TGF-(beta)1 maintains hematopoietic immaturity by a reversible negative control of cell cycle and induces CD34 antigen up-modulation.
Somatic stem cells are largely quiescent in spite of their considerable proliferative potential. Transforming growth factor-(beta)1 (TGF-(beta)1) appears to be a good candidate for controlling this quiescence. Indeed, various mutations in the TGF-beta signalling pathway are responsible for neoplasic proliferation of primitive stem/progenitor cells in human tissues of various origins. In hemopoietic single cell culture assays, blocking autocrine and endogeneous TGF-(beta)1 triggers the cell cycling of high proliferative potential undifferenciated stem/progenitor cells. However, it has never been demonstrated whether TGF-(beta)1 has an apoptotic effect or a differentiating effect on these primitive cells, as already described for more mature cells. Using single cell experiments both in liquid or semi-solid culture assays and dye tracking experiments by flow cytometry, we demonstrate that low, physiological concentrations of TGF-(beta)1, which specifically maintain primitive human hemopoietic stem/progenitor cells in quiescence, have a reversible effect and do not induce apoptosis. We moreover demonstrate that these low concentrations prevent the rapid loss of the mucin-like protein CD34, a most common marker of immature hematopoietic stem/progenitor cells, which is progressively lost during differentiation. TGF-(beta)1 not only up-modulated the CD34 antigen before S phase entry but also maintained a high level of CD34 expression on cells which had escaped cell cycle inhibition, suggesting that proliferation inhibition and differentiation control by TGF-(beta)1 may be independent. These data provide additional evidence that TGF-(beta)1 acts as a key physiological factor ensuring the maintenance of a stem cell reserve.
Batard
P
P
Laboratoire de Biologie Cellulaire et Moléculaire des Facteurs de Croissance, UPR 1983 du Centre National de la Recherche Scientifique, IFC1, rue Guy Moquet, France.
Monier
M N
MN
Fortunel
N
N
Ducos
K
K
Sansilvestri-Morel
P
P
Phan
T
T
Hatzfeld
A
A
Hatzfeld
J A
JA
D018952:Antigens, CD34 / Q000096:biosynthesis* / Q000235:genetics; D015415:Biomarkers; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D002454:Cell Differentiation / Q000187:drug effects; D002455:Cell Division; D002478:Cells, Cultured; D004396:Coloring Agents / Q000032:analysis; D004305:Dose-Response Relationship, Drug; D005312:Fetal Blood / Q000166:cytology; D005434:Flow Cytometry; D005456:Fluorescent Dyes / Q000032:analysis; D006410:Hematopoiesis / Q000502:physiology*; D016298:Hematopoietic Cell Growth Factors / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000494:pharmacology; D009930:Organic Chemicals; D011994:Recombinant Proteins / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000494:pharmacology / Q000502:physiology*
D018952:Antigens, CD34; D015415:Biomarkers; D004396:Coloring Agents; D005456:Fluorescent Dyes; D016298:Hematopoietic Cell Growth Factors; D015850:Interleukin-6; D009930:Organic Chemicals; C070080:PKH 26; D011994:Recombinant Proteins; D016212:Transforming Growth Factor beta