Changes in interstitial fluid flow, mass transport and the bone cell response in microgravity and normogravity

Abstract

In recent years, our scientific interest in spaceflight has grown exponentially and resulted in a thriving area of research, with hundreds of astronauts spending months of their time in space. A recent shift toward pursuing territories farther afield, aiming at near-Earth asteroids, the Moon, and Mars combined with the anticipated availability of commercial flights to space in the near future, warrants continued understanding of the human physiological processes and response mechanisms when in this extreme environment. Acute skeletal loss, more severe than any bone loss seen on Earth, has significant implications for deep space exploration, and it remains elusive as to why there is such a magnitude of difference between bone loss on Earth and loss in microgravity. The removal of gravity eliminates a critical primary mechano-stimulus, and when combined with exposure to both galactic and solar cosmic radiation, healthy human tissue function can be negatively affected. An additional effect found in microgravity, and one with limited insight, involves changes in dynamic fluid flow. Fluids provide the most fundamental way to transport chemical and biochemical elements within our bodies and apply an essential mechano-stimulus to cells. Furthermore, the cell cytoplasm is not a simple liquid, and fluid transport phenomena together with viscoelastic deformation of the cytoskeleton play key roles in cell function. In microgravity, flow behavior changes drastically, and the impact on cells within the porous system of bone and the influence of an expanding level of adiposity are not well understood. This review explores the role of interstitial fluid motion and solute transport in porous bone under two different conditions: normogravity and microgravity.

References

[1] Grigor’ev AI. [Physiological problems of manned mission to Mars]. Ross. Fiziol. Zh . IM. IM. Sechenova, 2007, 93: 473-484

[2] Grimm D et al. The impact of microgravity on bone in humans. Bone, 2015, 87: 44-56

[3] Moreno-Villanueva M, Wong M, Lu T, Zhang Y, Wu H. Interplay of space radiation and microgravity in DNA damage and DNA damage response. npj Microgravity, 2017, 3

[4] Krause AR, Speacht TL, Zhang Y, Lang CH, Donahue HJ. Simulated space radiation sensitizes bone but not muscle to the catabolic effects of mechanical unloading. PLoS One, 2017, 12: e0182403

[5] Brügmann B. Fundamentals of numerical relativity for gravitational wave sources. Science, 2018, 361: 366-371

[6] Devahdhanush VS et al. Experimental heat transfer results and flow visualization of vertical upflow boiling in Earth gravity with subcooled inlet conditions – In preparation for experiments onboard the International Space Station. Int. J. Heat. Mass Transf., 2022, 188: 122603

[7] Rezig M, Bellakhal G, Chahed J. On turbulence and interfacial momentum transfer in dispersed gas-liquid flows: Contribution of bubbly flow experiments under microgravity conditions. Int. J. Multiph. Flow., 2022, 147: 103903

[8] Neely AN, Maley MP. Survival of Enterococci and Staphylococci on hospital fabrics and plastic. J. Clin. Microbiol, 2000, 38: 724-726

[9] Ashkarran AA, Suslick KS, Mahmoudi M. Magnetically levitated plasma proteins. Anal. Chem., 2020, 92: 1663-1668

[10] Norouzi N, Bhakta HC, Grover WH. Sorting cells by their density. PLoS One, 2017, 12: e0180520

[11] Pain RW. Body fluid compartments. Anaesth. Intensive Care, 1977, 5: 284-294

[12] Leeman M, Choi J, Hansson S, Storm MU, Nilsson L. Proteins and antibodies in serum, plasma, and whole blood—size characterization using asymmetrical flow field-flow fractionation (AF4). Anal. Bioanal. Chem., 2018, 410: 4867-4873

[13] Zhang Z, Witham S, Alexov E. On the role of electrostatics in protein–protein interactions. Phys. Biol., 2011, 8: 035001

[14] Weber, C., Michaels, T., Mahadevan, L. Spatial control of irreversible protein aggregation. Elife. 8, e42315 (2019).

[15] Todd P. Gravity-dependent phenomena at the scale of the single cell. ASGSB Bull., 1989, 2: 95-113

[16] Coccarelli A, Boileau E, Parthimos D, Nithiarasu P. An advanced computational bioheat transfer model for a human body with an embedded systemic circulation. Biomech. Model Mechanobiol., 2016, 15: 1173-1190

[17] Ray L, Iliff JJ, Heys JJ. Analysis of convective and diffusive transport in the brain interstitium. Fluids Barriers CNS, 2019, 16: 6

[18] Kapellos, G. E. & Alexiou, T. S. Modeling momentum and mass transport in cellular biological media: from the molecular to the tissue scale. In: Transport in Biological Media. 1–40 (Elsevier, 2013).

[19] Swabb EA, Wei J, Gullino PM. Diffusion and convection in normal and neoplastic tissues. Cancer Res., 1974, 34: 2814-2822

[20] Waldeland JO, Evje S. Competing tumor cell migration mechanisms caused by interstitial fluid flow. J. Biomech., 2018, 81: 22-35

[21] Polacheck WJ, Charest JL, Kamm RD. Interstitial flow influences direction of tumor cell migration through competing mechanisms. Proc. Natl. Acad. Sci., 2011, 108: 11115-11120

[22] Yang, Y. & Leong, K. W. Microfluidic cell culture platforms with embedded nanoscale features. In: Microfluidic Cell Culture Systems. 3–26 (Elsevier, 2013).

[23] Chary SR, Jain RK. Direct measurement of interstitial convection and diffusion of albumin in normal and neoplastic tissues by fluorescence photobleaching. Proc. Natl. Acad. Sci., 1989, 86: 5385-5389

[24] Guevorkian, K., Brochard-Wyart, F., Gonzalez-Rodriguez, D. Flow dynamics of 3D multicellular systems into capillaries. In: Viscoelasticity and Collective Cell Migration. 193–223 (Elsevier, 2021).

[25] Wang L. Solute transport in the bone lacunar-canalicular system (LCS). Curr. Osteoporos. Rep., 2018, 16: 32-41

[26] Piekarski K, Munro M. Transport mechanism operating between blood supply and osteocytes in long bones. Nature, 1977, 269: 80-82

[27] Cummaudo M et al. Histomorphometric analysis of osteocyte lacunae in human and pig: exploring its potential for species discrimination. Int. J. Leg. Med., 2019, 133: 711-718

[28] Kameo Y, Adachi T, Sato N, Hojo M. Estimation of bone permeability considering the morphology of lacuno-canalicular porosity. J. Mech. Behav. Biomed. Mater., 2010, 3: 240-248

[29] Beno T, Yoon Y-J, Cowin SC, Fritton SP. Estimation of bone permeability using accurate microstructural measurements. J. Biomech., 2006, 39: 2378-2387

[30] Cowin SC, Cardoso L. Blood and interstitial flow in the hierarchical pore space architecture of bone tissue. J. Biomech., 2015, 48: 842-854

[31] Lovett M, Lee K, Edwards A, Kaplan DL. Vascularization strategies for tissue engineering. Tissue Eng. Part B Rev., 2009, 15: 353-370

[32] Weinbaum S, Cowin SC, Zeng Y. A model for the excitation of osteocytes by mechanical loading-induced bone fluid shear stresses. J. Biomech., 1994, 27: 339-360

[33] Gatti V, Azoulay EM, Fritton SP. Microstructural changes associated with osteoporosis negatively affect loading-induced fluid flow around osteocytes in cortical bone. J. Biomech., 2018, 66: 127-136

[34] Adachi T, Kameo Y, Hojo M. Trabecular bone remodelling simulation considering osteocytic response to fluid-induced shear stress. Philos. Trans. R. Soc. A Math. Phys. Eng. Sci., 2010, 368: 2669-2682

[35] Ganesh T, Laughrey LE, Niroobakhsh M, Lara-Castillo N. Multiscale finite element modeling of mechanical strains and fluid flow in osteocyte lacunocanalicular system. Bone, 2020, 137: 115328

[36] Wu X et al. Mathematically modeling fluid flow and fluid shear stress in the canaliculi of a loaded osteon. Biomed. Eng. Online, 2016, 15

[37] Liu H-Y et al. Research on solute transport behaviors in the lacunar-canalicular system using numerical simulation in microgravity. Comput. Biol. Med., 2020, 119: 103700

[38] Wang H, Liu H, Wang X, Zhang C. The lack of mass transfer in bone lacunar-canalicular system may be the decisive factor of osteoporosis under microgravity. Life Sci. Sp. Res., 2021, 31: 80-84

[39] Verbruggen SW, Vaughan TJ, McNamara LM. Fluid flow in the osteocyte mechanical environment: a fluid–structure interaction approach. Biomech. Model Mechanobiol., 2014, 13: 85-97

[40] Price C, Zhou X, Li W, Wang L. Real-time measurement of solute transport within the lacunar-canalicular system of mechanically loaded bone: Direct evidence for load-induced fluid flow. J. Bone Min. Res., 2011, 26: 277-285

[41] Jansen LE, Birch NP, Schiffman JD, Crosby AJ, Peyton SR. Mechanics of intact bone marrow. J. Mech. Behav. Biomed. Mater., 2015, 50: 299-307

[42] Curtis KJ, Oberman AG, Niebur GL. Effects of mechanobiological signaling in bone marrow on skeletal health. Ann. N. Y. Acad. Sci., 2020, 1460: 11-24

[43] Hu M et al. Dynamic hydraulic fluid stimulation regulated intramedullary pressure. Bone, 2013, 57: 137-141

[44] Birmingham E, Grogan JA, Niebur GL, McNamara LM, McHugh PE. Computational modelling of the mechanics of trabecular bone and marrow using fluid structure interaction techniques. Ann. Biomed. Eng., 2013, 41: 814-826

[45] Vaughan, T. J., Voisin, M., Niebur, G. L & McNamara, L. M. Multiscale modeling of trabecular bone marrow: understanding the micromechanical environment of mesenchymal stem cells during osteoporosis. J. Biomech. Eng. 37, https://doi.org/10.1115/1.4028986 (2015).

[46] Metzger TA, Schwaner SA, LaNeve AJ, Kreipke TC, Niebur GL. Pressure and shear stress in trabecular bone marrow during whole bone loading. J. Biomech., 2015, 48: 3035-3043

[47] Yao W, Li Y, Ding G. Interstitial fluid flow: the mechanical environment of cells and foundation of meridians. Evid.-Based Complement Alter. Med., 2012, 2012: 1-9

[48] Mogilner A, Manhart A. Intracellular fluid mechanics: coupling cytoplasmic flow with active cytoskeletal gel. Annu. Rev. Fluid Mech., 2018, 50: 347-370

[49] Vogel V, Sheetz M. Local force and geometry sensing regulate cell functions. Nat. Rev. Mol. Cell Biol., 2006, 7: 265-275

[50] Klein-Nulend J, Bacabac R, Bakker A. Mechanical loading and how it affects bone cells: the role of the osteocyte cytoskeleton in maintaining our skeleton. Eur. Cells Mater., 2012, 24: 278-291

[51] Vogel V, Sheetz M. Local force and geometry sensing regulate cell functions. Nat. Rev. Mol. Cell Biol., 2006, 7: 265-275

[52] Alfieri R, Vassalli M, Viti F. Flow-induced mechanotransduction in skeletal cells. Biophys. Rev., 2019, 11: 729-743

[53] Herrmann M et al. Interactions between muscle and bone—where physics meets biology. Biomolecules, 2020, 10: 432

[54] Wang L et al. Mechanical sensing protein PIEZO1 regulates bone homeostasis via osteoblast-osteoclast crosstalk. Nat. Commun., 2020, 11

[55] Sugimoto A et al. Piezo type mechanosensitive ion channel component 1 functions as a regulator of the cell fate determination of mesenchymal stem cells. Sci. Rep., 2017, 7

[56] Tsimbouri PM et al. Stimulation of 3D osteogenesis by mesenchymal stem cells using a nanovibrational bioreactor. Nat. Biomed. Eng., 2017, 1: 758-770

[57] Li MCM, Chow SKH, Wong RMY, Qin L, Cheung WH. The role of osteocytes-specific molecular mechanism in regulation of mechanotransduction – A systematic review. J. Orthop. Transl., 2021, 29: 1-9

[58] Ohashi K, Fujiwara S, Mizuno K. Roles of the cytoskeleton, cell adhesion and rho signalling in mechanosensing and mechanotransduction. J. Biochem., 2017, 161: 245-254

[59] Wittkowske, C., Reilly, G. C., Lacroix, D., Perrault, C. M. In vitro bone cell models: impact of fluid shear stress on bone formation. Front. Bioeng. Biotechnol. 4, 1–22 (2016).

[60] Arnsdorf EJ, Tummala P, Kwon RY, Jacobs CR. Mechanically induced osteogenic differentiation—the role of RhoA, ROCKII and cytoskeletal dynamics. J. Cell Sci., 2009, 122: 546-553

[61] Pavalko FM et al. Fluid shear-induced mechanical signaling in MC3T3-E1 osteoblasts requires cytoskeleton-integrin interactions. Am. J. Physiol., 1998, 275: C1591-C1601

[62] Malone AMD et al. The role of actin cytoskeleton in oscillatory fluid flow-induced signaling in MC3T3-E1 osteoblasts. Am. J. Physiol. Physiol., 2007, 292: C1830-C1836

[63] Myers KA, Rattner JB, Shrive NG, Hart DA. Osteoblast-like cells and fluid flow: cytoskeleton-dependent shear sensitivity. Biochem. Biophys. Res. Commun., 2007, 364: 214-219

[64] Chen JC, Jacobs CR. Mechanically induced osteogenic lineage commitment of stem cells. Stem Cell Res. Ther., 2013, 4: 107

[65] Fritton SP, Weinbaum S. Fluid and solute transport in bone: flow-induced mechanotransduction. Annu. Rev. Fluid Mech., 2009, 41: 347-374

[66] Shi W et al. Primary cilia act as microgravity sensors by depolymerizing microtubules to inhibit osteoblastic differentiation and mineralization. Bone, 2020, 136: 115346

[67] Jin J, Bakker AD, Wu G, Klein-Nulend J, Jaspers RT. Physicochemical niche conditions and mechanosensing by osteocytes and myocytes. Curr. Osteoporos. Rep., 2019, 17: 235-249

[68] Hinton PV, Rackard SM, Kennedy OD. In Vivo Osteocyte Mechanotransduction: Recent Developments and Future Directions. Curr. Osteoporos. Rep., 2018, 16: 746-753

[69] Haller, S. J. & Dudley, A. T. Extracellular mechanotransduction. J. Gen. Physiol. 154, e202113026 (2022).

[70] Wang J, Lü D, Mao D, Long M. Mechanomics: an emerging field between biology and biomechanics. Protein Cell, 2014, 5: 518-531

[71] Jacobs CR et al. Differential effect of steady versus oscillating flow on bone cells. J. Biomech., 1998, 31: 969-976

[72] Liu L et al. Different effects of intermittent and continuous fluid shear stresses on osteogenic differentiation of human mesenchymal stem cells. Biomech. Model Mechanobiol., 2012, 11: 391-401

[73] Tan SD et al. Osteocytes subjected to fluid flow inhibit osteoclast formation and bone resorption. Bone, 2007, 41: 745-751

[74] Correia C, Bhumiratana S, Sousa RA, Reis RL, Vunjak-Novakovic G. Sequential application of steady and pulsatile medium perfusion enhanced the formation of engineered bone. Tissue Eng. Part A, 2013, 19: 1244-1254

[75] Bacabac RG et al. Nitric oxide production by bone cells is fluid shear stress rate dependent. Biochem. Biophys. Res. Commun., 2004, 315: 823-829

[76] Yi W et al. Proteomic profiling of human bone marrow mesenchymal stem cells under shear stress. Mol. Cell Biochem., 2010, 341: 9-16

[77] Kämmerer PW et al. Cellular fluid shear stress on implant surfaces—establishment of a novel experimental set up. Int. J. Implant Dent., 2017, 3

[78] Anderson EJ, Falls TD, Sorkin AM, Tate MLK. The imperative for controlled mechanical stresses in unraveling cellular mechanisms of mechanotransduction. Biomed. Eng. Online, 2006, 5

[79] Riehl BD, Lee JS, Ha L, Lim JY. Fluid-flow-induced mesenchymal stem cell migration: role of focal adhesion kinase and RhoA kinase sensors. J. R. Soc. Interface, 2015, 12: 20141351

[80] Grayson WL et al. Optimizing the medium perfusion rate in bone tissue engineering bioreactors. Biotechnol. Bioeng., 2011, 108: 1159-1170

[81] Johnson DL, McAllister TN, Frangos JA. Fluid flow stimulates rapid and continuous release of nitric oxide in osteoblasts. Am. J. Physiol. Metab., 1996, 271: E205-E208

[82] Nauman EA, Satcher RL, Keaveny TM, Halloran BP, Bikle DD. Osteoblasts respond to pulsatile fluid flow with short-term increases in PGE2 but no change in mineralization. J. Appl. Physiol., 2001, 90: 1849-1854

[83] Yu W et al. A microfluidic-based multi-shear device for investigating the effects of low fluid-induced stresses on osteoblasts. PLoS One, 2014, 9: e89966

[84] Leclerc E et al. Study of osteoblastic cells in a microfluidic environment. Biomaterials, 2006, 27: 586-595

[85] Jang K, Sato K, Igawa K, Chung U, Kitamori T. Development of an osteoblast-based 3D continuous-perfusion microfluidic system for drug screening. Anal. Bioanal. Chem., 2008, 390: 825-832

[86] Galbraith CG, Yamada KM, Sheetz MP. The relationship between force and focal complex development. J. Cell Biol., 2002, 159: 695-705

[87] Orr AW, Ginsberg MH, Shattil SJ, Deckmyn H, Schwartz MA. Matrix-specific suppression of integrin activation in shear stress signaling. Mol. Biol. Cell, 2006, 17: 4686-4697

[88] Jagodzinski M et al. Effects of cyclic longitudinal mechanical strain and dexamethasone on osteogenic differentiation of human bone marrow stromal cells. Eur. Cells Mater., 2004, 7: 35-41

[89] Qi M-C et al. Mechanical strain induces osteogenic differentiation: Cbfa1 and Ets-1 expression in stretched rat mesenchymal stem cells. Int. J. Oral. Maxillofac. Surg., 2008, 37: 453-458

[90] Huang CH, Chen MH, Young TH, Jeng JH, Chen YJ. Interactive effects of mechanical stretching and extracellular matrix proteins on initiating osteogenic differentiation of human mesenchymal stem cells. J. Cell Biochem, 2009, 108: 1263-1273

[91] Sumanasinghe RD, Bernacki SH, Loboa EG. Osteogenic differentiation of human mesenchymal stem cells in collagen matrices: effect of uniaxial cyclic tensile strain on bone morphogenetic protein (BMP-2) mRNA expression. Tissue Eng., 2006, 12: 3459-3465

[92] Yu H-S, Kim J-J, Kim H-W, Lewis MP, Wall I. Impact of mechanical stretch on the cell behaviors of bone and surrounding tissues. J. Tissue Eng., 2016, 7: 204173141561834

[93] Bhatt KA et al. Uniaxial mechanical strain: an in vitro correlate to distraction osteogenesis. J. Surg. Res., 2007, 143: 329-336

[94] Liegibel UM et al. Concerted action of androgens and mechanical strain shifts bone metabolism from high turnover into an osteoanabolic mode. J. Exp. Med., 2002, 196: 1387-1392

[95] Koike M, Shimokawa H, Kanno Z, Ohya K, Soma K. Effects of mechanical strain on proliferation and differentiation of bone marrow stromal cell line ST2. J. Bone Min. Metab., 2005, 23: 219-225

[96] Ward DF Jr et al. Mechanical strain enhances extracellular matrix-induced gene focusing and promotes osteogenic differentiation of human mesenchymal stem cells through an extracellular-related kinase-dependent pathway. Stem Cells Dev., 2007, 16: 467-480

[97] Wang, Y. et al. Radiation induces primary osteocyte senescence phenotype and affects osteoclastogenesis in vitro. Int. J. Mol. Med. 47, 76 (2021).

[98] Dumas V et al. The effect of dual frequency cyclic compression on matrix deposition by osteoblast-like cells grown in 3D scaffolds and on modulation of VEGF variant expression. Biomaterials, 2009, 30: 3279-3288

[99] Jagodzinski M et al. Influence of perfusion and cyclic compression on proliferation and differentiation of bone marrow stromal cells in 3-dimensional culture. J. Biomech., 2008, 41: 1885-1891

[100] Liu J et al. Hydrostatic pressures promote initial osteodifferentiation with ERK1/2 not p38 MAPK signaling involved. J. Cell Biochem., 2009, 107: 224-232

[101] Anderson, E.J., Kaliyamoorthy, S., Knothe Tate, M.L. Modeling the effects of interstitial fluid flow on a single osteocyte and its processes. In: Advances in Bioengineering. 49–50 (ASMEDC, 2004).

[102] Sequeira Y, Maitra A, Pandey A, Jung S. Revisiting the NASA surface tension driven convection experiments. npj Microgravity, 2022, 8

[103] Meseguer J et al. Surface tension and microgravity. Eur. J. Phys., 2014, 35: 055010

[104] Jones SB, Or D. Microgravity effects on water flow and distribution in unsaturated porous media: Analyses of flight experiments. Water Resour. Res., 1999, 35: 929-942

[105] Yagi-Utsumi M et al. Characterization of amyloid β fibril formation under microgravity conditions. npj Microgravity, 2020, 6

[106] DeLucas LJ et al. Preliminary investigations of protein crystal growth using the space shuttle. J. Cryst. Growth, 1986, 76: 681-693

[107] Martirosyan A et al. Effect of macromolecular mass transport in microgravity protein crystallization. Gravitational Sp. Res., 2019, 7: 33-44

[108] Bell D et al. Self-assembly of protein fibrils in microgravity. Gravitational Sp. Res., 2018, 6: 10-26

[109] Matsushita H et al. Amyloid fibril formation is suppressed in microgravity. Biochem. Biophys. Rep., 2021, 25: 100875

[110] McPherson A, Malkin A, Kuznetsov Y. The science of macromolecular crystallization. Structure, 1995, 3: 759-768

[111] Tauber S et al. Cytoskeletal stability and metabolic alterations in primary human macrophages in long-term microgravity. PLoS One, 2017, 12: e0175599

[112] Tabony J, Job D. Gravitational symmetry breaking in microtubular dissipative structures. Proc. Natl Acad. Sci., 1992, 89: 6948-6952

[113] Tabony J, Job D. Spatial structures in microtubular solutions requiring a sustained energy source. Nature, 1990, 346: 448-451

[114] Mann V et al. Changes in human foetal osteoblasts exposed to the random positioning machine and bone construct tissue engineering. Int J. Mol. Sci., 2019, 20: 1357

[115] Xu H et al. Actin cytoskeleton mediates BMP2-Smad signaling via calponin 1 in preosteoblast under simulated microgravity. Biochimie, 2017, 138: 184-193

[116] Buken C et al. Morphological and molecular changes in juvenile normal human fibroblasts exposed to simulated microgravity. Sci. Rep., 2019, 9

[117] Thiel CS et al. Real-time 3D high-resolution microscopy of human cells on the international space station. Int J. Mol. Sci., 2019, 20: 2033

[118] Nabavi N, Khandani A, Camirand A, Harrison RE. Effects of microgravity on osteoclast bone resorption and osteoblast cytoskeletal organization and adhesion. Bone, 2011, 49: 965-974

[119] Testa F et al. Fractal analysis of shape changes in murine osteoblasts cultured under simulated microgravity. Rend. Lincei, 2014, 25: 39-47

[120] Tabony J, Pochon N, Papaseit C. Microtubule self-organisation depends upon gravity. Adv. Sp. Res., 2001, 28: 529-535

[121] Hughes-Fulford M, Lewis ML. Effects of microgravity on osteoblast growth activation. Exp. Cell Res., 1996, 224: 103-109

[122] Tabony J. Morphological bifurcations involving reaction-diffusion processes during microtubule formation. Science, 1994, 264: 245-248

[123] Chen Z, Luo Q, Lin C, Kuang D, Song G. Simulated microgravity inhibits osteogenic differentiation of mesenchymal stem cells via depolymerizing F-actin to impede TAZ nuclear translocation. Sci. Rep., 2016, 6

[124] Bradbury, P. et al. Modeling the impact of microgravity at the cellular level: implications for human disease. Front. Cell Dev. Biol. 8, https://doi.org/10.3389/fcell.2020.00096 (2020).

[125] Di SM et al. Graviresponses of osteocytes under altered gravity. Adv. Sp. Res., 2011, 48: 1161-1166

[126] Louis F et al. RhoGTPase stimulation is associated with strontium chloride treatment to counter simulated microgravity-induced changes in multipotent cell commitment. npj Microgravity, 2017, 3

[127] Corydon TJ et al. Alterations of the cytoskeleton in human cells in space proved by life-cell imaging. Sci. Rep., 2016, 6

[128] Bauer J. Microgravity and cell adherence. Int J. Mol. Sci., 2020, 21: 2214

[129] Hughes-Fulford M. Function of the cytoskeleton in gravisensing during spaceflight. Adv. Sp. Res., 2003, 32: 1585-1593

[130] Guignandon A et al. Cell cycling determines integrin-mediated adhesion in osteoblastic ROS 17/2.8 cells exposed to space-related conditions. FASEB J., 2001, 15: 2036-2038

[131] McCarthy ID. Fluid shifts due to microgravity and their effects on bone: a review of current knowledge. Ann. Biomed. Eng., 2005, 33: 95-103

[132] Baran R et al. The cardiovascular system in space: focus on in vivo and in vitro studies. Biomedicines, 2021, 10: 59

[133] Howden M, Siamwala JH, Hargens AR. Bone microvascular flow differs from skin microvascular flow in response to head-down tilt. J. Appl. Physiol., 2017, 123: 860-866

[134] Marshall-Goebel K et al. Assessment of jugular venous blood flow stasis and thrombosis during spaceflight. JAMA Netw. Open, 2019, 2: e1915011

[135] Hargens AR, Watenpaugh DE. Cardiovascular adaptation to spaceflight. Med. Amp. Sci. Sport Amp. Exerc., 1996, 28: 977-982

[136] Vernice NA, Meydan C, Afshinnekoo E, Mason CE. Long-term spaceflight and the cardiovascular system. Precis Clin. Med., 2020, 3: 284-291

[137] Colleran PN et al. Alterations in skeletal perfusion with simulated microgravity: a possible mechanism for bone remodeling. J. Appl. Physiol., 2000, 89: 1046-1054

[138] Klein-Nulend J, Bacabac RG, Veldhuijzen JP, Van Loon JJWA. Microgravity and bone cell mechanosensitivity. Adv. Sp. Res., 2003, 32: 1551-1559

[139] Amin S. Mechanical factors and bone health: effects of weightlessness and neurologic injury. Curr. Rheumatol. Rep., 2010, 12: 170-176

[140] Yang X, Sun L, Wang X, Fan Y. Effects of simulated microgravity on the mechanosensibility of osteocytes due to fluid shear stress. Bone, 2010, 47: S436-S437

[141] Sun Z et al. Simulated microgravity inhibits L-type calcium channel currents partially by the up-regulation of miR-103 in MC3T3-E1 osteoblasts. Sci. Rep., 2015, 5

[142] Gao X et al. Regulation of cell migration and osteogenic differentiation in mesenchymal stem cells under extremely low fluidic shear stress. Biomicrofluidics, 2014, 8: 052008

[143] Port JR et al. SARS-CoV-2 disease severity and transmission efficiency is increased for airborne but not fomite exposure in Syrian hamsters. Nat. Commun., 2020, 17: 4985

[144] Gao Y et al. Migration and differentiation of osteoclast precursors under gradient fluid shear stress. Biomech. Model Mechanobiol., 2019, 18: 1731-1744

[145] Seneviratne AN et al. M1 macrophages are an early feature of shear stress modulated vulnerable atherosclerotic plaques. Eur. Heart J., 2013, 34: P2398-P2398

[146] Miravète M et al. Renal tubular fluid shear stress facilitates monocyte activation toward inflammatory macrophages. Am. J. Physiol. Physiol., 2012, 302: F1409-F1417

[147] Yang D-H, Yang M-Y. The role of macrophage in the pathogenesis of osteoporosis. Int J. Mol. Sci., 2019, 20: 2093

[148] Shapouri‐Moghaddam A et al. Macrophage plasticity, polarization, and function in health and disease. J. Cell Physiol., 2018, 233: 6425-6440

[149] Shi L et al. Spaceflight and simulated microgravity suppresses macrophage development via altered RAS/ERK/NFκB and metabolic pathways. Cell Mol. Immunol., 2021, 18: 1489-1502

[150] Blaber EA et al. Mechanical unloading of bone in microgravity reduces mesenchymal and hematopoietic stem cell-mediated tissue regeneration. Stem Cell Res., 2014, 13: 181-201

[151] Li H et al. Biomechanical cues as master regulators of hematopoietic stem cell fate. Cell Mol. Life Sci., 2021, 78: 5881-5902

[152] Dai S et al. Effect of simulated microgravity conditions of hindlimb unloading on mice hematopoietic and mesenchymal stromal cells. Cell Biol. Int, 2020, 44: 2243-2252

[153] Fajgenbaum DC, June CH. Cytokine storm. N. Engl. J. Med., 2020, 383: 2255-2273

[154] Junttila, I. S. Tuning the cytokine responses: an update on interleukin (IL)-4 and IL-13 receptor complexes. Front. Immunol. 9, 888 (2018).

[155] Milovanovic, J., et al. Interleukin-17 in chronic inflammatory neurological diseases. Front. Immunol. 11, 947 (2020).

[156] Balasubbramanian D, Goodlett BL, Mitchell BM. Is IL-12 pro-inflammatory or anti-inflammatory? Depends on the blood pressure. Cardiovasc Res., 2019, 115: 998-999

[157] Paulsen K et al. Regulation of ICAM-1 in cells of the monocyte/macrophage system in microgravity. Biomed. Res. Int., 2015, 2015: 1-18

[158] Tauber S et al. Signal transduction in primary human T lymphocytes in altered gravity during parabolic flight and clinostat experiments. Cell Physiol. Biochem., 2015, 35: 1034-1051

[159] Crucian B et al. Immune system dysregulation occurs during short duration spaceflight on board the space shuttle. J. Clin. Immunol., 2013, 33: 456-465

[160] Marx RE, Harrell DB. Translational research: The CD34⁺ cell is crucial for large-volume bone regeneration from the milieu of bone marrow progenitor cells in craniomandibular reconstruction. Int. J. Oral. Maxillofac. Implants, 2014, 29: e201-e209

[161] Kuroda R et al. Clinical impact of circulating CD34-positive cells on bone regeneration and healing. Tissue Eng. Part B Rev., 2014, 20: 190-199

[162] Oliveira CS, Carreira M, Correia CR, Mano JF. The therapeutic potential of hematopoietic stem cells in bone regeneration. Tissue Eng. Part B Rev., 2022, 28: 379-392

[163] Wang P et al. Spaceflight/microgravity inhibits the proliferation of hematopoietic stem cells by decreasing Kit‐Ras/cAMP‐CREB pathway networks as evidenced by RNA‐Seq assays. FASEB J., 2019, 33: 5903-5913

[164] Plett PA, Abonour R, Frankovitz SM, Orschell CM. Impact of modeled microgravity on migration, differentiation, and cell cycle control of primitive human hematopoietic progenitor cells. Exp. Hematol., 2004, 32: 773-781

[165] Zou L et al. Simulated microgravity induce apoptosis and down-regulation of erythropoietin receptor of UT-7/EPO cells. Adv. Sp. Res., 2010, 46: 1237-1244

[166] Suo J et al. Hemodynamic shear stresses in mouse aortas. Arterioscler Thromb. Vasc. Biol., 2007, 27: 346-351

[167] Lundin V et al. YAP regulates hematopoietic stem cell formation in response to the biomechanical forces of blood flow. Dev. Cell, 2020, 52: 446-460.e5

[168] Wolfe RP, Ahsan T. Shear stress during early embryonic stem cell differentiation promotes hematopoietic and endothelial phenotypes. Biotechnol. Bioeng., 2013, 110: 1231-1242

[169] Ogawa H, Kozhemyakina E, Hung HH, Grodzinsky AJ, Lassar AB. Mechanical motion promotes expression of Prg4 in articular cartilage via multiple CREB-dependent, fluid flow shear stress-induced signaling pathways. Genes Dev., 2014, 28: 127-139

[170] Morbidelli L et al. Simulated hypogravity impairs the angiogenic response of endothelium by up-regulating apoptotic signals. Biochem. Biophys. Res. Commun., 2005, 334: 491-499

[171] Cialdai F et al. Modeled microgravity affects fibroblast functions related to wound healing. Microgravity Sci. Technol., 2017, 29: 121-132

[172] Muruganandan S, Govindarajan R, Sinal CJ. Bone marrow adipose tissue and skeletal health. Curr. Osteoporos. Rep., 2018, 16: 434-442

[173] Shin E, Koo JS. The role of adipokines and bone marrow adipocytes in breast cancer bone metastasis. Int. J. Mol. Sci., 2020, 21: 4967

[174] Choi J, Lee SY, Yoo Y M, Kim CH. Maturation of adipocytes is suppressed by fluid shear stress. Cell Biochem. Biophys., 2017, 75: 87-94

[175] Elashry MI, Gegnaw ST, Klymiuk MC, Wenisch S, Arnhold S. Influence of mechanical fluid shear stress on the osteogenic differentiation protocols for Equine adipose tissue-derived mesenchymal stem cells. Acta Histochem, 2019, 121: 344-353

[176] Yang F et al. A 3D human adipose tissue model within a microfluidic device. Lab Chip, 2021, 21: 435-446

[177] Kim HW, Lim J, Rhie JW, Kim DS. Investigation of effective shear stress on endothelial differentiation of human adipose-derived stem cells with microfluidic screening device. Microelectron. Eng., 2017, 174: 24-27

[178] Lau P, Vico L, Rittweger J. Dissociation of bone resorption and formation in spaceflight and simulated microgravity: potential role of myokines and osteokines. Biomedicines, 2022, 10: 342

[179] Juhl OJ et al. Update on the effects of microgravity on the musculoskeletal system. npj Microgravity, 2021, 7

[180] Kawao N, Morita H, Iemura S, Ishida M, Kaji H. Roles of Dkk2 in the linkage from muscle to bone during mechanical unloading in mice. Int. J. Mol. Sci., 2020, 21: 2547

[181] Takafuji Y et al. Effects of fluid flow shear stress to mouse muscle cells on the bone actions of muscle cell-derived extracellular vesicless. PLoS One, 2021, 16: e0250741

[182] Li X, Li B, Shi Y, Wang C, Ye L. Targeting reactive oxygen species in stem cells for bone therapy. Drug Disco. Today, 2021, 26: 1226-1244

[183] Kimball JS, Johnson JP, Carlson DA. Oxidative stress and osteoporosis. J. Bone Jt Surg., 2021, 103: 1451-1461

[184] Gómez X et al. Key points for the development of antioxidant cocktails to prevent cellular stress and damage caused by reactive oxygen species (ROS) during manned space missions. npj Microgravity, 2021, 7

[185] Ran F, An L, Fan Y, Hang H, Wang S. Simulated microgravity potentiates generation of reactive oxygen species in cells. Biophys. Rep., 2016, 2: 100-105

[186] Li N, An L, Hang H. Increased sensitivity of DNA damage response-deficient cells to stimulated microgravity-induced DNA lesions. PLoS One, 2015, 10: e0125236

[187] Davalli P, Mitic T, Caporali A, Lauriola A, D’Arca D. ROS, Cell senescence, and novel molecular mechanisms in aging and age-related diseases. Oxid. Med. Cell Longev., 2016, 2016: 1-18

[188] Ray PD, Huang B-W, Tsuji Y. Reactive oxygen species (ROS) homeostasis and redox regulation in cellular signaling. Cell Signal, 2012, 24: 981-990

[189] Atashi F, Modarressi A, Pepper MS. The role of reactive oxygen species in mesenchymal stem cell adipogenic and osteogenic differentiation: a review. Stem Cells Dev., 2015, 24: 1150-1163

[190] Koh JM et al. Homocysteine enhances bone resorption by stimulation of osteoclast formation and activity through increased intracellular ROS generation. J. Bone Min. Res., 2006, 21: 1003-1011

[191] Moon HJ et al. Simvastatin inhibits osteoclast differentiation by scavenging reactive oxygen species. Exp. Mol. Med., 2011, 43

[192] Harrison C. Targeting NOX4 knocks down osteoporosis. Nat. Rev. Drug Discov., 2013, 12: 904-905

[193] Agidigbi TS, Kim C. Reactive oxygen species in osteoclast differentiation and possible pharmaceutical targets of ROS-mediated osteoclast diseases. Int. J. Mol. Sci., 2019, 20: 3576

[194] Tao H et al. ROS signaling cascades: dual regulations for osteoclast and osteoblast. Acta Biochim. Biophys. Sin., 2020, 52: 1055-1062

[195] Domazetovic V. Oxidative stress in bone remodeling: role of antioxidants. Clin. Cases Min. Bone Metab., 2017, 14: 209

[196] Almeida M, O’Brien CA. Basic biology of skeletal aging: role of stress response pathways. J. Gerontol. Ser. A Biol. Sci. Med. Sci., 2013, 68: 1197-1208

[197] Angeloni C, Maraldi T, Vauzour D. Redox signaling in degenerative diseases: from molecular mechanisms to health implications. Biomed. Res. Int., 2014, 2014: 1-2

[198] Xin M et al. Attenuation of hind-limb suspension-induced bone loss by curcumin is associated with reduced oxidative stress and increased vitamin D receptor expression. Osteoporos. Int., 2015, 26: 2665-2676

[199] Morikawa D et al. Cytoplasmic reactive oxygen species and SOD1 regulate bone mass during mechanical unloading. J. Bone Min. Res., 2013, 28: 2368-2380

[200] Colaianni G et al. Irisin prevents and restores bone loss and muscle atrophy in hind-limb suspended mice. Sci. Rep., 2017, 7

[201] Hsieh H-J, Liu C-A, Huang B, Tseng AH, Wang DL. Shear-induced endothelial mechanotransduction: the interplay between reactive oxygen species (ROS) and nitric oxide (NO) and the pathophysiological implications. J. Biomed. Sci., 2014, 21: 3

[202] Pardo PS, Mohamed JS, Lopez MA, Boriek AM. Induction of Sirt1 by mechanical stretch of skeletal muscle through the early response factor EGR1 triggers an antioxidative response. J. Biol. Chem., 2011, 286: 2559-2566

[203] Chen X et al. Mechanical stretch induces antioxidant responses and osteogenic differentiation in human mesenchymal stem cells through activation of the AMPK-SIRT1 signaling pathway. Free Radic. Biol. Med., 2018, 126: 187-201

[204] Dick AS et al. Cyclic stretch stimulates nitric oxide synthase-1-dependent peroxynitrite formation by neonatal rat pulmonary artery smooth muscle. Free Radic. Biol. Med., 2013, 61: 310-319

[205] Chao Y et al. Low shear stress induces endothelial reactive oxygen species via the AT1R/eNOS/NO pathway. J. Cell Physiol., 2018, 233: 1384-1395

[206] Li B, Zhang J, Wang Z, Chen S. Ivabradine prevents low shear stress induced endothelial inflammation and oxidative stress via mTOR/eNOS pathway. PLoS One, 2016, 11: e0149694

[207] Brooks AR, Lelkes PI, Rubanyi GM. Gene expression profiling of human aortic endothelial cells exposed to disturbed flow and steady laminar flow. Physiol. Genomics, 2002, 9: 27-41

[208] Mueller CFH et al. The role of the multidrug resistance protein-1 in modulation of endothelial cell oxidative stress. Circ. Res., 2005, 97: 637-644

[209] Chao Y et al. Inhibition of angiotension II type 1 receptor reduced human endothelial inflammation induced by low shear stress. Exp. Cell Res., 2017, 360: 94-104

[210] Ishibazawa A, Nagaoka T, Yokota H, Ono S, Yoshida A. Low shear stress up-regulation of proinflammatory gene expression in human retinal microvascular endothelial cells. Exp. Eye Res., 2013, 116: 308-311

[211] Zhang J et al. Low shear stress induces human vascular endothelial cell apoptosis by activating Akt signal and increasing reactive oxygen species. Nan Fang. Yi Ke Da Xue Xue Bao, 2013, 33: 313-317

[212] Sorescu GP et al. Bone morphogenic protein 4 produced in endothelial cells by oscillatory shear stress induces monocyte adhesion by stimulating reactive oxygen species production from a Nox1-based NADPH oxidase. Circ. Res., 2004, 95: 773-779

[213] Qin X et al. Uptake of oxidative stress-mediated extracellular vesicles by vascular endothelial cells under low magnitude shear stress. Bioact. Mater., 2022, 9: 397-410

[214] Wang J, Kaplan JA, Colson YL, Grinstaff MW. Mechanoresponsive materials for drug delivery: harnessing forces for controlled release. Adv. Drug Deliv. Rev., 2017, 108: 68-82

[215] Wang J, Colson YL, Grinstaff MW. Tension-activated delivery of small molecules and proteins from superhydrophobic composites. Adv. Health. Mater., 2018, 7: 1701096

[216] Keune JA, Philbrick KA, Branscum AJ, Iwaniec UT, Turner RT. Spaceflight-induced vertebral bone loss in ovariectomized rats is associated with increased bone marrow adiposity and no change in bone formation. npj Microgravity, 2016, 2

[217] Endicott, J., Fitzgerald, J. Increased bone marrow adiposity in murine femoro-tibial epiphyses exposed to 30 days of microgravity. Matters Sel. https://doi.org/10.19185/matters.201904000010 (2019).

[218] Poloni A et al. Molecular and functional characterization of human bone marrow adipocytes. Exp. Hematol., 2013, 41: 558-566

[219] Zhou BO et al. Bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting SCF. Nat. Cell Biol., 2017, 19: 891-903

[220] Ambrosi TH et al. Adipocyte accumulation in the bone marrow during obesity and aging impairs stem cell-based hematopoietic and bone regeneration. Cell Stem Cell, 2017, 20: 771-784

[221] Miggitsch C et al. Human bone marrow adipocytes display distinct immune regulatory properties. EBioMedicine, 2019, 46: 387-398

[222] Chen Y et al. Simulated microgravity led to increased brown adipose tissue activity in rats. Acta Astronaut, 2019, 160: 538-551

[223] Wong CP, Iwaniec UT, Turner RT. Evidence for increased thermogenesis in female C57BL/6J mice housed aboard the international space station. npj Microgravity, 2021, 7

[224] Zhang C et al. Space microgravity drives transdifferentiation of human bone marrow‐derived mesenchymal stem cells from osteogenesis to adipogenesis. FASEB J., 2018, 32: 4444-4458

[225] Ouchi N, Parker JL, Lugus JJ, Walsh K. Adipokines in inflammation and metabolic disease. Nat. Rev. Immunol., 2011, 11: 85-97

[226] Ciani C, Sharma D, Doty SB, Fritton SP. Ovariectomy enhances mechanical load-induced solute transport around osteocytes in rat cancellous bone. Bone, 2014, 59: 229-234

[227] Metzger TA, Vaughan TJ, McNamara LM, Niebur GL. Altered architecture and cell populations affect bone marrow mechanobiology in the osteoporotic human femur. Biomech. Model Mechanobiol., 2017, 16: 841-850

[228] Zhao S et al. Numerical analysis of the flow field in the lacunar-canalicular system under different magnitudes of gravity. Med. Biol. Eng. Comput., 2020, 58: 509-518

[229] Consolo F et al. Computational modeling for the optimization of a cardiogenic 3D bioprocess of encapsulated embryonic stem cells. Biomech. Model Mechanobiol., 2012, 11: 261-277

[230] Marsano A et al. Use of hydrodynamic forces to engineer cartilaginous tissues resembling the non-uniform structure and function of meniscus. Biomaterials, 2006, 27: 5927-5934

[231] Podgorski, T., Coupier, G., Minetti, C. Red blood cell dynamics: the contribution of microgravity in the BIOMICS project. In: Preparation of Space Experiments. (IntechOpen, 2020). https://doi.org/10.5772/intechopen.93471.

[232] Xing J et al. Surface chemistry modulates osteoblasts sensitivity to low fluid shear stress. J. Biomed. Mater. Res Part A, 2014, 102: 4151-4160

[233] Li J, Rose E, Frances D, Sun Y, You L. Effect of oscillating fluid flow stimulation on osteocyte mRNA expression. J. Biomech., 2012, 45: 247-251

[234] Haasper C et al. Cyclic strain induces FosB and initiates osteogenic differentiation of mesenchymal cells. Exp. Toxicol. Pathol., 2008, 59: 355-363

[235] Shi Y et al. Continuous cyclic mechanical tension inhibited Runx2 expression in mesenchymal stem cells through RhoA-ERK1/2 pathway. J. Cell Physiol., 2011, 226: 2159-2169

[236] Fang, B. Osteogenic response of mesenchymal stem cells to continuous mechanical strain is dependent on ERK1/2-Runx2 signaling. Int. J. Mol. Med. 29, 1083–1089 (2012).

[237] Wu T et al. Involvement of mechanosensitive ion channels in the effects of mechanical stretch induces osteogenic differentiation in mouse bone marrow mesenchymal stem cells. J. Cell Physiol., 2021, 236: 284-293

[238] Stavenschi E, Corrigan MA, Johnson GP, Riffault M, Hoey DA. Physiological cyclic hydrostatic pressure induces osteogenic lineage commitment of human bone marrow stem cells: a systematic study. Stem Cell Res. Ther., 2018, 9: 276

[239] Ravichandran A et al. In vitro cyclic compressive loads potentiate early osteogenic events in engineered bone tissue. J. Biomed. Mater. Res Part B Appl Biomater., 2017, 105: 2366-2375

[240] Chen X et al. Cyclic compression stimulates osteoblast differentiation via activation of the Wnt/β-catenin signaling pathway. Mol. Med. Rep., 2017, 15: 2890-2896

[241] Wang D, Wang H, Gao F, Wang K, Dong F. ClC‐3 promotes osteogenic differentiation in MC3T3‐E1 cell after dynamic compression. J. Cell Biochem., 2017, 118: 1606-1613

[242] Nagatomi J, Arulanandam BP, Metzger DW, Meunier A, Bizios R. Cyclic pressure affects osteoblast functions pertinent to osteogenesis. Ann. Biomed. Eng., 2003, 31: 917-923

[243] Priam S et al. Identification of soluble 14-3-3∊ as a novel subchondral bone mediator involved in cartilage degradation in osteoarthritis. Arthritis Rheum., 2013, 65: 1831-1842

[244] Liu C et al. Effects of cyclic hydraulic pressure on osteocytes. Bone, 2010, 46: 1449-1456

[245] Sittichockechaiwut A, Scutt AM, Ryan AJ, Bonewald LF, Reilly GC. Use of rapidly mineralising osteoblasts and short periods of mechanical loading to accelerate matrix maturation in 3D scaffolds. Bone, 2009, 44: 822-829

[246] Kikuta J, Yamaguchi M, Shimizu M, Yoshino T, Kasai K. Notch signaling induces root resorption via RANKL and IL-6 from hPDL cells. J. Dent. Res., 2015, 94: 140-147

[247] Mosley JR, Lanyon LE. Strain rate as a controlling influence on adaptive modeling in response to dynamic loading of the ulna in growing male rats. Bone, 1998, 23: 313-318

[248] Rubin CT, Sommerfeldt DW, Judex S, Qin Y-X. Inhibition of osteopenia by low magnitude, high-frequency mechanical stimuli. Drug Discov. Today, 2001, 6: 848-858

[249] Nagaraja M, Jo H. The role of mechanical stimulation in recovery of bone loss—high versus low magnitude and frequency of force. Life, 2014, 4: 117-130

[250] Frost HM. Bone mass and the mechanostat: A proposal. Anat. Rec., 1987, 219: 1-9