TGF-beta and MIP-1 alpha exert their main inhibitory activity on very primitive CD34+2CD38- cells but show opposite effects on more mature CD34+CD38+ human hematopoietic progenitors.
We investigated the effects of transforming growth factor-beta (TGF-beta) and macrophage inflammatory protein-1 alpha (MIP-1 alpha) on very primitive CD34++CD38- and on more mature CD34++CD38+ human hematopoietic progenitor cells by means of a two stage pre-colony-forming cell (pre-CFC) assay. The first (liquid) stage of this assay allows evaluation of the effects of TGF-beta and MIP-1 alpha on the "primary" proliferation of the progenitors under study and on the generation of "secondary" colony-forming cells (CFC, cells for which a second stage semisolid clonogenic assay was used as a read-out). TGF-beta inhibited the proliferation and CFC generation of CD34++CD38- and CD34+CD38+ cells, showing the strongest inhibitory activity on CD34++CD38- cells. MIP-1 alpha exerted a weaker inhibitory activity on CD34+2CD38- cells, whereas it enhanced the primary proliferation of CD34+CD38+ cells and generation of secondary CFC in this subpopulation. Thus, TGF-beta, and MIP-1 alpha both inhibit very primitive CD34+2)CD38- cells, but they are not equally potent. The effects of TGF-beta and MIP-1 alpha on more mature progenitor cells are more complex. Our results and data from the literature indicate that, as progenitor cells mature, they reach a "pivotal point" at a certain stage in their differentiation pathway, depending on the inhibitor, where they are no longer inhibited or where they may even be stimulated by the former inhibitor to proliferate.
Van Ranst
P C
PC
Laboratory of Experimental Hematology, University of Antwerp (UIA/UZA), Belgium.
Snoeck
H W
HW
Lardon
F
F
Lenjou
M
M
Nijs
G
G
Weekx
S F
SF
Rodrigus
I
I
Berneman
Z N
ZN
Van Bockstaele
D R
DR
D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D015703:Antigens, CD; D018952:Antigens, CD34 / Q000032:analysis*; D000943:Antigens, Differentiation / Q000032:analysis*; D002453:Cell Cycle / Q000187:drug effects; D002478:Cells, Cultured; D054407:Chemokine CCL4; D006412:Hematopoietic Stem Cells / Q000166:cytology* / Q000276:immunology*; D006801:Humans; D019402:Macrophage Inflammatory Proteins / Q000494:pharmacology*; D008562:Membrane Glycoproteins; D009699:N-Glycosyl Hydrolases / Q000032:analysis*; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D015703:Antigens, CD; D018952:Antigens, CD34; D000943:Antigens, Differentiation; D054407:Chemokine CCL4; D019402:Macrophage Inflammatory Proteins; D008562:Membrane Glycoproteins; D016212:Transforming Growth Factor beta; D009699:N-Glycosyl Hydrolases; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1