Validation of human ex-vivo models for studies on wound healing process in microgravity conditions

There are many factors influencing the wound healing process, be they biochemical, physical, local, systemic, and exogenous factors, including microgravity, as gravity and mechanical forces have an effect at the tissue and cell level. Local factors are, for example, the presence of pathogens and/or extraneous bodies at the level of the wound, hypoxia, vascular defects, all factors that represent the characteristics of the wound itself. Systemic factors, on the other hand, are represented by the health status of the organism, i.e. disease (e.g. diabetes), age, sex, nutrition, stress, smoking, alcoholism, all factors that can affect wound regeneration.
Several studies on the effects of unloading or microgravity exposure have been conducted in vitro (cell cultures) and in vivo (rodents and invertebrates). To date, only a few have been conducted in the real space environment; most are conducted in terrestrial microgravity simulators, but it is known that the space environment, and thus microgravity conditions, have negative effects on the wound repair process. In fact, the ability to heal is compromised, as found in studies of skin wound repair in rats, due to reduced deposition of collagen and granulation tissue (Davidson, 1998).
Endothelial cells are mechanosensitive cytotypes; they undergo morphological changes in response to the tension exerted by fluid flow and are affected by mechanical forces such as gravity, vibration and pressure. Microgravity is able to induce a change in morphology (shape and size) (Kapitonova et al., 2012), metabolism (Chakraborty et al., 2018) and gene expression, with reference to genes whose products are involved in stress responses, oxidative phosphorylation and cell-ECM interaction and adhesion (Versari et al., 2013).
Many pathways are altered under microgravity conditions, and there are conflicting results in the literature. Altered is the recruitment of leucocytes, the expression of pro-inflammatory cytokines, and the rearrangement of the cytoskeleton with up-regulation and down-regulation of components such as F-actin, laminin, collagen I, fibronectin and osteopontin, which leads to an inflammatory phenotype. NO production is also altered, due to overexpression of eNOS (Shi et al., 2012; Siamwala et al., 2010), cell survival is reduced, cells are induced to apoptosis and angiogenesis is compromised (Morbidelli et al., 2005; Maier et al., 2015). Regarding angiogenesis, different studies have shown contrasting results, depending on different cytotypes, e.g. HUVECs would be induced to withdraw from the angiogenic process (Shi et al., 2017), in other ECs, however, this process, as well as cell proliferation and migration, would even be stimulated (Dittrich et al., 2018; Ratushnyy et al., 2018).