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A study published today in the journal Stem Cell Reports suggests that a combination of two clinically approved drugs – Viagra and Plerixafor – efficiently and rapidly mobilizes blood stem cells from the bone marrow into the bloodstream in a mouse model.1



Hematopoietic stem cell transplantation



Each year, over 25,000 hematopoietic stem cell transplantations (HSCTs) are performed as a curative treatment for conditions such as lymphoma, leukemia, hemoglobinopathies, myelodysplastic and myeloproliferative syndromes.2 HSCs are characterized by their ability to self-renew and differentiate into all mature blood lineages. Their transplantation to treat the aforementioned syndromes involves replacing abnormal blood-forming stem cells with healthy cells.



As HSCs reside in the bone marrow, collecting them for transplants traditionally involved drilling into the hip bone and using a needle to extract cells directly. In modern medicine, it is now more common to obtain the cells from whole blood, using drugs to coax the stem cells to migrate from the bone marrow into the bloodstream.



The current regimen used to encourage stem cell mobilization is multi-day injections of the pharmacological agent granulocyte-colony stimulating factor, or G-CSF, prior to stem cell collection. Whilst this approach has proven effective in most cases, it is limited by adverse side effects such as fatigue, bone pain and nausea, and is expensive. Certain subpopulations of patients are also unable to tolerate this drug regimen, for example individuals who have undergone chemotherapy, elderly frail patients or individuals with sickle cell disease. Unfortunately, this means that bone marrow transplantation is not a viable option for them.



A second pharmacological agent, Plerixafor (AMD3100), also used to mobilize HSCs. However, used as a single agent, it is limited in its efficacy, and is commonly adopted as a salvaging agent when the G-CSF regimen fails.



Scientists are therefore directing research efforts towards improving the harvesting protocols for HSCs. Professor Camilla Forsberg, a stem cell biologist from the University of California Santa Cruz says, "Better harvesting protocols would significantly improve the success rate for current indications and open curative hematopoietic cell therapies to a wider spectrum of disorders."



Let's talk about Viagra



Viagra (sildenafil citrate) is a drug approved by the U.S. Food and Drug Administration (FDA) for erectile dysfunction. A vasodilator, Viagra was first developed to treat patients with high blood pressure, heart disease, and associated vascular disorders. It exerts its effects by inhibiting the enzyme phosphodiesterase type 5 (PDE5), blocking the degradation of cyclic GMP in the smooth muscle cells lining blood vessels, causing vasodilation (in short, it widens your blood vessels).



In a new study published by the Forsberg lab in Stem Cell Reports, researchers have explored whether Viagra might be a viable option for HSCT to help overcome the issue of stem cell mobility.



This work is based on previous experiments by the team in which they demonstrated that increasing vascular permeability encourages HSC mobilization from the bone marrow to the bloodstream.3,4



Applying Viagra and Plerixafor



First, the scientists tested the effects of Viagra on HSC mobilization using a mouse model. They administered a single dose of Viagra orally at 3mg/kg. 2 hours later, analysis of total perfused blood did not show a detectable increase in HSCs. Higher doses of Viagra (10mg/kg) administered for three consecutive days still failed to mobilize a significant number of HSCs. The authors therefore emphasize to individuals taking this medication that they do not have to worry about unintentionally mobilizing their HSCs.



Forsberg and colleagues administered a single subcutaneous dose of Plerixafor to the mouse model. This led to "modest, but reproducible" HSC mobilization.



They then decided to test the effects of Viagra combined with Plerixafor. They found that just one single oral dose of Viagra significantly improved the Plerixafor-induced mobilization of HSCs in a 2-hour protocol. This increase was 7.5-fold in size compared to controls and was transient; HSC levels had returned to baseline four hours post-treatment. The scientists found that three days of oral Viagra, when combined with a single injection of Plerixafor, was yet more effective – resulting in an 8.4-fold increase in HSCs compared to control mice.



Combination therapy produces viable stem cells



In order to investigate the attributes of the HSCs produced from combination therapy, Forsberg and colleagues harvested HSCs from the blood or bone marrow of the mice treated with either Plerixafor alone or in combination with Viagra. They transplanted these cells into recipient mice and found that a combination of Plerixafor and Viagra resulted in the long-term engraftment of functional, self-renewing, multipotent hematopoietic stem cells. The results of the study therefore suggest that this approach may be a suitable option for HSCT in patients.



"Given that both drugs are FDA approved, they could be relatively quickly tested in human volunteers," says Forsberg, a stem cell biologist at the University of California, Santa Cruz. If proven safe and effective in human clinical studies, "clinicians could consider these findings when selecting treatment strategies for their patients and for volunteer donors of hematopoietic cells used in transplantation therapies."



The authors note that whilst this combination therapy may not completely replace G-CSF, it may be a more suitable option for individuals who cannot tolerate G-CSF therapy.



The next steps? Facilitating the movement of these results from the laboratory to the clinic. Forsberg says: "In our lab, we are also continuing to pursue the molecular and cellular mechanisms that influence hematopoietic stem cell trafficking and how these change with age and disease, with a focus on vascular integrity." She concludes, "One important goal is to overcome variability in hematopoietic stem cell mobilization among different people with different disease profiles and treatment histories."



References:





1. Hatzimichael and Tuthill (2010) Hematopoietic stem cell transplantation. Stem Cells and Cloning: Advances and Applications. DOI: 10.2147/SCCAA.S6815.





2. Smith-Berdan et al. (2019) Viagra Enables Efficient, Single-Day Hematopoietic Stem Cell Mobilization. Stem Cell Reports. DOI: http://dx.doi.org/10.1016/j.stemcr.2019.09.004.





3. Smith-Berdan et al. (2011) ROBO4 cooperates with CXCR4 to specify hematopoietic stem cell localization to bone marrow niches. Cell Stem Cell. DOI: https://doi.org/10.1016/j.stem.2010.11.030.





4. Smith-Berdan et al. (2015) ROBO4-mediated vascular integrity regulates the directionality of hematopoietic stem cell trafficking. Stem Cell Reports. DOI: https://doi.org/10.1016/j.stemcr.2014.12.013