Differentiation of human T-lymphoid leukemia cells into cells that have a suppressor phenotype is induced by phorbol 12-myristate 13-acetate.

Ryffel, Bernard; Henning, C.B.; Huberman, Eliezer

doi:10.1073/pnas.79.23.7336

Cited by 40 publications

(8 citation statements)

References 29 publications

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“…Treatment of four f-M⌽ cultures with 1,200 units͞ml IL-2 for 4 d induced the cells to acquire a round morphology. This treatment also caused Ϸ90% of the cells to express CD3, an indicator of mature T lymphocytes (13); Ϸ75% of CD3-positive cells also displayed CD8, which characterizes cytotoxic͞suppressor T lymphocytes (21,22). Control cultures contained 3-4% cells that immunostained for CD3 and CD8.…”

Section: Characterization Of Two Monocyte Subsetsmentioning

confidence: 99%

A human peripheral blood monocyte-derived subset acts as pluripotent stem cells

Zhao

Glesne

Huberman

2003

Proc. Natl. Acad. Sci. U.S.A.

430

309

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We have identified, cultured, characterized, and propagated adult pluripotent stem cells (PSC) from a subset of human peripheral blood monocytes. These cells, which in appearance resemble fibroblasts, expand in the presence of macrophage colony-stimulating factor and display monocytic and hematopoietic stem cell markers including CD14, CD34, and CD45. We have induced these cells to differentiate into mature macrophages by lipopolysaccharide, T lymphocytes by IL-2, epithelial cells by epidermal growth factor, endothelial cells by vascular endothelial cell growth factor, neuronal cells by nerve growth factor, and liver cells by hepatocyte growth factor. The pluripotent nature of individual PSC was further confirmed by a clonal analysis. The ability to store, expand, and differentiate these PSC from autologous peripheral blood should make them valuable candidates for transplantation therapy. P luripotent stem cells (PSC) are a valuable resource for research, drug discovery, and transplantation (1, 2). These cells or their mature progeny can be used to study differentiation processes, identify and test lineage-specific drugs, or replace tissues damaged by a disease. However, the use of PSC from human fetuses, umbilical cords, or embryonic tissues derived from in vitro fertilized eggs raises ethical and legal questions, poses a risk of transmitting infections, and͞or may be ineffective because of immune rejection. A way to circumvent these problems is by exploiting autologous stem cells, preferably from an accessible tissue. In this context, it has been reported that bone marrow contains cells that appear to have the ability to transdifferentiate into mature cells belonging to distinct cell lineages (2). A recent study indicated that bone marrow mesenchymal PSC can be expanded in vitro and after transplantation differentiate in vivo into cells belonging to distinct lineages (3). Other studies have, however, raised the possibility that such mature cells may result from fusion of stem cells with mature resident tissue cells (4,5).In the present studies, we have described the characterization and expansion in vitro of a yet unidentified subset of human peripheral blood monocytes that behave as PSC. We have shown that these cells can be induced to acquire macrophage, lymphocyte, epithelial, endothelial, neuronal, and hepatocyte phenotypes in the absence of a fusion with preexisting mature tissue cells. The ability to obtain these PSC from an easily accessible source such as peripheral blood and to store them in liquid nitrogen should make them valuable candidates for autologous transplantation. Materials and MethodsCell Culture. Monocytes were obtained from buffy coats (each from 500 ml of peripheral blood) of healthy individuals (LifeSource Blood Services, Glenview, IL) by using a selective attachment procedure as described (6, 7). Fresh mononuclear cells for this procedure and͞or after storage in liquid nitrogen in FBS (Harlan Breeders, Indianapolis) containing 10% dimethyl sulfoxide (Sigma) were obtained after Ficoll-...

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Section: Characterization Of Two Monocyte Subsetsmentioning

confidence: 99%

A human peripheral blood monocyte-derived subset acts as pluripotent stem cells

Zhao

Glesne

Huberman

2003

Proc. Natl. Acad. Sci. U.S.A.

430

309

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“…In a number of these cell types, PMA can inhibit cell replication and induce cell differentiation (2)(3)(4)(5)(6)(7)(8); for example, in cells derived from human HL-60 promyelocytic leukemia (9), PMA induces the cells to acquire a mature phenotype that resembles that of macrophages (4,5,10,11).…”

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confidence: 99%

Translocation of protein kinase C in human leukemia cells susceptible or resistant to differentiation induced by phorbol 12-myristate 13-acetate.

Homma¹,

Henning-Chubb²,

Huberman³

1986

Proc. Natl. Acad. Sci. U.S.A.

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We investigated the possible relationship between the susceptibility of cells to differentiation induced by phorbol 12-myristate 13-acetate (PMA) and the subcellular translocation of calcium-and phospholipid-dependent protein kinase (protein kinase C) activity from the cytosol to the membrane. These two events were analyzed in a number of human leukemia cell lines, including four cell variants of the promyelocytic cell line HL-60 that exhibit different degrees of susceptibility to PMA-induced differentiation. The phenotype of the differentiated cells was characterized by increased reactivity with monoclonal antibodies against maturationspecific cell surface antigens, increased nonspecific esterase activity, and acquisition of morphological cell maturation. Analysis of the subcellular distribution of protein kinase C activity in each of these cell types revealed that 90% of the kinase activity was present in the cytosolic fraction, with the remaining activity in the membrane fraction. Treatment of the differentiation-susceptible cells with 160 nM PMA resulted, within 5 min after treatment, in a >60% decrease in protein kinase C activity in the cytosolic fraction and a >1500% increase in the activity in the membrane fraction. No such subcellular redistribution of protein kinase C activity was found after treatment of the differentiation-resistant cells. On the basis of these findings, we suggest that the process of subcellular translocation of protein kinase C activity, initiated after the binding of PMA to this kinase, is required for the induction of cell differentiation by this phorbol diester.

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“…It has been shown that 12-0-tetra-decanoylphorbol 13-acetate (TPA) causes limited differentiation and a reduction of cell growth without loss of cell viability in cloned human T-lymphoblastic leukemia cells ( 13,14,16). While studying these effects of TPA on human pre-T Molt-4 leu-G1 cells do not enter the resting state but instead remain in the cycling compartment.…”

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confidence: 99%

Cell cycle progression and phenotypic modification of Ki67 antigen‐negative G1‐ and G2‐phase cells in phorbol ester‐treated molt‐4 human leukemia cells

Tsurusawa

Fujimoto

1995

Cytometry

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To elucidate the relationship between the level of cellular Ki67‐reactive antigen and cell proliferation, the effects of 12‐O‐tetra‐decanoylphorbol 13‐acetate (TPA) on Ki67 expression, cell cycle progression, and surface phenotypes of human T‐lymphoblastic leukemia Molt‐4 cells were investigated by multiparameter flow cytometry. The Ki67 antigen is constitutionally expressed in almost all untreated exponentially proliferating Molt‐4 cells. Treatment with 10 nM TPA prolonged the duration of the cell cycle time and resulted in a progression arrest of cells in G1‐ and G2‐phases, during which Ki67 expression was decreased to an undetectable level. However, in TPA‐treated cultures, the Ki67‐positive fraction was invariably smaller than the growth fraction as estimated from continuous 5‐bromodeoxyuridine (BrdUrd) labeling curves. This discrepancy could be explained by the finding that some Ki67‐negative G1 cells do not enter the resting state but instead remain in the cycling compartment. These results show that Ki67 expression of tumor cells with relatively long G1 duration is downregulated to undetectable levels in late G1‐phase and the difference in the level of Ki67 expression between late G1 cells and resting G1 cells is undetectable by conventional immunological methods. Although TPA induced differentiation of Molt‐4 cells into mature suppressor T cells, the phenotypic modification was not correlated with cell cycle position and Ki67 reactivity of the cells. These results suggest that growth arrest and phenotypic differentiation of Molt‐4 cells are independent effects of TPA. © 1995 Wiley‐Liss, Inc.

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Differentiation of human T-lymphoid leukemia cells into cells that have a suppressor phenotype is induced by phorbol 12-myristate 13-acetate.

Cited by 40 publications

References 29 publications

A human peripheral blood monocyte-derived subset acts as pluripotent stem cells

A human peripheral blood monocyte-derived subset acts as pluripotent stem cells

Translocation of protein kinase C in human leukemia cells susceptible or resistant to differentiation induced by phorbol 12-myristate 13-acetate.

Cell cycle progression and phenotypic modification of Ki67 antigen‐negative G1‐ and G2‐phase cells in phorbol ester‐treated molt‐4 human leukemia cells

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