| Mouse hematopoietic stem cells (HSC) are defined by their ability to produce all blood cells lineages, rescue lethally irradiated mice, and self-renew extensively. The most primitive HSC, long-term HSC (LT-HSC), has life-long hematopoietic potential and constitutes 0.01% of mouse bone marrow. To meet the large demand for blood cells, HSC undergo cell divisions resulting in daughter cells capable of differentiating into mature cells. The demand could be met if all LT-HSC divided continuously at a maximal rate. However LT-HSC must regulate cell divisions to prevent leukemogenesis, preserve metabolic energy, and to avoid exhaustion their proliferative capacity (especially if this capacity finite as postulated by some studies).; To study how LT-HSC divide and produce mature blood cells, the in vivo BrdUrd incorporation rates of these cells in steady-state adult mice were analyzed. This study demonstrated that LT-HSC cycled randomly at a rate of about 8.0 percent per day, with about one quarter of LT-HSC in the cell cycle. Short-term HSC and multi-potent progenitors entered the cell cycle at a greater rate than LT-HSC. All LT-HSC rapidly entered the cell cycle when mice were pretreated with cyclophosphamide/G-CSF. Also, the "normal" stress of bleeding mice promoted HSC proliferation and self-renewal. Finally in transgenic mice expressing Bcl2 driven by the H2K promoter, preventing apoptosis increased LT-HSC numbers while decreasing their rate of cell division.; This research established the baseline parameters of HSC proliferation in mice and also demonstrated that the decision of LT-HSC to enter the cell cycle is not clonal but stochastic. It provided direct evidence that LT-HSC regulate their divisions, by cycling slowly, and give rise to more restricted progenitors, which divide more rapidly, thus shifting the burden of blood cell production onto these cells. We demonstrated that LT-HSC rapidly responded to physiologic (bleeding) and supraphysiologic (cyclophosphamide/G-CSF) stress by increasing the rate of division and the fraction of cells in the cell cycle. Finally, LT-HSC may potentially increase their numbers by decreasing apoptosis. With these results, a detailed model of how HSC divide to meet the demands of hematopoiesis has been provided. |
