Release of early human hematopoietic progenitors from quiescence by antisense transforming growth factor beta 1 or Rb oligonucleotides.
We have used antisense oligonucleotides to study the roles of transforming growth factor beta (TGF-beta) and the two antioncogenes, retinoblastoma susceptibility (Rb) and p53, in the negative regulation of proliferation of early hematopoietic cells in culture. The antisense TGF-beta sequence significantly enhanced the frequency of colony formation by multi-lineage, early erythroid, and granulomonocytic progenitors, but did not affect colony formation by late progenitors. Single cell culture and limiting dilution analysis indicated that autocrine TGF-beta is produced by a subpopulation of early progenitors. Antisense Rb but not antisense p53 yielded similar results in releasing multipotential progenitors (colony-forming unit-granulocyte/erythroid/macrophage/megakaryocyte) from quiescence. Rb antisense could partially reverse the inhibitory effect of exogenous TGF-beta. Anti-TGF-beta blocking antibodies, antisense TGF-beta, or Rb oligonucleotides all had similar effects. No additive effects were observed when these reagents were combined, suggesting a common pathway of action. Our results are consistent with the model that autocrine production of TGF-beta negatively regulates the cycling status of early hematopoietic progenitors through interaction with the Rb gene product.
Hatzfeld
J
J
Laboratoire C.N.R.S. de Biologie Cellulaire et Moléculaire des Facteurs de Croissance, ICIG, Hôpital Paul-Brousse, Villejuif, France.
Li
M L
ML
Brown
E L
EL
Sookdeo
H
H
Levesque
J P
JP
O'Toole
T
T
Gurney
C
C
Clark
S C
SC
Hatzfeld
A
A
D015703:Antigens, CD / Q000032:analysis; D018952:Antigens, CD34; D001483:Base Sequence; D002455:Cell Division / Q000187:drug effects*; D003114:Colony-Forming Units Assay; D016161:Genes, Retinoblastoma; D016158:Genes, p53; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000276:immunology; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D016376:Oligonucleotides, Antisense / Q000494:pharmacology*; D013873:Thionucleotides / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000235:genetics*
D015703:Antigens, CD; D018952:Antigens, CD34; D016376:Oligonucleotides, Antisense; D013873:Thionucleotides; D016212:Transforming Growth Factor beta