Partial reprogramming preserves hematopoietic stem cells by suppressing AP‑1 and transposons

Preprint: brief activation of Yamanaka factors improved blood stem cell function in aged mice

On August 31, bioRxiv published a preprint describing a study in transgenic mice. The mice received doxycycline for 16 days to activate OCT4, SOX2, KLF4, and MYC, the Yamanaka factors that initiate cellular reprogramming. When the treatment was given at 18–20 months of age, their blood stem cells showed better hematopoietic reconstitution after transplantation four months later.

Hematopoietic stem cells reside in the bone marrow and replenish blood cells throughout life. With age, they become less effective at colonizing a new host’s bone marrow after transplantation and produce a greater proportion of myeloid cells. The authors therefore transplanted bone marrow into recipient mice and measured the proportion of reconstituted blood produced by donor cells.

In the first series of experiments, the mice received the treatment at two to three months of age and were assessed at 20–24 months. Donor cells exposed to this brief activation reconstituted hematopoiesis more effectively and showed less myeloid bias. In the second series, the factors were activated at 18–20 months of age. Four months later, competitive transplantation and other measures of stem cell function also showed improvement. Expression of Oct4 and Sox2 in these cells was no longer detectable one month after treatment, while the functional changes persisted into old age.

The study began with earlier work in mice by the same group. Chronic stress induced by lipopolysaccharide, a bacterial component, depleted H3K9me3 from hematopoietic stem cells. This mark helps keep specific regions of DNA tightly packed. LINE-1 mobile DNA sequences became more active, markers of DNA damage increased, and the stem cells formed fewer colonies.

In the new preprint, the authors tested this proposed sequence of events. More chromatin regions were open in aged stem cells. Chromatin is the packaged form of DNA, and its structure determines which genes are accessible. The open regions included binding sites for FOS and JUN, components of the stress-responsive AP-1 protein complex. Brief activation of the reprogramming factors reduced the accessibility of these sites. Under inflammatory stress, an AP-1 inhibitor preserved the stem cells’ capacity to form colonies and reduced markers of LINE-1 activity and DNA damage.

The authors also treated aged mice with lamivudine for four months. This drug inhibits the reverse transcriptase used by LINE-1. The stem cells showed fewer markers of DNA damage, while transplantation performance and self-renewal capacity improved. These experiments examine separate steps in the same model: stress activates AP-1, chromatin organization then changes, LINE-1 becomes active, and DNA damage accumulates.

In this mouse study, a brief course of Yamanaka factor activation improved hematopoietic reconstitution after transplantation and was associated with lower activity across the AP-1 → chromatin → LINE-1 → DNA damage pathway.