Mechanobiology and diseases
Seminal studies in the mid 2000s reported that extracellular matrix (ECM) stiffness (Engler et al., 2006), cell shape and cellular contractility (McBeath et al., 2004) can direct mesenchymal stem cell differentiation. During the subsequent 20Â years, the field of mechanobiology has been significant inspired and substantially developed. These studies helped to better understand how mechanical forces regulate complex cell behaviors and tissue functions (Han et al., 2018; Li et al., 2021a; Li et al., 2021b), and influence homeostasis and disease development (Chowdhury et al., 2021).
Mechanical forces play a pivotal role in regulating cellular biochemical signaling pathways, with reciprocal interactions influencing both cellular activities and mechanical properties in response to environmental cues (Han et al., 2018; Yang et al., 2023). These mutual interactions between mechanical forces and biochemical signaling pathways are critical to human health and disease development. In general, stiffening of the ECM during inflammatory diseases, fibrotic diseases or tumor development can regulate cellular signaling pathways, such as YAP/TAZ, via increasing cellular tractions on ECM, contributing to pathogenesis and exacerbating disease outcomes (Ingber, 2003; He et al., 2022; He et al., 2023). In the realm of glaucoma research, Du et al. uncovered a role for cellular senescence in disrupting the mechanoresponses of trabecular mesh cells (TMCs). Senescent TMCs, subjected to fluid shear stress, exhibited diminished F-actin formation, poor realignment of F-actin fibers, reduced cellular stiffness, and abnormal expression of ECM remodeling-related genes, compared to their non-senescent counterparts. In another study by Chi et al., deficiency in Integrin β4 expression led to increased lung tissue stiffness and elevated ECM components, such as collagen and elastin. Furthermore, Integrin β4 deficiency hindered the adaptation of bronchial epithelial cells to the ECM stiffening due to decreased cytoskeletal stabilization and impaired RhoA activity, ultimately contributing to the development of lung dysplasia.
In addition to affecting cytoskeletal proteins, mechanical forces can activate mechanosensitive Piezo proteins, which serve as pore-forming subunits of ion channels at the cell membrane. In response to mechanical stimuli, such as pressure, shear, and stretch, Piezo ion channels open and allow positively charged ions to flow into the cell, including calcium (Wu et al., 2017). As reviewed by George and Bates in this Research Topic, calcium oscillations occur in almost all cell types and tissues, playing a crucial role in morphogenesis and tissue development. Disruptions of these oscillations can lead to developmental abnormalities and pathogenesis. However, the underlying mechanisms by which mechanical stimuli impact bioelectrical signals and associated pathophysiological functions remains unclear.
Mechanobiology in organoid systems
The role of mechanical forces in cell proliferation, differentiation, and migration have been extensively studied (He et al., 2014; He et al., 2015; Guo et al., 2017; He et al., 2019; He et al., 2023). However, due to the complexity of living organisms, it is challenging to interpret how these mechano-biochemical coupling signaling pathways impact complex organ-level functions. The emerging technique of organoid culture provides a feasible platform recapitulating in vivo organ anatomy and functions for researchers to connect the cellular level mechanisms with the organ-level behaviors, including organoids of brain, lung, kidney, and gut, among others. In this Research Topic, Nauryzgaliyeva et al. presented a comprehensive reviews wherein they introduced the cutting-edge human pluripotent stem cells (hPSCs)- kidney organoid culture which faithfully captures in vivo kidney development and diseases. As they pointed out, the mechanical cues have largely been unexplored within hPSCs-derived organoid cultures. These studies in the future will help to better understand their impact on organ development and disease pathogenesis. They comprehensively reviewed the state-of-the-art techniques to interrogate organoid mechanobiology, including mimicking the extraembryonic microenvironment, using natural or synthetic substrates, combining with microfluidic devices, manipulating mechanosensing and mechanotransduction machineries, and measuring forces in complex organoids.
Regarding quantification of mechanical forces in 3D system, like organoids, Tian et al. reported a novel strategy in this Research Topic to analyze E-cadherin mediated intercellular forces using a series of DNA-hairpin molecular probes which they have developed for 2D cell models (Zhao et al., 2017; Zhao et al., 2020; Kes et al., 2021). Excitingly, after 1–2 h of incubation, these small molecule probes can penetrate a dosage-dependent depth of 50–200 µm of various 3D spheroids, including embryonic stem cell-derived embryoid bodies with strong cell-cell junctions. Combined with confocal microscopy or potentially more advanced imaging tools such as light sheet microscopy, this advanced technology will facilitate the quantification of complex intercellular mechanical interactions within 3D organoids.
Organoids and mechanomedicine
Throughout daily life, cells, composing living organisms, experience various mechanical forces, such as stretch, shear and pressure, as well as encounter different material properties, including varying stiffness, viscosity, surface roughness, and geometries. These constitutive/inherent mechanical cues can regulate cellular signaling pathways and reshape functions of muscles, bones, heart, and other organs, ultimately impacting human health as aforementioned. Targeting mechanosensing pathways is indispensable to tackle diseases and improve human health. Organoid-based systems bridge the cellular level signaling pathways with organ level functions in basic research and clinical studies, which are guaranteed to provide a powerful system for the fields of mechanobiology and mechanomedicine.
Statements
Author contributions
SH: Conceptualization, Funding acquisition, Writing–original draft, Writing–review and editing. CM: Conceptualization, Writing–original draft, Writing–review and editing. YS: Funding acquisition, Writing–original draft, Writing–review and editing. JE: Funding acquisition, Writing–original draft, Writing–review and editing. MG: Writing–original draft, Writing–review and editing.
Funding
The author(s) declare financial support was received for the research, authorship, and/or publication of this article. We acknowledge the support from the National Institutes of Health–National Cancer Institute (5R35CA253185-04) and Harvard Medical School Eleanor and Miles Shore Faculty Development Fellowship awards for SH; National Science Foundation (CMMI 1846866) for YS and (CMMI 2311640) for JE
Conflict of interest
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision.
Publisher’s note
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.
References
1
ChowdhuryF.HuangB.WangN. (2021). Cytoskeletal prestress: the cellular hallmark in mechanobiology and mechanomedicine. Cytoskeleton78 (6), 249–276. 10.1002/cm.21658
2
EnglerA. J.SenS.SweeneyH. L.DischerD. E. (2006). Matrix elasticity directs stem cell Lineage specification. Cell126 (4), 677–689. 10.1016/j.cell.2006.06.044
3
GuoM.PegoraroA. F.MaoA.ZhouE. H.AranyP. R.HanY.et al (2017). Cell volume change through water efflux impacts cell stiffness and stem cell fate. Proc. Natl. Acad. Sci.114 (41), E8618–E27. 10.1073/pnas.1705179114
4
HanY. L.RoncerayP.XuG.MalandrinoA.KammR. D.LenzM.et al (2018). Cell contraction induces long-ranged stress stiffening in the extracellular matrix. Proc. Natl. Acad. Sci.115 (16), 4075–4080. 10.1073/pnas.1722619115
5
HeS.AzarD. A.EsfahaniF. N.AzarG. A.ShazlyT.SaeidiN. (2022). Mechanoscopy: a novel device and procedure for in vivo detection of chronic colitis in mice. Inflamm. Bowel Dis.28 (8), 1143–1150. 10.1093/ibd/izac046
6
HeS.CarmanC. V.LeeJ. H.LanB.KoehlerS.AtiaL.et al (2019). The tumor suppressor p53 can promote collective cellular migration. PloS one14 (2), e0202065. 10.1371/journal.pone.0202065
7
HeS.LeiP.KangW.CheungP.XuT.ManaM.et al (2023). Stiffness restricts the stemness of the intestinal stem cells and skews their differentiation toward goblet cells. Gastroenterology164, 1137–1151. 10.1053/j.gastro.2023.02.030
8
HeS.LiuC.LiX.MaS.HuoB.JiB. (2015). Dissecting collective cell behavior in polarization and alignment on micropatterned substrates. Biophysical J.109 (3), 489–500. 10.1016/j.bpj.2015.06.058
9
HeS.SuY.JiB.GaoH. (2014). Some basic questions on mechanosensing in cell-substrate interaction. J. Mech. Phys. Solids70, 116–135. 10.1016/j.jmps.2014.05.016
10
IngberD. (2003). Mechanobiology and diseases of mechanotransduction. Ann. Med.35 (8), 564–577. 10.1080/07853890310016333
11
KeshriP.ZhaoB.XieT.BagheriY.ChambersJ.SunY.et al (2021). Quantitative and multiplexed fluorescence lifetime imaging of intercellular tensile forces. Angew. Chem. Int. Ed. Engl.60 (28), 15548–15555. 10.1002/anie.202103986
12
LiY.ChenM.HuJ.ShengR.LinQ.HeX.et al (2021b). Volumetric compression induces intracellular crowding to control intestinal organoid growth via wnt/β-catenin signaling. Cell Stem Cell28 (1), 63–78.e7. 10.1016/j.stem.2020.09.012
13
LiY.TangW.GuoM. (2021a). The cell as matter: connecting molecular biology to cellular functions. Matter4 (6), 1863–1891. 10.1016/j.matt.2021.03.013
14
McBeathR.PironeD. M.NelsonC. M.BhadrirajuK.ChenC. S. (2004). Cell shape, cytoskeletal tension, and RhoA regulate stem cell lineage commitment. Dev. Cell6 (4), 483–495. 10.1016/s1534-5807(04)00075-9
15
WuJ.LewisA. H.GrandlJ. (2017). Touch, tension, and transduction–the function and regulation of Piezo ion channels. Trends Biochem. Sci.42 (1), 57–71. 10.1016/j.tibs.2016.09.004
16
YangH.BerthierE.LiC.RoncerayP.HanY. L.BroederszC. P.et al (2023). Local response and emerging nonlinear elastic length scale in biopolymer matrices. Proc. Natl. Acad. Sci.120 (23), e2304666120. 10.1073/pnas.2304666120
17
ZhaoB.LiN.XieT.BagheriY.LiangC.KeshriP.et al (2020). Quantifying tensile forces at cell–cell junctions with a DNA-based fluorescent probe. Chem. Sci.11 (32), 8558–8566. 10.1039/d0sc01455a
18
ZhaoB.O’BrienC.MudiyanselageAPKKKLiN.BagheriY.WuR.et al (2017). Visualizing intercellular tensile forces by DNA-based membrane molecular probes. J. Am. Chem. Soc.139 (50), 18182–18185. 10.1021/jacs.7b11176
Summary
Keywords
mechanobiology, organoid, lung stiffening, senescence, 3D force quantification
Citation
He S, Mierke CT, Sun Y, Eyckmans J and Guo M (2024) Editorial: Mechanobiology of organoid systems. Front. Cell Dev. Biol. 12:1369713. doi: 10.3389/fcell.2024.1369713
Received
12 January 2024
Accepted
16 January 2024
Published
30 January 2024
Volume
12 - 2024
Edited and reviewed by
Akihiko Ito, Kindai University, Japan
Updates
Copyright
© 2024 He, Mierke, Sun, Eyckmans and Guo.
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
*Correspondence: Shijie He, she9@mgh.harvard.edu; Claudia Tanja Mierke, claudia.mierke@uni-leipzig.de; Yubing Sun, ybsun@umass.edu; Jeroen Eyckmans, eyckmans@bu.edu; Ming Guo, guom@mit.edu
Disclaimer
All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.