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    • Previous research has shown that

    2018-10-20

    Previous research has shown that spaceflight causes suppression of erythropoiesis (Davis et al., 1996), reduction in circulating red blood cells, increased platelet formation, and reduction in plasma volume resulting in a condition referred to as spaceflight anemia (Smith, 2002), however the molecular mechanism for these alterations is currently still being debated. Research has shown that in microgravity, erythrocytes are removed from circulation at a normal rate but fewer new resperidone replace those destroyed resulting in an overall decrease in circulating red blood cell mass, (Smith, 2002; Alfrey et al., 1996). This has been suggested to be due to either suppressed erythropoiesis during spaceflight, failure of reticulocytes to be released into the blood stream, or immediate destruction of newly released reticulocytes (Udden et al., 1995; Smith, 2002; Allebban et al., 1996; Lane et al., 1996; Talbot and Fisher, 1986). Our results show increased number and striking clustering of mature erythrocytes in the bone marrow cavity of microgravity samples, indicating that erythropoiesis occurs in microgravity but cells are retained within the bone marrow compartment rather than being released into circulation. This may explain the observed increased fucosylation of erythrocytes due to possible increased retention time in the bone marrow compartment rather than release into the blood stream (Holm et al., 2002). Furthermore, large numbers of highly fucosylated erythrocytes could result in activation of a negative feedback mechanism, possibly by fucose or fucosylation site depletion, and resulting inhibition of FUT1 expression as described above in our gene expression results. It is possible that marrow retention of non-motile red blood cells could be the result of decreased mechanical stimulation in microgravity. Specifically during walking or running at 1g, bone intramedullary pressure in the marrow compartment is known to undergo cyclical increase and decrease, possibly facilitating the adhesion to, and passage of, erythrocytes through the marrow endothelial sinus blood barrier into circulation. Loss or reduction of cyclical loading of the skeleton in microgravity likely prevents intramedullary pressure oscillations that may be required for dislodging and releasing mature erythrocytes into circulation, resulting in the observed accumulation of red blood cells in the marrow compartment and decreased red blood cell mass in circulation. These cells may then be released from the marrow compartment upon return to 1g and mechanical stimulation, allowing the organism to recover from spaceflight anemia. Alternatively, it is also possible that expression of adhesion molecules, such as integrins and cadherins, in erythrocytes or the sinus endothelium may be altered in such a way by microgravity that prevents erythrocyte–endothelial interactions and entry of erythrocytes into circulation. Finally, we observed a decrease in marrow compartment megakaryocytes in microgravity samples compared to 1g controls. Previous research has found an increase in megakaryocyte mobilization in the blood stream through expression of integrin-β1 in response to cardiovascular stress and/or disease (Van Pampus et al., 1994). This enables circulating megakaryocytes to produce and release platelets closer to the site of stress or injury (Van Pampus et al., 1994). As cardiovascular deconditioning and stress are known to occur in microgravity, it is possible that decreased numbers of megakaryocytes in microgravity marrow samples may be due to increased mobilization and release of these cells into the circulation. This is also in agreement with previous research indicating platelet number increases significantly in mice during spaceflight (Gridley et al., 2003).
    Conclusions
    Introduction Cardiovascular disease is one of the major causes of death in the United States, accounting for 31.9% of all deaths in 2010 (Go et al., 2014). The discovery that functional cardiomyocytes (CM) can be obtained from human embryonic stem cells (hESC) or human induced pluripotent stem cells (hiPSC) (Itskovitz-Eldor et al., 2000; Zwi et al., 2009), led to the increase in research directed toward the utilization of these CMs as a potential source for treating heart diseases by cell therapy (Burridge et al., 2012). As such, substantial effort has been made to improve CM differentiation efficiencies (Burridge et al., 2011; Lian et al., 2012) by developing multiple differentiation protocols with some capable of producing more than 90% pure populations of CMs (Burridge et al., 2012; Chen et al., 2014; Xu, 2012) in lab-scale 2D platforms. However, due to the large quantities of CMs needed for cell therapy, development of methodologies for 3D suspended scalable production platforms still remain a major challenge (Burridge et al., 2012; Chen et al., 2014).