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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.
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>
Dynamic Expression of Specific miRNAs during Erythroid Differentiation of Human Embryonic Stem Cells
Hong Lian Jin,김계성,김종수,Young June Kim,Su Jin Kim,Hal E. Broxmeyer 한국분자세포생물학회 2012 Molecules and cells Vol.34 No.2
MicroRNAs (miRNAs) are small non-coding RNAs that re-gulate gene expression at post-transcriptional levels through mRNA degradation or translation inhibition. Little is known regarding miRNA participation in regulating he-matopoietic, or more specifically erythroid differentiation. This study was aimed at identifying erythroid lineage-specific miRNAs expressed during in vitro erythropoiesis using human embryonic stem cells (hESCs) and human umbilical cord blood (CB) CD34+ cells. CD34+ hematopoietic cells were produced from hESCs in vitro and subsequently induced to differentiate into erythroid cells by culture in sequence on OP9 feeder cells and then with mesenchymal stromal cells (MSC) in the presence of cytokines. Expression profiles of erythroid lineage-specific miRNAs were analyzed by quantitative PCR during in vitro differentiation. Expression levels of miR-142-3p, miR-142-5p, miR-146a and miR-451 were dynamically changed during differentiation of hESCs to CD34+ hematopoietic cells, and in subsequent differentiation of the CD34+ cells into the erythroid lineage. This suggests that these four miRNAs might be involved in regulating erythropoiesis.
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.
Nonmarrow Hematopoiesis Occurs in a Hyaluronic-Acid-Rich Node and Duct System in Mice
Hwang, Sunhee,Lee, Seung J.,Park, Sang H.,Chitteti, Brahmananda R.,Srour, Edward F.,Cooper, Scott,Hangoc, Giao,Broxmeyer, Hal E.,Kwon, Byoung S. Mary Ann Liebert 2014 STEM CELLS AND DEVELOPMENT Vol.23 No.21
<P>A hyaluronic-acid-rich node and duct system (HAR-NDS) was found on the surface of internal organs of mice, and inside their blood and lymph vessels. The nodes (HAR-Ns) were filled with immune cells of the innate system and were especially enriched with mast cells and histiocytes. They also contained hematopoietic progenitor cells (HPCs), such as granulocyte-macrophage, erythroid, multipotential progenitors, and mast cell progenitors (MCPs). MCPs were the most abundant among the HPCs in HAR-Ns. Their frequency was fivefold higher than that of the MCPs in bone marrow. In addition, the system contained pluripotent stem cells (PSCs) capable of producing CD45(-)Flk1(+) hemangioblast-like cells, which subsequently generated various types of HPCs and differentiated blood cells. Although HAR-Ns did not appear to harbor enough number of cells capable of long-term reconstitution or short-term radioprotection of lethally irradiated recipients, bone marrow cells were able to engraft in the HAR-NDS and reconstitute hematopoietic potentials of the system. PSCs and HPCs were consistently found in intravenous, intralymphatic, and intestinal HAR-ND. We infer that PSCs and HPCs reside in the HAR-ND and that this novel system may serve as an alternative means to traffic immature and mature blood cells throughout the body.</P>