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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Medicinska och farmaceutiska grundvetenskaper -- Immunologi inom det medicinska området (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Basic Medicine -- Immunology in the medical area (hsv//eng)

Nyckelord

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

Publikations- och innehållstyp

art (ämneskategori)

ref (ämneskategori)