Stem cell factor enhances the survival but not the self-renewal of murine hematopoietic long-term repopulating cells

Cl, Li; Johnson, G. R.

doi:10.1182/blood.v84.2.408.408

Cited by 110 publications

(33 citation statements)

References 22 publications

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“…We found that KL as a single factor is capable of inducing mitogenic activity as well as expanding mature progenitors. However, we also show that KL as a single factor does not promote long-term production of colony-forming cells, a finding which parallels earlier findings with murine cells [7,32,33]. These observations indicate that self-renewal requires additional signals to supplement those from KIT.…”

Section: Discussionsupporting

confidence: 90%

Oncostatin M-Mediated Regulation of KIT-Ligand-Induced Extracellular Signal-Regulated Kinase Signaling Maintains Hematopoietic Repopulating Activity of Lin−CD34+CD133+ Cord Blood Cells

et al. 2008

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We investigated whether KIT signaling was sufficient to maintain human hematopoietic stem cells in culture or whether, as with murine stem cells, signaling through glycoprotein 130 (gp130) is additionally required. Sorted CD34 ؉ CD133؉ (CD33/CD38/CD71) ؊ cells from human umbilical cord blood (UCB) were cultured in the presence of combinations of KIT-ligand (KL) and the gp130 stimulating molecule oncostatin M (OSM). We found that OSM increased KL-induced proliferation, which was accompanied by an expansion in numbers of mature progenitors colonyforming cells (CFC, CAFCw2). More primitive progenitors, CAFCw6 and long-term culture-CFC, were not maintained by KL as a single factor. Although addition of OSM did not improve survival, the KL/OSM combination showed improved maintenance of immature progenitors as well as higher CD34 expression. Similarly, both KL and OSM were required to maintain NOD/SCID-repopulating activity. In experiments to investigate the underlying mechanism, we found that extracellular signal-regulated kinase (ERK) and its downstream target p90 ribosomal S6 kinase were activated by KL and downregulated by the inclusion of OSM during stimulation. The p38 mitogen-activated protein kinase (p38 MAPK) was not modulated by either KL or OSM. Indeed, many of the effects of OSM (increased cell division, maintenance of CFC, and maintenance of high CD34 expression) could be mimicked by using the mitogen-activated protein kinase kinase inhibitor U0126. More importantly, NOD/SCID-repopulating activity was preserved in the KL/ U0126-stimulated cells, but not in cells stimulated with a combination of KL and the p38 MAPK inhibitor SB203580. Our results show that the loss of repopulating activity during KL stimulation is counteracted by OSM through the downregulation of ERK pathway signaling. STEM CELLS

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Section: Discussionsupporting

confidence: 90%

Oncostatin M-Mediated Regulation of KIT-Ligand-Induced Extracellular Signal-Regulated Kinase Signaling Maintains Hematopoietic Repopulating Activity of Lin−CD34+CD133+ Cord Blood Cells

et al. 2008

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“…Stem cell factor (SCF) is a dimeric molecule that exerts its biological functions by binding to and activating the receptor tyrosine kinase KIT [4]. KIT is highly expressed in HSCs and SCF/KIT signaling plays a critical role in HSC maintenance [5][6][7][8][9][10][11][12][13][14]. SCF is an early acting cytokine that promotes HSC proliferation and survival [5][6][7][8].…”

Section: Introductionmentioning

confidence: 99%

PRL2/PTP4A2 Phosphatase Is Important for Hematopoietic Stem Cell Self-Renewal

et al. 2014

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Hematopoietic stem cell (HSC) self-renewal is tightly controlled by cytokines and other signals in the microenvironment. While stem cell factor (SCF) is an early acting cytokine that activates the receptor tyrosine kinase KIT and promotes HSC maintenance, how SCF/KIT signaling is regulated in hematopoietic stem cells is poorly understood. The protein tyrosine phosphatase 4A (PTP4A) family [aka PRL (phosphatase of regenerating liver) phosphatases], consisting of PTP4A1/PRL1, PTP4A2/PRL2 and PTP4A3/PRL3, represents an intriguing group of phosphatases implicated in cell proliferation and tumorigenesis. However, the role of PTP4A in hematopoiesis remains elusive. To define the role of PTP4A in hematopoiesis, we analyzed HSC behavior in Ptp4a2 (Prl2) deficient mice. We found that Ptp4a2 deficiency impairs HSC self-renewal as revealed by serial bone marrow transplantation assays. Moreover, we observed that Ptp4a2 null hematopoietic stem and progenitor cells (HSPCs) are more quiescent and show reduced activation of the AKT and ERK signaling. Importantly, we discovered that the ability of PTP4A2 to enhance HSPC proliferation and activation of AKT and ERK signaling depends on its phosphatase activity. Furthermore, we found that PTP4A2 is important for SCF-mediated HSPC proliferation and loss of Ptp4a2 decreased the ability of oncogenic KIT/D814V mutant in promoting hematopoietic progenitor cell proliferation. Thus, PTP4A2 plays critical roles in regulating HSC self-renewal and mediating SCF/KIT signaling.

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“…The growth of 7TD1 cells required direct contact between the 7TD1 cells and the stromal cells, because growth did not occur on prevention of cell contact by a microporous membrane. It is known that IL-3, GM-CSF, and SCF are stored within the extracellular matrix (ECM) in the BM microenvironment (Gordon et al, 1987;Harrison et al, 1994;Li and Johnson, 1994;Yanai et al, 1995). However, the proliferation of 7TD1 cells was not affected by these cytokines stored within ECM.…”

Section: Discussionmentioning

confidence: 99%

Induction of IL-6 production by bone marrow stromal cells on the adhesion of IL-6-dependent hematopoietic cells

Ogasawara¹,

Tsuji

Hirano³

et al. 1996

J. Cell. Physiol.

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Cellular interactions between hematopoietic cells and stromal cells play crucial roles in the proliferation and differentiation of the hematopoietic cells. Interleukin-6 (IL-6)-dependent 7TD1 cells markedly proliferated without IL-6 when they were co-cultured with hematopoietic-supportive bone marrow stromal cells, HESS-5 cells and HESS-1 CL.3 cells, which can support long-term hematopoiesis in vitro with but not without direct cell contact, cell contact being prevented with a microporous membrane. The production of IL-6 and the amount of IL-6 mRNA in hematopoietic-supportive stromal cells but not 7TD1 cells significantly increased only when the stromal cells were co-cultured in direct contact with 7TD1 cells. Furthermore, the amount of IL-6 mRNA increased according to the number of 7TD1 cells co-cultured. These inductions were not observed on co-culture with a murine myeloid cell line, M1 cells, or on the addition of the co-culture supernatant. These results suggest that 7TD1 cells transmit the signal to stromal cells that enhances IL-6 production by stromal cells via direct cell contact. A certain specific molecule for transduction of the signals may exist on the surface membrane of stromal cells and hematopoietic cells.

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Stem cell factor enhances the survival but not the self-renewal of murine hematopoietic long-term repopulating cells

Cited by 110 publications

References 22 publications

Oncostatin M-Mediated Regulation of KIT-Ligand-Induced Extracellular Signal-Regulated Kinase Signaling Maintains Hematopoietic Repopulating Activity of Lin−CD34+CD133+ Cord Blood Cells

Oncostatin M-Mediated Regulation of KIT-Ligand-Induced Extracellular Signal-Regulated Kinase Signaling Maintains Hematopoietic Repopulating Activity of Lin−CD34+CD133+ Cord Blood Cells

PRL2/PTP4A2 Phosphatase Is Important for Hematopoietic Stem Cell Self-Renewal

Induction of IL-6 production by bone marrow stromal cells on the adhesion of IL-6-dependent hematopoietic cells

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