Control of progenitor cell number by mitogen supply and demand

Background: Much is known about how cell proliferation is controlled at the single cell level, but much less about the control of cell numbers in deve loping populations. Cell number might be determined by an intracellular div ision limiter or, alternatively, by the availability of mitogens or other f actors outside the cell, We investigated the relative importance of intrace llular and extracellular controls for one well-defined population of neural precursor cells, namely the glial progenitors that give rise to oligodendr ocytes in the mouse spinal cord. Results: We found by cumulative BrdU labeling in vivo that the progenitor c ell division cycle slows down markedly as their numbers increase during emb ryogenesis. When cultured in saturating PDGF, the main mitogen for these ce lls, their cell cycle accelerated and was independent of their prior rate o f division in vivo. This shows that mitogens are limiting in vivo, and sugg ests that division normally slows down because the PDGF concentration decli nes. In PDGF-transgenic mice, cell number was proportional to the PDGF supp ly and apparently unsaturable; at ten times the normal rate of supply, cell number was still increasing but the animals were no longer viable. Conclusions: Progenitor cell proliferation in the embryo is limited by envi ronmental factors, not a cell-intrinsic mechanism. The linear relationship between PDGF supply and final cell number strongly suggests that cells depl ete the mitogenic activity in their environment at a rate proportional to t he total number of cells. The cells might simply consume the available PDGF or they might secrete autocrine inhibitors, or both.