Control of hematopoietic stem/progenitor cell fate by transforming growth factor-beta.
A major obstacle to the use of adult somatic stem cells for cell therapy is our current inability to fully exploit stem cell self-renewal properties. The challenge is to obtain defined culture systems where cycling of primitive stem/progenitor cells is stimulated, while their differentiation and senescence are prevented. The cytokine transforming growth factor-beta1 (TGF-beta1) appears as a potential regulator of hematopoietic stem/ progenitor cell self-renewal, as it participates in the control of cell proliferation, survival/apoptosis, and cell immaturity/differentiation. TGF-beta1 acts via a complex regulatory network involving intracellular signaling molecules and cell surface receptors. According to the High Proliferative Potential-Quiescent (HPP-Q) cell working model that we introduced previously, TGF-beta1 maintains primitive hematopoietic stem/progenitor cells in a quiescent or slow cycling state, in part by downmodulating the cell surface expression of mitogenic cytokine receptors, thus preventing cells from responding rapidly to a mitogenic signal. We have established that this modulation concerns the tyrosine kinase receptors KIT and FLT3, and the IL-6 receptor (IL-6R), three important cytokine receptors controlling early human hematopoietic stem/progenitor cell development. In this article. we show a similar modulation by TGF-beta1 of a fourth receptor: the TPO receptor (MPL). As a consequence, TGF-beta1 decreased the cell cycle entry of stem/progenitor cells stimulated by the respective ligands of these receptors, the cytokines SF, FL, IL-6, and TPO, whereas neutralization of TGF-beta1 increased the cell responsiveness to these mitogenic cytokines. Other aspects of the function of TGF-beta1 in the regulation of early hematopoiesis (i.e., the control of stem/progenitor cell survival and immaturity) are reviewed in the discussion.
Laboratoire de Biologic des Cellules Souches Humaines, CNRS-UPR 9045, Institut André Lwoff, 94800 Villejuif, France.
Nicolas Olivier
NO
Fortunel
Jacques Alexandre
JA
Hatzfeld
Marie-Noëlle
MN
Monier
Antoinette
A
Hatzfeld
D018952:Antigens, CD34 / Q000032:analysis; D018929:Cell Culture Techniques / Q000379:methods; D002453:Cell Cycle / Q000502:physiology; D002460:Cell Line; D002469:Cell Separation; D002999:Clone Cells / Q000166:cytology / Q000378:metabolism; D015536:Down-Regulation; D005312:Fetal Blood / Q000166:cytology; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000378:metabolism*; D006801:Humans; D009000:Monocytes / Q000737:chemistry / Q000378:metabolism; D009363:Neoplasm Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D019947:Receptors, Interleukin-6 / Q000378:metabolism; D053628:Receptors, Thrombopoietin; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D018952:Antigens, CD34; D009363:Neoplasm Proteins; D011518:Proto-Oncogene Proteins; D018121:Receptors, Cytokine; D019947:Receptors, Interleukin-6; D053628:Receptors, Thrombopoietin; D016212:Transforming Growth Factor beta; C082218:MPL protein, human; D020794:Receptor Protein-Tyrosine Kinases