Microgravity and Cell Adherence

Cell adhesion is an inevitable precondition for enabling cells to assemble into three-dimensional tissues [...].

last 31st parabola was observed [16]. This suggested that genes of adhesion-related proteins responded to microgravity, before apoptosis became obvious. A very fast induction of structural changes of adhesion and cytoskeletal proteins was also proved by a rocket flight, which exposed the cells to real microgravity for six minutes. At the end of this flight, structural alterations of tubulin and F-actin were observed by life-cell microscopy [17]. Although very quickly induced, cytoskeletal changes persisted in Ewing's sarcoma cells at least over 24 h culturing on the RPM [13]. The changes were more obvious in spheroid cells than in adherent cells, which both had been cultured on the RPM. Only in spheroid cells, CXCR4 and CD44 expression were significantly enhanced, while CD44 protein decreased in spheroids and adherent cells. However, the inhibition of CXCR4 did not change spheroid count or structure. While the changes described above occurred in Ewing's Sarcoma cells, CAV1 was up-regulated. This is further proof of the important role which CAV1 plays in the regulation of cell adherence under microgravity. Caveolin-1 is a scaffold protein that is anchored in the lipid bilayer and has binding sites for various proteins. It responds to changes in gravity and has influence on spheroid formation [20]. The observations on the sarcoma cells [13] fits to the knowledge obtained by a semantic approach, which revealed two enzymes whose activity depends on a binding to caveolin-1. These enzymes either sialylate (ST6GAL1) or de-sialylate (NEU1) the extracellular domains of receptor proteins, which recognize neighboring cells or ECM proteins. In this way they generate a status of sialylation, which has influence on binding activity of adhesion receptor proteins and regulates cell migration and metastasis in vivo [18]. A link between cell adhesion in vitro and metastasis in vivo was also proved by reviewing the behavior of human melanoma cells with different metastatic potential [19]. Different types of melanocyte showed different melanocyte-extracellular matrix interactions under simulated microgravity, while intracellular signals of cyclic guanosine-monophosphate (cGMP) were regulated differently.
The importance of the strength by which tissue cells bind to the underlay was further shown by Shuliang Shi et al. [11]. After culturing healthy human umbilical vein endothelial cells (HUVEC) or malignant human breast cancer cells in a rotating wall vessel (RWVS), the authors observed that adhesion strength of the cells to the underlay decreased so that more cells could be exfoliated under equal treatment from slips mounted on the RWVS than from equal slips used for culturing these cells at 1g normal gravity. Together with the decrease of adhesion strength integrin β1, paxillin and e-cadherin proteins were reduced, while the EMT (epithelial-mesenchymal transition) transcription factors Snail, Twist, and ZEB1 were up-regulated. Hence, the paper strongly suggests a link between the adhesion strength to the extracellular matrix via integrin β1 or to neighboring cells via e-cadherin and an induction of EMT. Paxillin appears to be an important mediator between the adhesion receptors and the EMT. When cells are exposed to simulated microgravity, paxillin regulates the stability of adhesion complexes depending on the presence of ASAP1 or Bcar1 [21].
The strength of cell adherence appears to play a role in wound healing also. This can be suggested upon the report of Cialdai et al. [15]. They had investigated the influence of simulated microgravity on wound healing in vivo [15]. The authors observed a delay and structural alterations in the repair tissue, when a leech with a wound was kept on an RPM. This impairment of wound healing appeared to be due to an impairment in fibroblast migration to the wound site under simulated microgravity. It could be counteracted by adding platelet rich plasma (PRP), but a defined factor causing this effect remains to be determined, Overall, this Special Issue provides new data and novel insights into the complexity of cell adherence and its alteration upon omitting gravity. Knowledge is provided about the causes and consequences of microgravity-caused reduction in cell adhesion strength and their relationships to tumor growth and metastasis as well as to wound healing. Further investigation of the numerous proteins and genes linked to the cell adhesion behavior under microgravity will surely show targets for curing cancer or supporting wound healing.
Acknowledgments: Many thanks to all authors and co-authors contributing to this special issue.

Conflicts of Interest:
The author declares no conflict of interest. Zinc finger E-box-binding homeobox 1