in the bone marrow
Shortening the G1 phase of the cell cycle can improve the production and function of hematopoietic stem cells (HSCs), according to research published in the Journal of Experimental Medicine.
When investigators shortened the G1 phase in human HSCs, they found the cells were better able to resist differentiation in vitro and exhibited enhanced engraftment in vivo.
However, these benefits only occurred when the team shortened the early phase of G1, not the late phase.
Claudia Waskow, PhD, of Technische Universitaet Dresden in Germany, and her colleagues conducted this research to determine whether the function of human HSCs is controlled by the kinetics of cell-cycle progression.
The investigators knew that the body’s pool of HSCs is maintained through self-renewing divisions tightly regulated by enzymatically active cyclin (CCN)/cyclin-dependent kinase (CDK) complexes.
So they enforced expression of functional CCND1–CDK4 complexes, which are important for progression through the early G1 phase of the cell cycle, and CCNE1–CDK2 complexes, which are key in the transition from the G1 phase to the S phase.
Overexpression of CCND1–CDK4 complexes (also referred to as elevated 4D) promoted the transit from G0 to G1 and successfully shortened the G1 phase. However, the total length of the cell cycle did not change much, as the G2 or M phase was prolonged slightly.
The investigators also found that elevated 4D levels protected HSCs from differentiation-inducing signals in vitro and provided a “competitive advantage” in vivo.
When they transplanted HSCs with elevated 4D into mice, the team observed improved donor-leukocyte engraftment but no increase in the HSC pool. They said the improvement in engraftment was based on an elevated output of myeloid cells.
In contrast to elevated 4D, overexpression of CCNE1–CDK2 (also referred to as elevated 2E) conferred detrimental effects. Elevated 2E did accelerate cell-cycle progression, but it led to the loss of functional HSCs and poor engraftment.
The investigators said a large proportion of cells with elevated 2E contained fragmented DNA and underwent apoptosis after transduction.
In addition, many HSCs with elevated 2E exited G0 and shifted to the S–G2–M phases of the cell cycle. The G1 phase was significantly shortened, and the time HSCs spent in each cycle was reduced.
Dr Waskow and her colleagues said these results suggest transit velocity through the early and late G1 phase is an important regulator of HSC function and therefore makes an essential contribution to the maintenance of hematopoiesis.
Furthermore, alterations of G1 transition kinetics may be the basis for functional defects observed in HSCs from old mice or elderly humans.
