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Inhibition of MEK/ERK signalling pathway promotes erythroid differentiation and reduces HSCs engraftment in ex vivo expanded haematopoietic stem cells.
- Source :
-
Journal of cellular and molecular medicine [J Cell Mol Med] 2018 Mar; Vol. 22 (3), pp. 1464-1474. Date of Electronic Publication: 2017 Oct 10. - Publication Year :
- 2018
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Abstract
- The MEK/ERK pathway is found to be important in regulating different biological processes such as proliferation, differentiation and survival in a wide variety of cells. However, its role in self-renewal of haematopoietic stem cells is controversial and remains to be clarified. The aim of this study was to understand the role of MEK/ERK pathway in ex vivo expansion of mononuclear cells (MNCs) and purified CD34 <superscript>+</superscript> cells, both derived from human umbilical cord blood (hUCB). Based on our results, culturing the cells in the presence of an inhibitor of MEK/ERK pathway-PD0325901 (PD)-significantly reduces the expansion of CD34 <superscript>+</superscript> and CD34 <superscript>+</superscript>  CD38 <superscript>-</superscript> cells, while there is no change in the expression of stemness-related genes (HOXB4, BMI1). Moreover, in vivo analysis demonstrates that PD reduces engraftment capacity of ex vivo expanded CD34 <superscript>+</superscript> cells. Notably, when ERK pathway is blocked in UCB-MNCs, spontaneous erythroid differentiation is promoted, found in concomitant with increasing number of burst-forming unit-erythroid colony (BFU-E) as well as enhancement of erythroid glycophorin-A marker. These results are in total conformity with up-regulation of some erythroid enhancer genes (TAL1, GATA2, LMO2) and down-regulation of some erythroid repressor genes (JUN, PU1) as well. Taken together, our results support the idea that MEK/ERK pathway has a critical role in achieving the correct balance between self-renewal and differentiation of UCB cells. Also, we suggest that inhibition of ERK signalling could likely be a new key for erythroid induction of UCB-haematopoietic progenitor cells.<br /> (© 2017 The Authors. Journal of Cellular and Molecular Medicine published by John Wiley & Sons Ltd and Foundation for Cellular and Molecular Medicine.)
- Subjects :
- Adaptor Proteins, Signal Transducing genetics
Adaptor Proteins, Signal Transducing immunology
Animals
Animals, Newborn
Antigens, CD genetics
Antigens, CD immunology
Cell Differentiation
Cell Proliferation
Cells, Cultured
Diphenylamine pharmacology
Erythroid Cells cytology
Erythroid Cells immunology
Female
Fetal Blood cytology
Fetal Blood immunology
GATA2 Transcription Factor genetics
GATA2 Transcription Factor immunology
Gene Expression Regulation
Glycophorins genetics
Glycophorins immunology
Graft Survival
Hematopoietic Stem Cells cytology
Hematopoietic Stem Cells immunology
Humans
Immunophenotyping
LIM Domain Proteins genetics
LIM Domain Proteins immunology
Mice
Pregnancy
Proto-Oncogene Proteins genetics
Proto-Oncogene Proteins immunology
T-Cell Acute Lymphocytic Leukemia Protein 1 genetics
T-Cell Acute Lymphocytic Leukemia Protein 1 immunology
Transplantation, Heterologous
Benzamides pharmacology
Diphenylamine analogs & derivatives
Erythroid Cells drug effects
Hematopoietic Stem Cell Transplantation
Hematopoietic Stem Cells drug effects
MAP Kinase Signaling System drug effects
Subjects
Details
- Language :
- English
- ISSN :
- 1582-4934
- Volume :
- 22
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- Journal of cellular and molecular medicine
- Publication Type :
- Academic Journal
- Accession number :
- 28994199
- Full Text :
- https://doi.org/10.1111/jcmm.13379