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13 aprile 2018

Microgravity as a biological tool to examine host–pathogen interactions and to guide development of therapeutics

Space exploration programs have long been interested in the effects of spaceflight on biology. Bacterial behavior has been shown to be altered both in space and under simulated microgravity conditions. In some cases, bacteria appear attenuated, whereas in others virulence is enhanced. The microgravity environment can be exploited as a tool in the search for new therapeutics and preventatives against pathogenic bacteria for use both in space and on Earth.

For many years, the effects of spaceflight on cell physiology have been explored in experiments performed both on Earth and in orbit. An extensive list of cell types has been investigated, including human cells of the gut, heart muscle and liver, immune cells, cancer cells and organisms such as bacteria and fungi (Ellen E et al., 2016). These cells almost universally showed alterations in cell function during spaceflight, when compared to ground controls e.g. changes in cell distribution, morphology and activation, as well as specific effects such as decreased leukocyte levels, decreased proliferation of bone marrow progenitor cells and altered proprioception. However, the cost and physical limitations of performing experiments on space missions made these experiments prohibitively expensive and in the 1970s, engineers at the National Aeronautics and Space Administration (NASA) began to develop a cell culture system to model fluid dynamics experienced during space flight: the rotating wall vessel (RWV). This apparatus utilizes solid body rotation about the horizontal axis to minimize shear stress and decrease the gravitational force on particles in the fluid (Wolf and Schwarz 1991). It is composed of a cylindrical chamber which is completely filled with growth medium and it utilizes a gas exchange system which delivers oxygen to the media via axial diffusion of dissolved gases. The RWV environment is advantageous in tissue engineering, due largely to the extremely low shear conditions. This allows cells to aggregate (Dintenfass et al. 1986; Hymer et al. 1996), forming large, complex spheroids (organoids). The microgravity environment may also help to promote aggregation, as cells grown under microgravity conditions show higher levels of collagen made by human-derived fibroblasts and integrins and other adhesion molecules generated by splenocytes and lymphocytes (Grove, Pishak and Mastro 1995; Seitzer et al. 1995). This has allowed researchers to cultivate complex aggregates which recreate the structural diversity of living tissue, such as bone (Hwang et al. 2009), cardiac muscle (Freed and Vunjak-Novakovic 1997), gut (Nickerson et al. 2001; Salerno- Goncalves, Fasano and Sztein 2011; Sato et al. 2011) and liver (Zhang et al. 2014). These organoid models are becoming increasingly used in the areas of host–pathogen interactions because they are more complex than traditional cell culture monolayers, allowing for more natural interactions between host cells and pathogens. The majority of work on RWV-developed organoids for host–pathogen interactions has been performed using cells from the gastrointestinal tract. Several authors have shown that culture of immortalized gut epithelial cells in the RWV allows for the differentiation of cells into multiple lineages, including enterocytes, M cells, goblet cells and Paneth cells (Nickerson et al. 2001; Honer Zu Bentrup et al. 2006; Salerno-Goncalves, Fasano and Sztein 2011; Drummond, Nickerson and Coyne 2016). The results of these experiments have been immensely informative and have directed future pharmacological research. Further explorations of the effects of microgravity on cell biology will undoubtedly open up new avenues of research and development of novel therapeutics, which could in turn have unforeseen benefits to the prevention and treatment of disease both on Earth and in space (Higginson E et al., 2016).

 

 

Figure 1 from Costa-Almeida R et al., Gravity, Tissue Engineering, and the Missing Link. Trend in Biotechnology, 11:2017. Strategies for Bidirectional Crosstalk between Altered-Gravity Research and Tissue Engineering. (A) Microgravity as a tool in tissue engineering. (i) Cellular self-assembly process for microtissue formation. Cell s exposed to microgravity, either in cell suspension or detaching from 2D culture, tend to aggregate and form multicellular spheroids, which can be later combined and fused to form microtissues. (ii) Microgravity can be used for stem cell expansion and maintenance of stemness properties, including pluripotency markers and multilineage differentiation. The example provided uses adipose stem cells(ASCs).   (iii) Given the existence of pluripotent stem cell markers in ASCs, early control over stem cell fate constitutes an interesting hypothes is to be further explored through the use of cultures under microgravity to potentially generate new cell sources for tissue engineering approaches. (B) Hypergravity as a tool in tissue engineering.(i) Exposing cells to hypergravity may constitute a way of simulating (over) loading and of modulating the behavior of various cell types, a potential strategy for tissue engineering. (ii) Exposing endothelial cells to hypergravity resulted in enhanced endothelial barrier formation and integrity. (iii) Hypergravity exposure improved myoblast differentiation in a g-level-dependent.

 

 

References

 Ellen E. Higginson, James E. Galen, Myron M. Levine, Sharon M. Tennant; Microgravity as a biological tool to examine host–pathogen interactions and to guide development of therapeutics and preventatives that target pathogenic bacteriaPathogens and Disease, Volume 74, Issue 8, 1 November 2016.

Costa-Almeida R et al., Gravity, Tissue Engineering, and the Missing Link. Trend in Biotechnology, 11:2017. Strategies for Bidirectional Crosstalk between Altered-Gravity Research and Tissue Engineering.

Dintenfass L, Osman P, Maguire B et al. Experiment on aggregation of red cells under microgravity on STS 51-C. Adv Space Res 1986;6:81–84.

Drummond CG, Nickerson CA, Coyne CB. A three-dimensional cell culturemodel to study enterovirus infection of polarized intestinal epithelial cells. mSphere 2016;1:e00030-15.

Freed LE, Vunjak-Novakovic G. Microgravity tissue engineering. In Vitro Cell Dev-An 1997;33:381–5.

Grove DS, Pishak SA, Mastro AM. The effect of a 10-day space flight on the function, phenotype, and adhesionmolecule expression of splenocytes and lymph node lymphocytes. Exp Cell Res 1995;219:102–9.

Honer Zu Bentrup K, Ramamurthy R, Ott C et al. Threedimensional organotypic models of human colonic epithelium to study the early stages of enteric salmonellosis. Microbes Infect 2006;8:1813–25.

Hymer W, Grindeland R, Salada T et al. Experimental modification of rat pituitary growth hormone cell function during and after spaceflight. J Appl Physiol 1996;80:955–70.

Hwang Y-S, Cho J, Tay F et al. The use ofmurine embryonic stem cells, alginate encapsulation, and rotary microgravity bioreactor in bone tissue engineering. Biomaterials 2009;30:499–507.

Nickerson CA, Goodwin TJ, Terlonge J et al. Three-dimensional tissue assemblies: novel models for the study of Salmonella enterica serovar Typhimurium pathogenesis. Infect Immun 2001;69:7106–20.

Nickerson CA, Ott CM, Mister SJ et al. Microgravity as a novel environmental signal affecting Salmonella enterica serovar Typhimurium virulence. Infect Immun 2000;68:3147–52.

Salerno-Goncalves R, Fasano A, Sztein MB. Engineering of a multi-cellular organotypic model of the human intestinal mucosa. Gastroenterology 2011;141:e18.

Sato T, Stange DE, Ferrante M et al. Long-term expansion of epithelial organoids from human colon, adenoma, adenocarcinoma, and Barrett’s epithelium. Gastroenterology 2011;141:1762–72.

Seitzer U, Bodo M, Mu¨ ller PK et al. Microgravity and hypergravity effects on collagen biosynthesis of human dermal fibroblasts. Cell Tissue Res 1995;282:513–7.

Wolf D, Schwarz RP. Analysis of gravity-induced particle motion and fluid perfusion flow in the NASA-designed rotating zerohead-space tissue culture vessel. NASA Technical Paper 3143, Houston, TX, 1991.

Zhang S, Zhang B, Chen X et al. Three-dimensional culture in a microgravity bioreactor improves the engraftment efficiency of hepatic tissue constructs in mice. J Mater Sci: Mater M 2014;25:2699–709.

 

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