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( Hal E Broxmeyer ) 대한내과학회 2013 The Korean Journal of Internal Medicine Vol.28 No.6
Dipeptidylpeptidase (DPP) 4, also known as CD26, is an enzyme present on the surface of a number of different cell types. It is also found within cells and as a soluble protein in body fluids. It can specifically truncate proteins at the penultimate N-terminus residue for some amino acids, such as alanine, proline, serine, and perhaps others. DPP4 has been implicated in regulating the in vitro and in vivo functional activities of a number of hematopoietically active molecules, and this information, along with that on inhibition of DPP4, has been studied in efforts to enhance hematopoietic cell transplantation (HCT), hematopoiesis after stress in mouse models, and in the clinical setting of single-unit cord blood (CB) HCT. This article reviews the current status of this compound`s effects on regulatory proteins, the field of CB HCT, a potential role for modulating DPP4 activity in enhancing single-unit CB HCT in adults, and future aspects in context of other cellular therapies and the area of regenerative medicine.
Synergistic activation of p70S6 kinase associated with stem cell factor in MO7e cells
YoungheeLee,HalE.Broxmeyer,CharlieMantel,Hyung-JooKwon,JaeWhaKim,JinSookKim,DurhanKwon,InSeongChoe 생화학분자생물학회 2003 Experimental and molecular medicine Vol.35 No.3
Stem cel factor (SCF) is an early-acting cytokine inducing proliferative synergy with other cytokines in hematopoietic cels. We earlier showed that p21 was synergisticaly induced in SCF synergy and the p44/42 MAPK pathway was essential for the transcriptional control of p21. SCF synergy accom-panies protein synthesis. p70S6K implicated in translational control in many other systems has not been shown in SCF synergy induced system. ulated with GM-CSF with SCF, and investigated ac-tivation of p70S6K by using phospho-specific anti-body. A possible contribution of p70S6K to SCF synergy was examined by measuring p21 induc-tion as a model system. p70S6K was slightly acti-vated by GM-CSF alone and markedly activated by SCF alone. Combined stimulation with these two cytokines synergisticaly activated p70S6K resulting in persistent activation. Adition of the pathway- specific inhibitors for PI3K or FRAP/TOR, two up-stream pathways of p70S6K resulted in abolish-ficant reduction of p21 protein level. These data sugest that synergisticaly activated p70S6K by GM-CSF plus SCF involves, at least in part, protein translational control including regulation of p21 protein.
Hwang, Yongsung,Broxmeyer, Hal E.,Lee, Man Ryul CURRENT SCIENCE 2017 CURRENT OPINION IN HEMATOLOGY Vol.24 No.4
<P>Purpose of reviewHematopoietic cell transplantation (HCT) is a successful treatment modality for patients with malignant and nonmalignant disorders, usually when no other treatment option is available. The cells supporting long-term reconstitution after HCT are the hematopoietic stem cells (HSCs), which can be limited in numbers. Moreover, finding an appropriate human leukocyte antigen-matched donor can be problematic. If HSCs can be stably produced in large numbers from autologous or allogeneic cell sources, it would benefit HCT. Induced pluripotent stem cells (iPSCs) established from patients' own somatic cells can be differentiated into hematopoietic cells in vitro. This review will highlight recent methods for regulating human (h) iPSC production of HSCs and more mature blood cells.Recent findingsAdvancements in transcription factor-mediated regulation of the developmental stages of in-vivo hematopoietic lineage commitment have begun to provide an understanding of the molecular mechanism of hematopoiesis. Such studies involve not only directed differentiation in which transcription factors, specifically expressed in hematopoietic lineage-specific cells, are overexpressed in iPSCs, but also direct conversion in which transcription factors are introduced into patient-derived somatic cells which are dedifferentiated to hematopoietic cells. As iPSCs derived from patients suffering from genetically mutated diseases would express the same mutated genetic information, CRISPR-Cas9 gene editing has been utilized to differentiate genetically corrected iPSCs into normal hematopoietic cells.SummaryIPSCs provide a model for molecular understanding of disease, and also may function as a cell population for therapy. Efficient differentiation of patient-specific iPSCs into HSCs and progenitor cells is a potential means to overcome limitations of such cells for HCT, as well as for providing in-vitro drug screening templates as tissue-on-a-chip models.</P>
Guo, Bin,Huang, Xinxin,Lee, Man Ryul,Lee, Sang A,Broxmeyer, Hal E Nature Publishing Group 2018 Nature medicine Vol. No.
Hematopoietic stem cells (HSCs) quiescently reside in bone marrow niches and have the capacity to self-renew or differentiate to form all of the blood cells throughout the lifespan of an animal. Allogeneic HSC transplantation is a life-saving treatment for malignant and nonmalignant disorders. HSCs isolated from umbilical cord blood (CB) are used for hematopoietic cell transplantation (HCT), but due to the limited numbers of HSCs in single units of umbilical CB, a number of methods have been proposed for ex vivo expansion of human HSCs. We show here that antagonism of peroxisome proliferator-activated receptor (PPAR)-γ promotes ex vivo expansion of phenotypically and functionally defined subsets of human CB HSCs and hematopoietic progenitor cells (HSPCs). PPAR-γ antagonism in CB HSPCs strongly downregulated expression of several differentiation-associated genes, as well as fructose-bisphosphatase 1 (FBP1; which encodes a negative regulator of glycolysis), and enhanced glycolysis without compromising mitochondrial metabolism. The expansion of CB HSPCs by PPAR-γ antagonism was completely suppressed by removal of glucose or inhibition of glycolysis. Moreover, knockdown of FBP1 expression promoted glycolysis and ex vivo expansion of long-term repopulating CB HSPCs, whereas overexpression of FBP1 suppressed the expansion of CB HSPCs that was induced by PPAR-γ antagonism. Our study suggests the possibility for a new and simple means for metabolic reprogramming of CB HSPCs to improve the efficacy of HCT.
Cells enter a unique intermediate 4N stage, not 4N-G1, after aborted mitosis.
Mantel, Charlie,Guo, Ying,Lee, Man Ryul,Han, Myung Kwan,Rhorabough, Sara,Kim, Kye Seong,Broxmeyer, Hal E Landes Bioscience 2008 Cell Cycle Vol.7 No.4
<P>It is widely accepted that mammalian cells enter the next G(1)-phase (G(1)) with 4N DNA after slippage from prolonged drug-induced mitotic block caused by activation of the transient spindle checkpoint. Understanding cell fate after mitotic slippage (MS) has significant clinical importance. The conclusion the MS cells enter 4N-G(1) is based on morphology and mitotic cyclin destruction. Definitive biochemical evidence for G(1) is scarce or unconvincing, in part because of methods of protein extraction required for immunoblot analysis that cannot take into account the cell cycle heterogeneity of cell cultures. We used single-cell-intracellular-flow-cytometric analysis to further define important factors determining cell fate after MS. Results from human and mouse embryonic stem cells (ESC) that reenter polyploid cell cycles are compared to human somatic cells that die after MS. We conclude that phosphorylation status of pRb, p53, CDK1, and especially cyclin B1 levels are important for cell fate decision in MS cells, which occur in a unique, intervening, non-G(1), tetraploid subphase.</P>