Maintenance of the hematopoietic system requires constant replenishment of mature blood cells from HSCs. For patients with malignant and non-malignant disorders of the blood and immune system, myeloablation and subsequent HSC transplantation is often necessary. However, exposure to ionizing radiation to induce myeloablation also causes DNA damage that can induce cell-cycle arrest or apoptosis of HSCs and their progenitor cells 1. Studies have shown that treatment with cytokines can prevent cell-cycle arrest. For example, administration of stem cell factor (SCF) before radiation exposure protected mice from radiation-induced lethality by inducing HSCs into late S phase 2, which is the most radioresistant phase of the cell cycle. Further studies to identify additional cytokines that mediate HSC regeneration following radiation exposure are critical for the development of therapies to minimize myelosuppression in patients receiving chemotherapy.
Recently, in Nature Medicine, Doan et al discovered a new function of epidermal growth factor (EGF) signaling in regulation of HSC regeneration following myelosuppressive injury 3. The authors previously generated a mouse model in which pro-apoptotic proteins, BAK and BAX, were deleted in Tie2+ bone marrow endothelial cells 4. Mice lacking BAK and BAX expression demonstrated significantly increased numbers of HSCs and progenitor cells and increased survival following total body irradiation (TBI) compared to wild-type mice expressing the pro-apoptotic proteins. This was the first indication that bone marrow endothelial cells might have therapeutic potential in enhancing hematopoietic reconstitution following myelosuppression. However, the mechanism through which these cells regulate hematopoietic regeneration was unknown.
In their most recent study, Doan et al performed a cytokine array on bone marrow serum from mice lacking BAK and BAX expression and found a significant enrichment of EGF compared to wild-type mice 3. Using multiparametric flow cytometry, they demonstrated that ~9% of c-Kit+Sca-1+Lin- SLAM+ HSCs express functional EGF receptor (EGFR), and expression increased by 6-fold following irradiation. Systemic administration of EGF augmented HSC recovery in vivo and improved the survival of mice following TBI compared to saline-treated control mice. In contrast, administration of erlotinib, an EGFR antagonist, suppressed HSC regeneration and significantly decreased the survival of mice following TBI, further suggesting that EGFR signaling is critical for radioprotection of bone marrow HSCs and progenitor cells. They found that EGFR signaling promotes HSC proliferation by activation of the PI3K-AKT pathway. In addition, EGF treatment inhibited expression of the p53 upregulated modulator of apoptosis (PUMA), an essential mediator of radiation-induced HSC apoptosis.
In summary, EGF promotes HSC cycling and survival following radiation-induced myelosuppression. The study by Doan et al was the first demonstration that bone marrow HSCs express functional EGFR, and that EGFR signaling plays a role in HSC self-renewal. The results of this study suggest that EGF may have therapeutic potential to enhance hematopoietic regeneration in patients receiving myelosuppressive chemotherapy or undergoing HSC transplantation.
1. Liu, Y. et al. p53 regulates hematopoietic stem cell quiescence. Cell Stem Cell 4, 37-48, doi:10.1016/j.stem.2008.11.006 (2009).
2. Zsebo, K. M. et al. Radioprotection of mice by recombinant rat stem cell factor. Proc Natl Acad Sci U S A 89, 9464-9468 (1992).
3. Doan, P. L. et al. Epidermal growth factor regulates hematopoietic regeneration after radiation injury. Nat Med, doi:10.1038/nm.3070 (2013).
4. Doan, P. L. et al. Tie2(+) Bone Marrow Endothelial Cells Regulate Hematopoietic Stem Cell Regeneration Following Radiation Injury. Stem Cells, doi:10.1002/stem.1275 (2012).