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1 Department of Cell Differentiation, Institute of Molecular Embryology and Genetics, Kumamoto University, Kumamoto, Japan
2 Global COE ‘Cell Fate Regulation Research and Education Unit’, Kumamoto University, Kumamoto, Japan
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Abstract |
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Introduction |
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After TPO binds to Mpl, the latter is phosphorylated by Janus kinases (JAKs), leading to activation of downstream signaling factors including signal transducer and activator of transcriptions (STAT; Kaushansky 1999). Previous studies showed that Mpl signaling activates Tyk2 and JAK2 among JAKs, and STAT3 and STAT5 among STATs (Sattler et al. 1995; Rodriguez-Linares & Watson 1996; Drachman et al. 1999). STAT5, but not STAT3, compensates for TPO/Mpl signal in BM HSC self-renewal (Kato et al. 2005), but little is known about which JAK and STAT function in MPPs of embryos in TPO/Mpl signaling.
In this study, utilizing liquid cultures, we clearly showed that MPPs expressing Mpl in the YS and the embryo proper (EP) proliferated by TPO/Mpl activation in the presence of stem cell factor (SCF). However, in the absence of SCF, TPO maintained MPPs from the YS and EP. In contrast, MPPs of the BM were maintained even under TPO and SCF. Proliferation of MPPs of the FL was at a level intermediate between embryo and BM. These results suggest that MPPs can be divided into two types, early embryonic and adult MPPs. Moreover, we show that the proliferative signal in early embryonic MPPs is mediated via JAK2-STAT5.
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Results |
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We first examined Mpl expression in developing hematopoietic tissues by using Mpl antibody AMM2. Mpl was expressed in all the hematopoietic tissues that we examined: YS and EP of E9.5 and E10.5, E14.5 fetal liver (FL) and adult BM (Fig. 1a). In particular, Mpl was highly expressed in the c-Kit+ population. Next, to investigate multilineage hematopoietic differentiation ability of the Mpl-expressing cells, we purified c-Kit+Mpl– and c-Kit+Mpl+ cells from the hematopoietic tissues and used them in a colony assay using IL3, EPO and SCF. The c-Kit+Mpl+ cells formed CFU-Mix colonies but the c-Kit+Mpl– cells did not (Fig. 1b), suggesting that the Mpl-expressing cells in the c-Kit+ fraction possessed the ability to generate multilineage colonies. In this colony assay, we found that the c-Kit+ Mpl+ cells could also efficiently generate other types of hematopoietic colonies including CFU-GM, CFU-M, CFU-G and BFU-E colonies, although only a few of them were formed from the c-Kit+Mpl– cells (data not shown). Thus, we concluded that MPPs in the embryonic hematopoietic tissues express Mpl.
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We next investigated effects of TPO on the MPPs of embryos. Because the antibody against Mpl, AMM2, inhibited the TPO signal (Yoshihara et al. 2007), c-Kit+ cells, instead of the c-Kit+ Mpl+cells, were sorted from YS and EP at E9.5. Sorted c-Kit+ cells were divided into two groups (Fig. 2a). The cells in the first group were immediately subjected to the colony assay with SCF, IL-3 and EPO; whereas those of the second group were cultured in a medium in the presence or absence of TPO and SCF for 7 days. Then, the cultured cells were counted and subjected to hematopoietic colony assay. In the colony assay, the numbers of CFU-Mix per culture from the sorted c-Kit+cells in the first group and in the second group are defined as ‘input’ and ‘output,’ respectively. The ratio of output/input of CFU-Mix numbers above 1 indicates an increase in the number of MPPs after the cells were cultured with or without cytokines. As shown in Fig. 2(b), the number of floating cells recovered from the cultures of 2000 c-Kit+ cells in E9.5 YS was increased by SCF. TPO alone barely increased their number, whereas TPO and SCF added together greatly enhanced the number of floating cells. No hematopoietic cells survived without any cytokine present in the medium. The ratio of output/input of CFU-Mix showed that, when TPO was added to the cultures, the number of CFU-Mix was maintained (Fig. 2c). However, TPO and SCF present together greatly enhanced the number of MPPs (sevenfold increase for YS cultures and 6.3-fold for EP ones). SCF alone did not even maintain CFU-Mix numbers. Therefore, TPO not only maintained the number of MPP in the embryo but also expanded them in the presence of SCF. Cytospin preparations from CFU-Mix of input and output were not significantly different in terms of multipotency of CFU-Mix colonies (Fig. 2d). This was confirmed by counting hematopoietic cell types in these preparations (Fig. 2e). Consequently, TPO maintains MPPs in embryos and promotes them to proliferate cooperatively with SCF without loss of the ability for multipotent differentiation.
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CD41+ c-Kit+ cells generate multilineage hematopoietic colonies and proliferate in response to TPO and SCF
TPO augmented CFU-Mix colony formation from the cells from YS and the whole embryo in a methylcellose colony assay (Xie et al. 2003). In that study, the cultured cells also contained early progenitor cells such as mesoderm cells, apart from committed hematopoietic progenitor cells. So we investigated the effect of TPO on MPPs that had been further purified from c-Kit+ cells. Since CD41 is one of the earliest hematopoietic markers in the embryo (Emambokus & Frampton 2003; Ferkowicz et al. 2003; Hashimoto et al. 2007), CD41 expression was examined on Mpl+ cells of the E9.5 and E10.5 embryos, E14.5 FL and BM. In E9.5 embryos, CD41 expression well correlated with Mpl expression, although a few Mpl+CD41– cells were also present (Fig. 3a). Nearly all Mpl+ cells from E10.5 embryos expressed CD41. In contrast, CD41 expression decreased in FL and almost diminished in the adult BM. These results indicated that CD41 expression could be utilized as a substitute for Mpl expression at least in the c-Kit+ population from YS or EP at E10.5. After the liquid cultures with TPO and SCF, CFU-Mix from the cultured c-Kit+CD41+ cells (Fig. 3b) greatly increased (Table 1). Thus, within the c-Kit+ population, a subpopulation of c-Kit+CD41+ cells, which are committed to the hematopoietic cell lineage, contains MPPs responsible for proliferation by TPO and SCF.
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Mpl transduces TPO signal in the cell, some of which transduction is mediated by JAK2 (Miyakawa et al. 1996). However, it remains unclear whether JAK2 mediates the TPO/Mpl signal in embryonic progenitors. To examine the role of JAK2 in TPO/Mpl signaling in embryonic progenitor, we cultured c-Kit+CD41+cells in a medium with TPO and SCF in the absence or presence of a JAK2 inhibitor, AG490. Whereas addition of AG490 did not inhibit the production of floating cells from c-Kit+CD41+ cells (Fig. 4a), the ratio of output/input of CFU-Mix numbers was repressed by AG490 (Fig. 4b). These data indicate that TPO/Mpl signaling is mainly transduced via JAK2 in embryonic MPPs.
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Discussion |
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TPO/Mpl signaling led to proliferation of MPPs of YS and EP; however, the proliferative activity significantly changed depending on developmental stages. Frequency of Mpl+ cells in the c-Kit+ population at E9.5 were similar to that at E10.5 (Fig. 1), although the proliferation activity of c-Kit+ cells from EP at E10.5 increased up to twofold, compared to that at E9.5. We showed that MPP activity is confined in the Mpl+ population. Therefore, changes in proliferative activity of MPPs can not be expressed as a function of the frequency of Mpl+ cells in the c-Kit+ population, rather be considered as a function of genetic program inherent in the Mpl+ cells. In contrast to the proliferative effects of TPO/Mpl signaling on MPPs of YS and EP prior to E10.5, MPPs of the BM were only maintained by the TPO/Mpl signaling (Fig. 2). Although a proliferative effect on MPPs of the BM was reported in the previous studies using in vitro cultures (Ema et al. 2000; Kato et al. 2005), it was not as high as the one we observed for YS and EP. Thus, both in vitro studies suggest that MPPs of the BM are less potent than embryonic MPPs in terms of proliferation. In addition, activation of TPO/Mpl signaling increased the number of quiescent BM HSCs in adult mice (Qian et al. 2007; Yoshihara et al. 2007). Interestingly, the proliferative activity of MPPs of the FL was lower than that of MPPs from YS and EP but higher than that of MPPs from BM (Fig. 2f). Therefore, we consider that there are two types of MPPs in the mouse: an early embryonic type and an adult type (Fig. 5). The early embryonic type of MPP, existing in the YS and EP, has the ability to proliferate actively in the presence of TPO and SCF. This type of MPP may contribute to expanding the pool of MPPs in the mouse embryo. On the other hand, the adult type of MPPs in the BM may be suppressed in terms of TPO/Mpl-induced proliferation via a cell-intrinsic factor that is not expressed in the early embryonic type. In the FL, the MPP population could be a mixture of both types of MPPs, thereby indicating the value of the proliferative activity between the early embryonic type and the adult type. Most of the MPPs might be the early embryonic type at early stage of FL, whereas MPP population become gradually occupied with the adult type at later developmental age. Thus, in the mouse embryo, the early embryonic MPPs are likely to be replaced by the adult-type MPPs. However, it remains to be elucidated whether the adult MPPs are directly derived from the early embryonic MPPs, or two types of MPP populations possess different developmental origins.
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Among STATs, STAT3 and STAT5 were reported to be activated by TPO (Mu et al. 1995; Miyakawa et al. 1996). In the present study, we showed that constitutively active STAT5 caused the proliferation of MPPs, even without TPO, in the presence of SCF (Table 2). In adult HSCs, constitutively active STAT5, but not STAT3, contributed to self-renewal of HSCs in in vitro cultures (Kato et al. 2005). Thus, STAT5 appears to transduce the TPO/Mpl signal in both embryo and adult MPPs. It is well known that STAT5 induces the expression of Bcl-XL, an anti-apoptotic protein (Socolovsky et al. 1999). However, STAT5A/B–/– mice were not rescued from their hematopoietic defects by bcl-2 expression (Snow et al. 2003). Moreover, TPO–/– mice intercrossed with bcl2-transgenic mice under control of the H2K promoter failed to recover the anti-apoptotic effect due to the lack of TPO/Mpl signaling (Qian et al. 2007). Therefore, STAT5, but probably not STAT3, could send not only survival signals but also other signals via TPO/Mpl, one of which is the proliferative signal in early embryonic MPPs.
Cytokine signaling is regulated in their intensity and duration by negative feedback pathways (Valentino & Pierre 2006). Indeed, the TPO-induced increase in the number of quiescent HSCs in the BM disappeared on day 6 when TPO was injected daily into mice (Yoshihara et al. 2007), indicating that TPO/Mpl signaling is also regulated by negative-feedback pathways. However, the introduction of CA-STAT5 can induce downstream signals for a long time as shown in this report, escaping some of negative feedback signals induced by the activation of TPO/Mpl signaling. Hence, the introduction of CA-STAT5 into BM HSCs also induced them to proliferate (Kato et al. 2005). The G-CSF receptor regulates the proliferation and survival of Ba/F3 cells by regulating the intensity and duration of STAT5 activation (Dong et al. 1998). Recently, the level of STAT5 expression was reported to influence the balance between self-renewal and differentiation of hematopoietic progenitors (Wierenga et al. 2008). Therefore, the proliferative activity of early embryonic-type MPPs induced by TPO and SCF may be ascribed to prolonged or strong activation of STAT5. In contrast, in adult MPPs, STAT5 activation induced by TPO might be quickly inhibited by negative feedback signals, so that MPPs are probably maintained or weakly proliferate by TPO/Mpl activation. In addition to STAT5, TPO/Mpl is known to be affected by other intracellular proteins such as PI3K and MAPK (Millot et al. 2002). Consequently, the relative contribution of individual signals, including negative feedback signals, in MPPs could make a difference in the response of MPPs to TPO/Mpl activation between the embryo and adult. This mechanism could contribute to the regulation of MPP numbers, depending on the site and the age, during hematopoietic development in the mouse.
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Experimental procedures |
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Pregnant ICR mice were purchased from Japan SLC (Shizuoka, Japan). Embryonic development was estimated by defining the time of vaginal plug observation as E0.5. At specified times (E9.5, E10.5, E14.5), mice were sacrificed. Yolk sac and embryonic body were separated from the conceptuses removed from the mice as previously described (Fraser et al. 2002). This protocol was approved by the institutional review board of Kumamoto University. The yolk sac were separated from several embryos and pooled, and the embryonic trunk lower than the heart level of embryos was also pooled. The omphalomesenteric artery and umbilical artery were included in the yolk sac tissues. The pooled yolk sac and lower trunk tissues were dissociated in Dispase II (Roche Diagnostics, Basel, Switzerland) and Cell Dissociation Buffer (Invitrogen, Carlsbad, CA) as previously described (Ogawa et al. 1999). The cells were harvested, blocked with normal mouse serum, and washed with Hank's balanced salt solution (Invitrogen) containing 1% BSA (Sigma-Aldrich, St Louis, MO) prior to cell staining with mAbs.
Antibodies
Monoclonal antibodies against c-Kit (ACK4) and CD41 (MWReg30) were purified from hybridoma culture supernatants by using CELLine (BD Biosciences, San Jose, CA). The mAbs were labeled with allophycocyanin (ProZyme, San Leandro, CA) or biotin (Pierce, Rockford, IL) by using standard procedures. Fluorescently labeled mAb against CD41 and streptavidin-PE were purchased from BD Biosciences and eBioscience (San Diego, CA), respectively. Mpl monoclonal antibody (AMM2) was kindly provided by Kirin Brewery (Tokyo, Japan).
Hematopoietic cytokines and inhibitors
Recombinant murine interleukin 3 (IL-3) was purchased from PeproTech (Rocky Hill, NJ). Recombinant human erythropoietin (EPO) and thrombopoitin (TPO) were provided by Kirin Brewery. A culture supernatant of a cell line that produces murine SCF was used for cell cultures and colony assays. The JAK2 inhibitor AG490 was purchased from Calbiochem (La Jolla, CA). AG490 was dissolved in dimethyl sulfoxide (DMSO) and used at a final concentration of 5 µM (final DMSO concentration: 0.05%).
Flow cytometry analysis and cell sorting
Flow cytometry analysis and cell sorting were carried out with a FACSAria (BD Biosciences). Acquired data were analyzed and plotted by using FlowJo (Tree Star, Ashland, OR).
Liquid culture
Cells (2000 cells) were added to 6-well culture dishes (BD Biosciences) and cultured for 7 days with or without 2% SCF supernatant and 100 ng/mL TPO in 3 mL medium (StemPro®-34 SFM; Invitrogen) supplemented with 2 mM L-glutamine and 0.5 µM 2-mercaptoethanol. Fresh medium (1 mL) was added on day 3 of the culture.
Methylcellulose colony assay
Sorted cells were plated in triplicate (2500 cells/well) in semisolid medium consisting of 
-MEM, 10% fetal calf serum (FCS; Japan Bioserum, Hiroshima, Japan), 0.5 µM mol/L 2-mercaptoethanol, 1.2% methylcellulose (Muromachi Technos, Tokyo, Japan), 2% SCF supernatant, 20 ng/mL IL-3, and 2 IU/mL EPO. Hematopoietic colonies were counted on day 10 for CFU-Mix. To investigate alteration of the ability to form CFU-Mix by the liquid cultures, CFU-Mix numbers were compared before and after the culture. CFU-Mix numbers before the liquid culture was defined as ‘input’. CFU-Mix numbers from the cells after the culture for 7 days were indicated as ‘output’. The ratio of output per input shows the increase of CFU-Mix after the culture period. Cytospin preparations of CFU-Mix were stained with May–Gruenwald Giemsa solution for morphological examination of colonies.
Retroviral infection
Constitutively active mouse STAT5 (CA-STAT5) inserted into pMX-IRES-EGFP (pMX-IRES-EGFP/CA-STAT5), a bicistronic retroviral vector, was kindly provided by Dr Toshio Kitamura (Ariyoshi et al. 2000). To obtain retrovirus with CA-STAT5, we transfected PlatE packaging cells maintained in DMEM supplemented with 10% FCS with the above retroviral constructs by using Lipofectamine (Invitrogen). The medium was changed 1 day after the transfection; and retroviruses were harvested 48 h after the transfection, as previously described (Morita et al. 2000; Kitamura et al. 2003). Sorted cells were infected with the retrovirus by using RetroNectin (Takara, Shiga, Japan) according to the manufacturer's recommendations. Briefly, retrovirus supernatants harboring pMX-IRES-EGFP/CA-STAT5 or an empty vector were added to wells precoated with RetroNectin, and centrifugation was carried out at 1000 g at 4 °C for 20 min, after which the wells were washed with PBS(–). Then, sorted c-Kit+CD41+ cells (20 000 cells) in StemPro-34 medium supplemented with 2% SCF and 100 ng/mL TPO were added to the wells, after which incubation was carried out for 48 h (experiment 1 in Table 2). To improve infection efficiency, the virus supernatant was added to the medium in the retrovirus-coated wells; and the medium were renewed to virus-free medium the next day (experiments 2 and 3 in Table 2).
Statistical analysis
Results of CFU-Mix numbers and floating cell numbers are presented as the mean ± standard error (SEM). Significance of differences was determined by using Student's t-test.
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Acknowledgements |
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Footnotes |
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* Correspondence: hisaka{at}kumamoto-u.ac.jp
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References |
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Received: 12 January 2009
Accepted: 15 April 2009
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