Granulocyte colony-stimulating factor acts on lymphoid-biased, short-term hematopoietic stem cells

Granulocyte colony-stimulating factor (G-CSF) is a cytokine that increases myelopoiesis,¹ impairs lymphopoiesis by inhibiting committed progenitor cells,^2,3 and enhances hematopoietic stem cell (HSC) mobilization. ⁴ The direct effects of G-CSF on purified subpopulation of HSC remained to be delineated. In this issue of Haematologica, Xie et al.⁵ investigate the influence of G-CSF on proliferation and the repopulating potential of myeloidbiased, long-term HSC (CD201⁺CD150⁺CD48^–CD41^– CD34^–KSL) and lymphoid-biased, short-term HSC (CD201⁺CD150^–CD48^–CD41^–CD34^–KSL).

Understanding the direct influences of G-CSF on HSC could improve our understanding of HSC responses to an increase in G-CSF level caused by inflammation.⁶ The study by Xie et al. shows that G-CSF acts directly on lymphoid- biased, short-term HSC but not on myeloid-biased HSC. Interestingly, G-CSF cooperates with stem cell factor in driving the expansion of lymphoid-biased, shortterm HSC in culture and in maintaining the in vivo repopulating potential of such cultures. These findings suggest that G-CSF-mediated effects on lymphoid-biased, shortterm HSC may contribute to the previously noted enhancement of early lymphopoiesis of bone marrow stem and progenitor cells after exposure to G-CSF.⁷ In contrast, however, G-CSF is also known to instruct bone marrow stromal cells to suppress the function of committed progenitors of B-lymphopoiesis.² The functional relevance of the G-CSF-mediated priming of early lymphoid progenitor cells and lymphoid-biased HSC^5,7 in association with G-CSF-mediated impairment in the progression of lymphopoiesis from committed progenitor cells² should be delineated in future studies.

The primary role of G-CSF is currently seen in activation of myelopoiesis to strengthen myeloid immune responses, such as the recruitment of neutrophils during bacterial lung infections.⁸ However, the simultaneous priming of early lymphoid progenitor cells and lymphoidbiased HSC by G-CSF may also be important to ensure prompt reactivation of lymphopoiesis after the initial induction of myeloid cell-driven immune responses. The sequential coordination of such immune actions by GCSF seems to be an interesting area of future research.

Understanding direct influences of G-CSF on HSC could also be relevant for our understanding of HSC aging. During mouse aging, the number of myeloidbiased HSC increases more than 10-fold, whereas the number of lymphoid-biased HSC shows only a mild (2- fold) increase.^9,10 Xie et al. revealed that G-CSF improves the maintenance of lymphoid-biased HSC in culture, but does not have direct effects on myeloid-biased HSC. Whether G-CSF could contribute to the in vivo maintenance of lymphoid-biased HSC remains to be seen. Interestingly, in humans, G-CSF levels in the serum were reported to decrease during aging and this decrease was pronounced in patients with Alzheimer disease.¹¹ The findings of Xie et al. suggest that aging-associated declines in G-CSF level could contribute to the relative reduction in the self-renewal of lymphoid-biased HSC versus myeloid-biased HSC during aging. It would be interesting to investigate whether G-CSF has similar effects on human lymphoid-biased HSC as those on murine HSC described by Xie et al. However, the discrimination between different subtypes of HSC (lymphoid vs. myeloid-biased) has not yet been established in humans.

Figure 1.Granulocyte colony-stimulating factor influences the balance of myelopoiesis and lymphopoiesis. Granulocyte colony-stimulating factor (G-CSF) leads to mobilization of hematopoietic stem cells (HSC) by disrupting the function and maintenance of specific niche cells. G-CSF enhances expansion of lymphoid (Ly)-biased, shortterm HSC in culture and maintains their in vivo repopulating potential. In contrast, G-CSF does not have a direct effect on purified myeloid (My)-biased, long-term HSC. Apart from regulating HSC, G-CSF can also increase myelopoiesis and impair lymphopoiesis by regulating committed progenitor cells.

In addition, it would be of great interest to analyze the influence of other aging-related factors on G-CSF levels and HSC aging. Telomere dysfunction occurs as a consequence of telomere shortening and represents one of the hallmarks of aging. Telomere shortening induces cellular senescence and a strong increase in the secretion of proinflammatory cytokines by senescent cells - referred to as the senescence-associated secretory phenotype (SASP).¹² Of note, senescent cells also show strong increases in the secretion of G-CSF.¹³ An accumulation of senescent cells have been described to occur in various tissues of primates, including humans, during aging.^14-16 Interestingly, genetic studies on telomerase knockout mice revealed that G-CSF increases in blood serum as a consequence of telomere dysfunction, which led to impairments in lymphopoiesis and myeloid-skewed hematopoiesis.¹⁷ This phenotype is very similar to that present in aging humans, which is also characterized by increases in myeloid relative to lymphoid cells in the blood.¹⁸ While studies on human serum showed decreases in G-CSF during aging, future studies should investigate whether the accumulation of senescent cells in bone marrow tissue may lead to increases in G-CSF levels in the micro-milieu of HSC and lymphoid progenitor cells. If G-CSF does indeed contribute to the reduction in lymphopoiesis during aging, this could be related to the inhibitory effect of G-CSF on committed lymphoid progenitor cells.²

A direct influence of G-CSF on HSC could also be relevant for the clinical usage of G-CSF. It has been shown that macrophage colony-stimulating factor acts directly on HSC to enhance myeloid differentiation, which has positive effects in protecting HSC-transplanted mice from Aspergillus infection.¹⁹ Two of the main applications of G-CSF are to ameliorate chemotherapy-induced neutropenia and to mobilize HSC to be used for mobilized peripheral blood (MPB) transplantation. G-CSF leads to the mobilization of HSC by disrupting the function and maintenance of specific niche cells.²⁰ It remains to be determined whether direct effects of G-CSF on lymphoid- biased HSC would influence the mobilization of sub-populations of HSC. If so, the method of mobilization could have an impact on transplantation results. In breast cancer patients who need a transplant of autologous MPB as part of their anticancer therapy, the transplantation of purified HSC improved the survival outcomes compared to those receiving non-purified MPB (https://doi.org/10.1016/j.bbmt.2011.07.009). It remains to be seen whether direct effects of G-CSF on HSC may influence transplantation outcomes.

In brief, the study by XIe et al. provides very interesting new data indicating that G-CSF can act directly on lymphoid- biased but not on myeloid biased HSC. This finding may have implications for our understanding of immune responses, HSC aging, and bone marrow transplantation therapies.

Footnotes

Correspondence

K. LENHARD RUDOLPH - lenhard.rudolph@leibniz-fli.de

Disclosures

No conflicts of interest to disclose.

Contributions

YC and KLR wrote the editorial together.