Transient disruption of autocrine TGF-beta signaling leads to enhanced survival and proliferation potential in single primitive human hemopoietic progenitor cells.

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Abstract

Hemopoietic stem cells (HSCs) are maintained at relative quiescence by the balance between the positive and negative regulatory factors that stimulate or inhibit their proliferation. Blocking the action of negative regulatory factors may provide a new approach for inducing HSCs into proliferation. A variety of studies have suggested that TGF-beta negatively regulates cell cycle progression of HSCs. In this study, a dominant negatively acting mutant of TGF-beta type II receptor (TbetaRIIDN) was transiently expressed in HSCs by using adenoviral vector-mediated gene delivery, such that the effects of disrupting the autocrine TGF-beta signaling in HSCs can be directly examined at a single cell level. Adenoviral vectors allowing the expression of TbetaRIIDN and green fluorescence protein in the same CD34(+)CD38(-)Lin(-) cells were constructed. Overexpression of TbetaRIIDN specifically disrupted TGF-beta-mediated signaling. Autocrine TGF-beta signaling in CD34(+)CD38(-)Lin(-) cells was studied in single cell assays under serum-free conditions. Transient blockage of autocrine TGF-beta signaling in CD34(+)CD38(-)Lin(-) cells enhanced their survival. Furthermore, the overall proliferation potential and proliferation kinetics in these cells were significantly enhanced compared with the CD34(+)CD38(-)Lin(-) cells expressing green fluorescence protein alone. Therefore, we have successfully blocked the autocrine TGF-beta-negative regulatory loop of primitive hemopoietic progenitor cells.

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Subject classification (UKÄ) – MANDATORY

  • Immunology in the medical area

Keywords

  • Cell Lineage : genetics, Cell Division : genetics, Cell Survival : genetics, Cells Cultured, Culture Media Serum-Free, Genetic Vectors : biosynthesis, Hela Cells, Hematopoietic Stem Cells : cytology : immunology : metabolism, Human, Immunophenotyping, NAD+ Nucleosidase : biosynthesis, K562 Cells, Signal Transduction : genetics : physiology, Support Non-U.S. Gov't, Transforming Growth Factor beta : antagonists & inhibitors : genetics : pharmacology : physiology, Transduction Genetic, Cell Cycle : genetics, Cattle, Autocrine Communication : genetics, Antigens Differentiation : biosynthesis, Antigens CD34 : biosynthesis, Animal, Adenoviridae : genetics
Original languageEnglish
Pages (from-to)755-762
JournalJournal of Immunology
Volume168
Issue number2
Publication statusPublished - 2002
Publication categoryResearch
Peer-reviewedYes