinoma cells in a dose dependent manner.

P19 teratocarcinoma cells differentiate into neurons or muscle when treated with varying doses of retinoic acid, dimethylsulfoxide, thioguanine or butyrate. We induced cardiac differentiation in P19 cells by treating them with 3,5,3'-Triiodo-L-Thyronine (T3). P19 cells received doses of T3 ranging from 30 pM to 300 nM. The beating colonies were counted, and a dose response curve showed that the optimal concentration of T3 was 30 nM. The colonies beat rhythmically for 4-6 weeks, and the cardiac myocytes showed clearly evident cardiac-specific organelles such as nexuses and atrial granules. No evidence of neuronal or skeletal muscle differentiation was seen with any of the concentrations of T3 used. Reverse transcription-polymerase chain reaction showed these cells to express the cardiac ventricular specific marker myosin light chain 2V. T3 is capable of inducing P19 cells to differentiate, in a dose related manner, into spontaneously beating cardiac myocytes identified as such on the basis of ultrastructural criteria. The induction of differentiation is accompanied by expression of cardiac-specific genes. These findings suggest that perhaps genes bearing thyroid response elements in their promoter regions play an important role in the cardiac differentiation induced by T3 in P19 teratocarcinoma cells.

Animals↗
PubMed1994

Regulated expression of Wnt family members during neuroectodermal differentiation of P19 embryonal carcinoma cells: overexpression of Wnt-1 perturbs normal differentiation-specific properties.

The P19 embryonal carcinoma (EC) cell line represents a useful model system for analysis of neural development and differentiation processes that are difficult to study in mammalian embryos. Since many members of the Wnt family of signaling molecules are expressed in the developing as well as adult nervous system, we have examined expression of these genes in P19 cells. Analysis of the mRNA accumulation profiles for Wnt genes during retinoic acid (RA)-induced neural differentiation of P19 cells showed that nine Wnt family members were expressed in a regulated manner during this process. Most were induced by RA treatment, and some were also expressed in undifferentiated P19 cells. Since Wnt-1 is not expressed in undifferentiated P19 cells but is induced during neuroectodermal differentiation we have generated P19 cell lines that overexpress Wnt-1 in the absence of RA treatment, in order to address the role of Wnt-1 in P19 differentiation. In the presence of ectopic Wnt-1, expression of other endogenous Wnt genes, which serve as early differentiation markers in this system, were induced without RA, which is normally required for appearance of these gene products. Furthermore, ectopic expression of Wnt-1 resulted in a loss of SSEA-1 antigen expression, a marker of undifferentiated P19 cells. Similarly to the parental cell line, addition of RA to P19 cells overexpressing Wnt-1 induced the neuroectodermal pathway, but expression of cell type-specific markers such as MASH-1, HNK-1, and GAP-43 was diminished and the morphology of neuronal processes, stained with an antibody to neurofilament, was abnormal. These data suggest that Wnt-1 itself can induce some aspects of early neuroectodermal differentiation and, furthermore, that the correct timing of Wnt-1 expression is necessary for proper RA-induced expression of the neural phenotype.

Animals↗
PubMed1995

Ricin toxicity and intracellular routing in tumoral HT-29 cells. II. Differential ricin toxicity from the apical and basolateral surfaces of differentiated HT-29 cells.

We previously showed that ricin, a toxin commonly used in the construction of immunotoxins, was more toxic to undifferentiated than to differentiated HT-29 tumoral cells. This results from differences in the intracellular routings of the toxin. As these studies concerned the entry through the apical pole of differentiated polarized HT-29 cells, we investigated and compared the intracellular routing of ricin from the apical and basolateral membranes of differentiated HT-29 cells and the toxicity of ricin depending on the pole of administration. For this purpose, we developed the culture of polarized HT-29 cells on porous membrane filters and demonstrated that differentiated HT-29 cells can establish a leakproof monolayer. Ricin is 2.5-fold less toxic when it is added at the basolateral than at the apical pole of the cells, which may result from different observations: (1) less ricin is bound at the basolateral membrane than at the apical one, leading to a lesser internalization of the toxin; (2) ricin sorting in the apical and basolateral endocytic compartments of HT-29 cells differs: apically internalized ricin is targeted intracellularly while basolaterally internalized ricin uses mainly the transcytotic pathway; using NH4Cl and monensin, we observed that ricin follows the same pathway from both sides of the cells, namely the endosomal system, to reach the Golgi apparatus from which toxin intoxication occurs; (3) kinetics studies showed that a delay exists before an efficient intoxication by the basolateral pole is observed. The use of monensin at low concentration in order to perturb only the Golgi functions indicated that this delay could account for a different presentation of the toxin toward the membrane of the apical and basolateral endocytic compartments. Together, our results showed that, in differentiated HT-29 cells, if the pathways carrying ricin from the apical and basolateral membranes to the Golgi apparatus appear identical, ricin exerts differentially its toxicity depending upon the surface of administration, i.e., the apical or the basolateral surface of the cells.

Cell Differentiation↗
PubMed2000

Haldane's rule: hybrid sterility affects the heterogametic sex first because sexual differentiation is on the path to species differentiation.

Prevention of recombination is needed to preserve both phenotypic differentiation between species and sexual phenotypic differentiation within species. For species differentiation (speciation), isolating barriers preventing recombination may be pre-zygotic (gamete transfer barriers), or post-zygotic (either a developmental barrier resulting in hybrid inviability, or a chromosomal-pairing barrier resulting in hybrid sterility). The sterility barrier is usually the first to appear and, although often initially only manifest in the heterogametic sex (Haldane's rule), is finally manifest in both sexes. For sexual differentiation, the first and only barrier is chromosomal-pairing, and always applies to the heterogametic sex. For regions of sex chromosomes affecting sexual differentiation there must be something analogous to the process generating the hybrid sterility seen when allied species cross. Explanations for Haldane's rule have generally assumed that the chromosomal-pairing barrier initiating evolutionary divergence into species is due to incompatibilities between gene products ("genic), or sets of gene products ("polygenic), rather than between chromosomes per se ("chromosomal"). However, if chromosomal incompatibilities promoting incipient sexual differentiation could also contribute to the process of incipient speciation, then a step towards speciation would have been taken in the heterogametic sex. Thus, incipient speciation, manifest as hybrid sterility when "varieties" are crossed, would appear at the earliest stage in the heterogametic sex, even in genera with homomorphic sex chromosomes (Haldane's rule for hybrid sterility). In contrast, it has been proposed that Haldane's rule for hybrid inviability needs differences in dosage compensation, so could not apply to genera with homomorphic sex chromosomes.

Animals↗
PubMed1996

The transcription factors SCIP and Krox-20 mark distinct stages and cell fates in Schwann cell differentiation.

We have studied the transcription factors SCIP and Krox-20 in differentiating Schwann cells-during normal development, in experimentally induced degenerating and regenerating peripheral nerves, and in cell culture-and have compared the expression of these regulators to a battery of genes that mark distinct stages in Schwann cell differentiation. In the myelinating Schwann cell lineage, we find that SCIP is initially induced by contact with axons and first appears near the last round of cell division in immature cells. This expression is transient--it is maximal in "promyelinating" cells and is then extinguished as Schwann cells overtly differentiate and myelinate axons. In contrast, Krox-20 appears in cells 24-36 h after they become SCIP+ and continues to be expressed in mature myelinating cells. These differences in regulation are seen in normal development, in regenerating nerves following nerve crush, and in cultured Schwann cells stimulated to adopt a myelination phenotype by elevation of intracellular cyclic AMP. Importantly, transient SCIP expression is also observed in the nonmyelinating Schwann cell lineage, but Krox-20 expression is not. Together with the myelination phenotypes exhibited by SCIP and Krox-20 mutant mice, these results suggest that SCIP preferentially acts during the predifferentiated phases of Schwann cell development, while in contrast, Krox-20 is associated with the later commitment to myelination and may therefore function as a direct transactivator of myelination genes.

Animals↗
PubMed1998

Changes in epidermal growth factor receptor expression and competence to generate glia regulate timing and choice of differentiation in the retina.

Previous studies demonstrated that the level of epidermal growth factor receptors (EGF-Rs) expressed by progenitor cells in the newborn (P0) rat retina was limiting for the generation of Muller glial cells but not for proliferation. To determine whether EGF-R signaling biases cells to generate a specific cell type or regulates more general processes during progenitor cell development, we have introduced extra copies of the EGF-R into progenitor cells at earlier stages (E15 and E18), when different cell types are produced. We show that progenitor cells in early embryonic retina (E15) normally express lower levels of EGF-Rs than progenitor cells in later retina (E18 and P0). Whereas lower levels of stimulation of endogenous and virally transduced EGF-Rs enhanced proliferation, higher levels reduced proliferation, resulting in premature differentiation. At E15, very few EGF-R-Infected progenitor cells differentiated prematurely into Muller glial cells, unlike E18 and P0 cells, even when they were exposed to an older retinal environment. Higher levels of EGF-R-mediated signaling alone therefore do not specify a glial fate, indicating that competence to generate glia is temporally regulated by additional mechanisms. The differences in EGF-R expression observed among retinal progenitor cells at distinct developmental stages may instead help to define signaling thresholds which delay or accelerate their differentiation.

3T3 Cells↗
PubMed2005

Differentiation of acute and chronic myeloid leukemic blasts into the dendritic cell lineage: analysis of various differentiation-inducing signals.

PURPOSE: Ex vivo differentiation of myeloid leukemic blasts into dendritic cells (DCs) holds significant promise for use as cellular vaccines, as they may present a constellation of endogenously expressed known and unknown leukemia antigens to the immune system. Although variety of stimuli can drive leukemia --> DC differentiation in vitro, these blast-derived DCs typically have aberrant characteristics compared with DCs generated from normal progenitors by the same stimuli. It is not clear whether this is due to underlying leukemogenic mechanisms (e.g., specific oncogenes), genetic defects, stage of maturation arrest, defects in cytokine receptor expression or signal transduction pathways, or whether different stimuli themselves induce qualitatively dissimilar DC differentiation. METHODS: To assess what factors may contribute to aberrant leukemic blast --> DC differentiation, we have examined how the same leukemic blasts (AML and CML) respond to different DC differentiation signals--including extracellular (the cytokine combination GM-CSF + TNF-alpha + IL-4) and intracellular (the protein kinase C agonist PMA, the calcium ionophore A23187, and the combination of PMA plus A23187) stimuli. RESULTS: We have found that the same leukemic blasts will develop qualitatively different sets of DC characteristics in response to differing stimuli, although no stimuli consistently induced all of the characteristic DC features. There were no clear differences in the responses relative to specific oncogene expression or stage of maturation arrest (AML vs CML). Signal transduction agonists that bypassed membrane receptors/proximal signaling (in particular, the combination of PMA and A23187) consistently induced the greatest capability to activate T cells. Interestingly, this ability did not clearly correlate with expression of MHC/costimulatory ligands. CONCLUSIONS: Our findings suggest that signal transduction may play an important role in the aberrant DC differentiation of leukemic blasts, and demonstrate that direct activation of PKC together with intracellular calcium signaling may be an effective method for generating immunostimulatory leukemia-derived DCs.

Antigens, Surface↗
PubMed2001

Requirement of thrombopoietin-induced activation of ERK for megakaryocyte differentiation and of p38 for erythroid differentiation.

Thrombopoietin (TPO) plays a critical role not only in proliferation and differentiation of megakaryocytes but also in erythroid differentiation. We have investigated whether the different pathway of mitogen-activated protein kinase (MAPK) after TPO stimulation may discriminate megakaryocyte and erythroid differentiation. In this study, we have used human CD34+ hematopoietic progenitor cells (HPCs) from cord blood (CB) in serum-free liquid culture supplemented with TPO, to compare the respective effects of specific inhibitors of MAPK kinase (MEK) (PD98059) and p38 MAP kinase (p38) (SB203580) on megakaryocyte and erythroid development. PD98059, but not SB203580, significantly suppressed TPO-induced megakaryocyte differentiation when examined by the expression of CD41 and polyploidy assay. In the presence of SB203580, CD34+/CD36+ erythroid progenitors clearly decreased, whereas they increased when cultured with PD98059. These results indicate that activation of extracellular-signal-regulated kinase (ERK) is required for TPO-induced megakaryocyte differentiation and that p38 is required for TPO-induced erythroid differentiation.

Antigens, CD34↗