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Mechanobiology of cells and cell systems, such as organoids

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Abstract

Organoids are in vitro 3D self-organizing tissues that mimic embryogenesis. Organoid research is advancing at a tremendous pace, since it offers great opportunities for disease modeling, drug development and screening, personalized medicine, as well as understanding organogenesis. Mechanobiology of organoids is an unexplored area, which can shed light to several unexplained aspects of self-organization behavior in organogenesis. It is becoming evident that collective cell behavior is distinctly different from individual cells’ conduct against certain stimulants. Inherently consisting of higher number of degrees of freedom for cell motility and more complex cell-to-cell and cell-to-extracellular matrix behavior, understanding mechanotransduction in organoids is even more challenging compared with cell communities in 2D culture conditions. Yet, deciphering mechanobiology of organoids can help us understand effects of mechanical cues in health and disease, and translate findings of basic research toward clinical diagnosis and therapy.

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References

  • Akhmanova M, Osidak E, Domogatsky S, Rodin S, Domogatskaya A (2015) Physical, spatial, and molecular aspects of extracellular matrix of in vivo niches and artificial scaffolds relevant to stem cells research. Stem Cells Int 35

  • Alberts B, Johnson A, Lewis J, Raff M, Roberts K and Walter P (2002) The extracellular matrix of animals. In: Molecular biology of the cell. 4th edition. New York Garland Science. https://www.ncbi.nlm.nih.gov/books/NBK26810/. Accessed 24 June 2019

  • Allende ML et al (2018) Cerebral organoids derived from Sandhoff disease-induced pluripotent stem cells exhibit impaired neurodifferentiation. J Lipid Res 59:550–563

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ambrosini A et al (2019) Mechanical function of the nucleus in force generation during epithelial morphogenesis. Dev Cell 50:1–15

    Google Scholar 

  • Amonlirdviman K, Khare NA, Tree DR, Chen WS, Axelrod JD, Tomlin CJ (2005) Mathematical modeling of planar cell polarity to understand domineering nonautonomy. Science 307:423–426

    CAS  PubMed  Google Scholar 

  • Ardhanareeswaran K, Mariani J, Coppola G, Abyzov A, Vaccarino FM (2017) Human induced pluripotent stem cells for modelling neurodevelopmental disorders. Nat Rev Neurol 13:265–278

    PubMed  PubMed Central  Google Scholar 

  • Ashby WR (1962) Principles of the self-organizing system. In: Von Foerster H, Zopf GW (eds) Principles of self-organization: transactions of the University of Illinois Symposium. Pergamon Press, London, UK, pp 255–278

    Google Scholar 

  • Baker BM, Chen CS (2012) Deconstructing the third dimension–how 3D culture microenvironments alter cellular cues. J Cell Sci 125:3015–3024

    CAS  PubMed  PubMed Central  Google Scholar 

  • Baumgarten CM (2013) Origin of mechanotransduction: stretch-activated ion channels. In: Madame curie bioscience database [Internet]. Austin (TX), Landes Bioscience, pp 2000–2013 Available from: https://www.ncbi.nlm.nih.gov/books/NBK6374/. Accessed 27 June 2019

    Google Scholar 

  • Beningo KA, Dembo M, Kaverina I, Small JV, Wang Y-l (2001) Nascent focal adhesions are responsible for the generation of strong propulsive forces in migrating fibroblasts. J Cell Biol 153:881–888

    CAS  PubMed  PubMed Central  Google Scholar 

  • Berger E et al (2018) Millifluidic culture improves human midbrain organoid vitality and differentiation. Lab Chip 18:3172–3183

    CAS  PubMed  Google Scholar 

  • Bhat SP (2001) The ocular lens epithelium. Biosci Rep 21:537–563. https://doi.org/10.1023/A:1017952128502

    Article  CAS  PubMed  Google Scholar 

  • Buske P, Przybilla J, Loeffler M, Sachs N, Sato T, Clevers H, Galle J (2012) On the biomechanics of stem cell niche formation in the gut–modelling growing organoids. FEBS J 279:3475–3487

    CAS  PubMed  Google Scholar 

  • Cerruti B et al (2013) Polarity, cell division, and out-of-equilibrium dynamics control the growth of epithelial structures. J Cell Biol 203(2):359–372

    CAS  PubMed  PubMed Central  Google Scholar 

  • Chan CJ, Heisenberg C-P, Hiiragi T (2017) Coordination of morphogenesis and cell-fate specification in development. Curr Biol 27:R1024–R1035

    CAS  PubMed  Google Scholar 

  • Classen AK, Anderson KI, Marois E, Eaton S (2005) Hexagonal packing of Drosophila wing epithelial cells by the planar cell polarity pathway. Dev Cell 9:805–817. https://doi.org/10.1016/j.devcel.2005.10.016

    Article  CAS  PubMed  Google Scholar 

  • Coste et al (2012) Piezo proteins are pore-forming subunits of mechanically activated channels. Nature 483:176–181

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cukierman E, Pankov R, Stevens DR, Yamada KM (2001) Taking cell-matrix adhesions to the third dimension. Science 294:1708–1712

    CAS  PubMed  Google Scholar 

  • Dahl-Jensen SB, Figueiredo-Larsen M, Grapin-Botton A, Sneppen K (2016) Short-range growth inhibitory signals from the epithelium can drive non-stereotypic branching in the pancreas. Phys Biol 13:016007

    PubMed  Google Scholar 

  • Drost J, Clevers H (2017) Translational applications of adult stem cell-derived organoids. Development 144:968–975

    CAS  PubMed  Google Scholar 

  • Dupont et al (2011) Role of YAP/TAZ in mechanotransduction. Nature 474:179–183

    CAS  PubMed  Google Scholar 

  • Dutta D, Heo I, Clevers H (2017) Disease modeling in stem cell-derived 3D organoid systems. Trends Mol Med 23:393–410

    CAS  PubMed  Google Scholar 

  • Duval K, Grover H, Han L-H, Mou Y, Pegoraro AF, Fredberg J, Chen Z (2017) Modeling physiological events in 2D vs. 3D cell culture. Physiology 32:266–277

    CAS  PubMed  PubMed Central  Google Scholar 

  • Eiraku M, Adachi T, Sasai Y (2012) Relaxation-expansion model for self-driven retinal morphogenesis. Bioessays 34(1):17–25

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ellison D et al (2016) Cell-cell communication enhances the capacity of cell ensembles to sense shallow gradients during morphogenesis. Proceedings of the National Academy of Sciences of the United States of America (PNAS) 113(6):E679–88

    CAS  Google Scholar 

  • Engler AJ, Sen S, Sweeney HL, Discher DE (2006) Matrix elasticity directs stem cell lineage specification. Cell 126:677–689

    CAS  PubMed  Google Scholar 

  • Eshghi S, Schaffer DV (2008) Engineering microenvironments to control stem cell fate and function. In: StemBook [Internet]. Ed. Lisa Girard Harvard Stem Cell Institute. https://doi.org/10.3824/stembook.1.5.1

  • Fang Y, Eglen RM (2017) Three-dimensional cell cultures in drug discovery and development. Slas discovery: Advancing Life Sciences R&D 22:456–472

    CAS  Google Scholar 

  • Fiorotto R, Amenduni M, Mariotti V, Fabris L, Spirli C, Strazzabosco M (2018) Liver diseases in the dish: iPSC and organoids as a new approach to modeling liver diseases. Biochim Biophys Acta, Mol Basis Dis 1865(5):920–928. https://doi.org/10.1016/j.bbadis.2018.08.038

    Article  CAS  Google Scholar 

  • Fordham RP, Yui S, Hannan NRF, Soendergaard C, Madgwick A et al (2013) Transplantation of expanded fetal intestinal progenitors contributes to colon regeneration after injury. Cell Stem Cell 13:734–744

    CAS  PubMed  PubMed Central  Google Scholar 

  • Frisch SM, Francis H (1994) Disruption of epithelial cell-matrix interactions induces apoptosis. J Cell Biol 124:619–626

    CAS  PubMed  Google Scholar 

  • Gähwiler B, Capogna M, Debanne D, McKinney R, Thompson S (1997) Organotypic slice cultures: a technique has come of age. Trends Neurosci 20:471–477

    PubMed  Google Scholar 

  • Gaitantzi H, Breitkopf-Heinlein K (2018) Spontaneous self-assembly of liver organoids from differentiated human cells: human liver organoids. In: Davies JA, Lawrence ML (eds) Organs and organoids. Elsevier, Part 2, Chapter 7 145–156

  • Gattazzo F, Urciuolo A, Bonaldo P (2014) Extracellular matrix: a dynamic microenvironment for stem cell niche. Biochim Biophys Acta, Gen Subj 1840:2506–2519

    CAS  Google Scholar 

  • Geiger B, Yamada KM (2011) Molecular architecture and function of matrix adhesions. Cold Spring Harb Perspect Biol 3(5):a005033. https://doi.org/10.1101/cshperspect.a005033

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Greggio C, De Franceschi F, Figueiredo-Larsen M, Gobaa S, Ranga A, Semb H, Lutolf M, Grapin-Botton A (2013) Artificial three-dimensional niches deconstruct pancreas development in vitro. Development 140:4452–4462

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ho B, Pek N, Soh B-S (2018) Disease modeling using 3D organoids derived from human induced pluripotent stem cells. Int J Mol Sci 19:936

    PubMed Central  Google Scholar 

  • Hofer H, Carroll J, Neitz J, Neitz M, Williams DR (2005) Organization of the human trichromatic cone mosaic. J Neurosci 25:9669–9679. https://doi.org/10.1523/JNEUROSCI.2414-05.2005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Irie Y, Mizumoto H, Fujino S, Kajiwara T (2008) Development of articular cartilage grafts using organoid formation techniques. Transplant Proc 40(2):631–633

    CAS  PubMed  Google Scholar 

  • Jackson EL, Lu H (2016) Three-dimensional models for studying development and disease: moving on from organisms to organs-on-a-chip and organoids. Integr Biol 8:672–683

    CAS  Google Scholar 

  • Jalbert I, Stapleton F, Papas E, Sweeney DF, Coroneo M (2003) In vivo confocal microscopy of the human cornea. Br J Ophthalmol 87:225–236. https://doi.org/10.1136/bjo.87.2.225

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jansen KA, Donato DM, Balcioglu HE, Schmidt T, Danen EH, Koenderink GH (2015) A guide to mechanobiology: where biology and physics meet. Biochim Biophys Acta, Mol Cell Res 1853(11B):3043–3052

    CAS  PubMed  Google Scholar 

  • Kapałczyńska M et al (2018) 2D and 3D cell cultures–a comparison of different types of cancer cell cultures. Arch Med Sci 14(4):910–919. https://doi.org/10.5114/aoms.2016.63743

    Article  CAS  PubMed  Google Scholar 

  • Karolak A, Markov DA, McCawley LJ, Rejniak KA (2018) Towards personalized computational oncology: from spatial models of tumour spheroids, to organoids, to tissues. J R Soc Interface 15:20170703. https://doi.org/10.1098/rsif.2017.0703

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Karzbrun E, Reiner O (2019) Brain organoids—a bottom-up approach for studying human neurodevelopment. Bioengineering 6(1):9. https://doi.org/10.3390/bioengineering6010009

    Article  PubMed Central  Google Scholar 

  • Kim YK, Nam SA, Yang CW (2018) Applications of kidney organoids derived from human pluripotent stem cells. Korean J Intern Med 33(4):649–659

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kirby TJ, Lammerding J (2018) Emerging views of the nucleus as a cellular mechanosensor. Nat Cell Biol 20:373–381

    CAS  PubMed  PubMed Central  Google Scholar 

  • Kohl P (2018) Cardiac stretch-activated channels and mechano-electric coupling. In: Zipes DP, Jalife J, Stevenson WG (eds) Cardiac electrophysiology: from cell to bedside (Seventh Edition). Elsevier Inc. Chapter 14 128–139

  • Lancaster MA, Knoblich JA (2014) Organogenesis in a dish: modeling development and disease using organoid technologies. Science 345(6194):1247125. https://doi.org/10.1126/science.1247125

    Article  CAS  PubMed  Google Scholar 

  • Lancaster MA et al (2013) Cerebral organoids model human brain development and microcephaly. Nature 501:373–379

    CAS  PubMed  Google Scholar 

  • Leipzig ND, Shoichet MS (2009) The effect of substrate stiffness on adult neural stem cell behavior. Biomaterials 30:6867–6878

    CAS  PubMed  Google Scholar 

  • Li Z, Lee H, Zhu C (2016) Molecular mechanisms of mechanotransduction in integrin-mediated cell-matrix adhesion. Exp Cell Res 349:85–94. https://doi.org/10.1016/j.yexcr.2016.10.001

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Mammoto T, Mammoto A, Ingber DE (2013) Mechanobiology and developmental control. Annu Rev Cell Dev Biol 29:27–61

    CAS  PubMed  Google Scholar 

  • Mariani J et al (2015) FOXG1-dependent dysregulation of GABA/glutamate neuron differentiation in autism spectrum disorders. Cell 162:375–390

    CAS  PubMed  PubMed Central  Google Scholar 

  • Martinac B (2014) The ion channels to cytoskeleton connection as potential mechanism of mechanosensitivity. Biochim Biophys Acta 1838:682–691

    CAS  PubMed  Google Scholar 

  • Martino F, Perestrelo AR, Vinarský V, Pagliari S, Forte G (2018) Cellular mechanotransduction: from tension to function. Front Physiol 9:824

    PubMed  PubMed Central  Google Scholar 

  • Milde F, Tauriello G, Haberkern H, Koumoutsakos P (2014) SEM++: a particle model of cellular growth, signaling and migration. Comput Particle Mech 1(2):211–227

    Google Scholar 

  • Miroshnikova YA, Nava MM, Wickstroem SA (2017) Emerging roles of mechanical forces in chromatin regulation. J Cell Sci 130:2243–2250

    CAS  PubMed  Google Scholar 

  • Misra M, Audoly B, Kevrekidis IG, Shvartsman SY (2016) Shape transformations of epithelial shells. Biophys J 110(7):1670–1678. https://doi.org/10.1016/j.bpj.2016.03.009

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Missirlis YF (2016) Mechanoepigenetics. Front Cell Dev Biol 4:113

    PubMed  PubMed Central  Google Scholar 

  • Mizuno S, Takada E, Fukai N (2016) Spheroidal organoids reproduce characteristics of longitudinal depth zones in bovine articular cartilage. Cells Tissues Organs 202:382–392

    CAS  PubMed  Google Scholar 

  • Muncie JM, Weaver VM (2018) The physical and biochemical properties of the extracellular matrix regulate cell fate. Curr Top Dev Biol 130:1–37

  • Na S et al (2008) Rapid signal transduction in living cells is a unique feature of mechanotransduction. PNAS 105(18):6626–6631

    CAS  PubMed  PubMed Central  Google Scholar 

  • Nakamura T, Sato T (2018) Advancing intestinal organoid technology toward regenerative medicine. Cell Mol Gastroenterol Hepatol 5:51–60

    PubMed  Google Scholar 

  • Park SE, Georgescu A, Huh D (2019) Organoids-on-a-chip. Science 364:960–965

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pertz O et al (2006) Spatiotemporal dynamics of RhoA activity in migrating cells. Nature 440:1069–1072

    CAS  PubMed  Google Scholar 

  • Poli D, Magliaro C, Ahluwalia A (2019) Experimental and computational methods for the study of cerebral organoids: a review. Front Neurosci 13:162

  • Portrian D et al (2017) Tubulin acetylation protects long-lived microtubules against mechanical ageing. Nat Cell Biol 19:391–398

    Google Scholar 

  • Qian X et al (2016) Brain-region-specific organoids using mini-bioreactors for modeling ZIKV exposure. Cell 165:1238–1254

    CAS  PubMed  PubMed Central  Google Scholar 

  • Qian X, Song H, Ming G-L (2019) Brain organoids: advances, applications and challenges. Development 146:dev166074. https://doi.org/10.1242/dev.166074

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qiu X, Müller U (2018) Mechanically gated ion channels in mammalian hair cells. Front Cell Neurosci 12:100

  • Rahmani S, Breyner NM, Su H-M, Verdu EF, Didar TF (2018) Intestinal organoids: a new paradigm for engineering intestinal epithelium in vitro. Biomaterials 194:195–214

    PubMed  Google Scholar 

  • Seo J et al (2017) Inhibition of p25/Cdk5 attenuates tauopathy in mouse and iPSC models of frontotemporal dementia. J Neurosci 37:9917–9924

    CAS  PubMed  PubMed Central  Google Scholar 

  • Singh A et al (2018) Polarized microtubule dynamics directs cell mechanics and coordinates forces during epithelial morphogenesis. Nat Cell Biol 20:1126–1133

    CAS  PubMed  Google Scholar 

  • Stachowiak MR et al (2014) A mechanical-biochemical feedback loop regulates remodeling in the actin cytoskeleton. PNAS 111(49):17528–17533

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stathopoulos A, Iber D (2013) Studies of morphogens: keep calm and carry on. Development 140:4119–4124

    CAS  PubMed  PubMed Central  Google Scholar 

  • Sugawara T, Sasaki K, Akutsu H (2018) Organoids recapitulate organs? Stem Cell Investig 5:3. https://doi.org/10.21037/sci.2018.01.02

    Article  PubMed  PubMed Central  Google Scholar 

  • Sunyer R, Trepat X (2017) Mechanobiology of collective cell systems. Biofisica 7:1–7 http://biofisica.info. Accessed 18 June 2019

  • Suzuki A et al (2016) How the kinetochore couples microtubule force and centromere stretch to move chromosomes. Nat Cell Biol 18:382–392

    CAS  PubMed  PubMed Central  Google Scholar 

  • Swift J et al (2013) Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science 341(6149):1240104. https://doi.org/10.1126/science.1240104

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tajik A et al (2016) Transcription upregulation via force-induced direct stretching of chromatin. Nat Mater 15:1287–1296

    CAS  PubMed  PubMed Central  Google Scholar 

  • Todhunter ME, Jee NY, Hughes AJ, Coyle MC, Cerchiari A, Farlow J, Garbe JC, LaBarge MA, Desai TA, Gartner ZJ (2015) Programmed synthesis of three-dimensional tissues. Nat Methods 12:975–981

    CAS  PubMed  PubMed Central  Google Scholar 

  • Turner DA, Baillie-Johnson P, Martinez Arias A (2016) Organoids and the genetically encoded self-assembly of embryonic stem cells. BioEssays 38:181–191

    PubMed  Google Scholar 

  • Ungrin MD, Clarke G, Yin T, Niebrugge S, Nostro MC, Sarangi F, Wood G, Keller G, Zandstra PW (2012) Rational bioprocess design for human pluripotent stem cell expansion and endoderm differentiation based on cellular dynamics. Biotechnol Bioeng 109:853–866

    CAS  PubMed  Google Scholar 

  • Vyas D et al (2018) Self-assembled liver organoids recapitulate hepatobiliary organogenesis in vitro. Hepatology 67:750–761

    CAS  PubMed  Google Scholar 

  • Watt FM, Huck WT (2013) Role of the extracellular matrix in regulating stem cell fate. Nat Rev Mol Cell Biol 14(8):467–473

    CAS  PubMed  Google Scholar 

  • Xu H, Jiao Y, Qin S, Zhao W, Chu Q, Wu K (2018) Organoid technology in disease modelling, drug development, personalized treatment and regeneration medicine. Exp Hematol Oncol 7:30. https://doi.org/10.1186/s40164-018-0122-9

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yin X, Mead BE, Safaee H, Langer R, Karp JM, Levy O (2016) Engineering stem cell organoids. Cell Stem Cell 18:25–38

    CAS  PubMed  PubMed Central  Google Scholar 

  • Zaidel-Bar R, Ballestrem C, Kam Z, Geiger B (2003) Early molecular events in the assembly of matrix adhesions at the leading edge of migrating cells. J Cell Sci 116:4605–4613

    CAS  PubMed  Google Scholar 

  • Zijl S, Lomakin AJ (2019) The “nuclear physics” behind genetic and epigenetic control of cell fate. Exp Cell Res 376(2):236–239

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Acknowledgments

The authors acknowledge COST Action 16122 (BIONECA) for financing Prof. Dr. Yannis F. Missirlis for an STSM to visit and collaborate with the rest of the authors at Ege University; COST Action 16217 (ENIUS) for designating him as a disseminator to “promote” the Action at 4th international Symposium on Nanoengineering for Mechanobiology (N4M), where some of the ideas presented in this review were discussed; and Republic of Turkey Ministry of Development [EGEMATAL;2010K120810] for financing Dr. Ece Bayir.

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  1. Central Research Test and Analysis Laboratory Application and Research Center (EGE-MATAL), Ege University, Izmir, Turkey

    Ece Bayir

  2. Department of Bioengineering, Ege University, Izmir, Turkey

    Aylin Sendemir

  3. Department of Mechanical Engineering & Aeronautics, University of Patras, Patras, Greece

    Yannis F. Missirlis

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  1. Ece Bayir
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Bayir, E., Sendemir, A. & Missirlis, Y.F. Mechanobiology of cells and cell systems, such as organoids. Biophys Rev 11, 721–728 (2019). https://doi.org/10.1007/s12551-019-00590-7

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