Advances in cell nuclear mechanobiology and its regulation mechanisms_Journal of Biomedical Engineering

Authors：

YAN Ran ^1,2 , CHEN Xiangyan ¹ , ZHANG Yixi ¹ , WANG Meng ¹ ,  LI Shun ¹ ,  LIU Yiyao ^1,2

1. School of Life Science and Technology, University of Electronic Science and Technology of China, Chengdu 610054, P. R. China;
2. Hospital of Chengdu University of Traditional Chinese Medicine, Chengdu 610072, P. R. China;

Corresponding author：

Keywords：

Nuclear deformation; Cytoskeletal mechanics; Nuclear mechanotransduction; Chromatin reconstitution; Tumor

DOI：

10.7507/1001-5515.202304036

Video：

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As an important intracellular genetic and regulatory center, the nucleus is not only a terminal effector of intracellular biochemical signals, but also has a significant impact on cell function and phenotype through direct or indirect regulation of nuclear mechanistic cues after the cell senses and responds to mechanical stimuli. The nucleus relies on chromatin-nuclear membrane-cytoskeleton infrastructure to couple signal transduction, and responds to these mechanical stimuli in the intracellular and extracellular physical microenvironments. Changes in the morphological structure of the nucleus are the most intuitive manifestation of this mechanical response cascades and are the basis for the direct response of the nucleus to mechanical stimuli. Based on such relationships of the nucleus with cell behavior and phenotype, abnormal nuclear morphological changes are widely used in clinical practice as disease diagnostic tools. This review article highlights the latest advances in how nuclear morphology responds and adapts to mechanical stimuli. Additionally, this article will shed light on the factors that mechanically regulate nuclear morphology as well as the tumor physio-pathological processes involved in nuclear morphology and the underlying mechanobiological mechanisms. It provides new insights into the mechanisms that nuclear mechanics regulates disease development and its use as a potential target for diagnosis and treatment.

Citation： YAN Ran, CHEN Xiangyan, ZHANG Yixi, WANG Meng, LI Shun, LIU Yiyao. Advances in cell nuclear mechanobiology and its regulation mechanisms. Journal of Biomedical Engineering, 2023, 40(4): 617-624. doi: 10.7507/1001-5515.202304036 Copy

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2.	Kalukula Y, Stephens A D, Lammerding J, et al. Mechanics and functional consequences of nuclear deformations. Nat Rev Mol Cell Biol, 2022, 23(9): 583-602.
3.	Song Y, Soto J, Chen B, et al. Transient nuclear deformation primes epigenetic state and promotes cell reprogramming. Nat Mater, 2022, 21(10): 1191-1199.
4.	Kalukula Y, Luciano M, Gabriele S. Translating cell mechanobiology and nuclear deformations to the clinic. Clin Transl Med, 2022, 12(7): e1000.
5.	Echarri A. A multisensory network drives nuclear mechanoadaptation. Biomolecules, 2022, 12(3): 404.
6.	Lomakin A J, Cattin C J, Cuvelier D, et al. The nucleus acts as a ruler tailoring cell responses to spatial constraints. Science, 2020, 370(6514): eaba2894.
7.	Shen Z, Niethammer P. A cellular sense of space and pressure. Science, 2020, 370(6514): 295-296.
8.	Enyedi B, Jelcic M, Niethammer P. The cell nucleus serves as a mechanotransducer of tissue damage-induced inflammation. Cell, 2016, 165(5): 1160-1170.
9.	Aureille J, Buffière-Ribot V, Harvey B E, et al. Nuclear envelope deformation controls cell cycle progression in response to mechanical force. EMBO Rep, 2019, 20(9): e48084.
10.	Seelbinder B, Ghosh S, Schneider S E, et al. Nuclear deformation guides chromatin reorganization in cardiac development and disease. Nat Biomed Eng, 2021, 5(12): 1500-1516.
11.	Heo S J, Cosgrove B D, Dai E N, et al. Mechano-adaptation of the stem cell nucleus. Nucleus, 2018, 9(1): 9-19.
12.	Aifuwa I, Kim B C, Kamat P, et al. Senescent stroma induces nuclear deformations in cancer cells via the inhibition of RhoA/ROCK/myosin II-based cytoskeletal tension. PNAS Nexus, 2022, 2(1): pgac270.
13.	Li Y, Chen M, Chang W. Roles of the nucleus in leukocyte migration. J Leukoc Biol, 2022, 112(4): 771-783.
14.	Venturini V, Pezzano F, Català Castro F, et al. The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior. Science, 2020, 370(6514): eaba2644.
15.	Lautscham L A, Kämmerer C, Lange J R, et al. Migration in confined 3D environments is determined by a combination of adhesiveness, nuclear volume, contractility, and cell stiffness. Biophys J, 2015, 109(5): 900-913.
16.	Fracchia A, Asraf T, Salmon-Divon M, et al. Increased Lamin B1 levels promote cell migration by altering perinuclear actin organization. Cells, 2020, 9(10): 2161.
17.	Roberts A B, Zhang J, Raj Singh V, et al. Tumor cell nuclei soften during transendothelial migration. J Biomech, 2021, 121: 110400.
18.	Xu Zichen, Li Keming, Xin Ying, et al. Fluid shear stress regulates the survival of circulating tumor cells via nuclear expansion. J Cell Sci, 2022, 135(10): jcs259586.
19.	Shah P, Hobson C M, Cheng S, et al. Nuclear deformation causes DNA damage by increasing replication stress. Curr Biol, 2021, 31(4): 753-765.
20.	Bone C R, Chang Y T, Cain N E, et al. Nuclei migrate through constricted spaces using microtubule motors and actin networks in C. elegans hypodermal cells. Development, 2016, 143(22): 4193-4202.
21.	Strouhalova K, Přechová M, Gandalovičová A, et al. Vimentin intermediate filaments as potential target for cancer treatment. Cancers, 2020, 12(1): 184.
22.	Pogoda K, Byfield F, Deptuła P, et al. Unique role of vimentin networks in compression stiffening of cells and protection of nuclei from compressive stress. Nano Lett, 2022, 22(12): 4725-4732.
23.	Cruz V E, Esra D F, Schwartz T U. Structural analysis of different LINC complexes reveals distinct binding modes. J Mol Biol, 2020, 432(23): 6028-6041.
24.	Funkhouser C M, Sknepnek R, Shimi T, et al. Mechanical model of blebbing in nuclear lamin meshworks. Proc Natl Acad Sci U S A, 2013, 110(9): 3248–3253.
25.	Bell E S, Shah P, Zuela-Sopilniak N, et al. Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer. Oncogene, 2022, 41(36): 4211-4230.
26.	Vortmeyer-Krause M, Lindert M T, Riet J T, et al. Lamin B2 follows lamin A/C-mediated nuclear mechanics and cancer cell invasion efficacy. Cold Spring Harbor Laboratory, 2020. DOI: 10.1101/2020.04.07.028969.
27.	Katiyar A, Zhang J, Antani J D, et al. The nucleus bypasses obstacles by deforming like a drop with surface tension mediated by lamin A/C. Adv Sci, 2022, 9(23): e2201248.
28.	Fernandez A, Bautista M, Wu L, et al. Emerin self-assembly and nucleoskeletal coupling regulate nuclear envelope mechanics against stress. J Cell Sci, 2022, 135(6): jcs258969.
29.	Niethammer P. Components and mechanisms of nuclear mechanotransduction. Annu Rev Cell Dev Biol, 2021, 37:233-256.
30.	Stephens A D, Liu P Z, Banigan E J, et al. Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins. Mol Biol Cell, 2018, 29(2): 220-233.
31.	Sun J, Chen J, Mohagheghian E, et al. Force-induced gene up-regulation does not follow the weak power law but depends on H3K9 demethylation. Sci Adv, 2020, 6(14): eaay9095.
32.	Hansen J C, Maeshima K, Hendzel M J. The solid and liquid states of chromatin. Epigenetics Chromatin, 2021, 14(1): 50.
33.	Antmen E, Ermis M, Kuren O, et al. Nuclear deformability of breast cells analyzed from patients with malignant and benign breast diseases. ACS Biomater Sci Eng, 2023, 9(3): 1629-1643.
34.	Antmen E, Demirci U, Hasirci V. Amplification of nuclear deformation of breast cancer cells by seeding on micropatterned surfaces to better distinguish their malignancies. Colloids Surf B Biointerfaces, 2019, 183: 110402.
35.	Stowers R S, Shcherbina A, Israeli J, et al. Matrix stiffness induces a tumorigenic phenotype in mammary epithelium through changes in chromatin accessibility. Nat Biomed Eng, 2019, 3(12): 1009-1019.
36.	Ribeiro A J, Khanna P, Sukumar A, et al. Nuclear stiffening inhibits migration of invasive melanoma cells. Cell Mol Bioeng. 2014, 7(4): 544-551.
37.	Senigagliesi B, Penzo C, Severino L U, et al. The high mobility group A1 (HMGA1) chromatin architectural factor modulates nuclear stiffness in breast cancer cells. Int J Mol Sci, 2019, 20(11): 2733.
38.	Tusamda Wakhloo N, Anders S, Badique F, et al. Actomyosin, vimentin and LINC complex pull on osteosarcoma nuclei to deform on micropillar topography. Biomaterials, 2020, 234: 119746.
39.	Fischer T, Hayn A, Mierke C T. Effect of nuclear stiffness on cell mechanics and migration of human breast cancer cells. Front Cell Dev Biol, 2020, 8: 393.

1. Nia H T, Munn L L, Jain R K. Physical traits of cancer. Science. 2020, 370(6516): eaaz0868.
2. Kalukula Y, Stephens A D, Lammerding J, et al. Mechanics and functional consequences of nuclear deformations. Nat Rev Mol Cell Biol, 2022, 23(9): 583-602.
3. Song Y, Soto J, Chen B, et al. Transient nuclear deformation primes epigenetic state and promotes cell reprogramming. Nat Mater, 2022, 21(10): 1191-1199.
4. Kalukula Y, Luciano M, Gabriele S. Translating cell mechanobiology and nuclear deformations to the clinic. Clin Transl Med, 2022, 12(7): e1000.
5. Echarri A. A multisensory network drives nuclear mechanoadaptation. Biomolecules, 2022, 12(3): 404.
6. Lomakin A J, Cattin C J, Cuvelier D, et al. The nucleus acts as a ruler tailoring cell responses to spatial constraints. Science, 2020, 370(6514): eaba2894.
7. Shen Z, Niethammer P. A cellular sense of space and pressure. Science, 2020, 370(6514): 295-296.
8. Enyedi B, Jelcic M, Niethammer P. The cell nucleus serves as a mechanotransducer of tissue damage-induced inflammation. Cell, 2016, 165(5): 1160-1170.
9. Aureille J, Buffière-Ribot V, Harvey B E, et al. Nuclear envelope deformation controls cell cycle progression in response to mechanical force. EMBO Rep, 2019, 20(9): e48084.
10. Seelbinder B, Ghosh S, Schneider S E, et al. Nuclear deformation guides chromatin reorganization in cardiac development and disease. Nat Biomed Eng, 2021, 5(12): 1500-1516.
11. Heo S J, Cosgrove B D, Dai E N, et al. Mechano-adaptation of the stem cell nucleus. Nucleus, 2018, 9(1): 9-19.
12. Aifuwa I, Kim B C, Kamat P, et al. Senescent stroma induces nuclear deformations in cancer cells via the inhibition of RhoA/ROCK/myosin II-based cytoskeletal tension. PNAS Nexus, 2022, 2(1): pgac270.
13. Li Y, Chen M, Chang W. Roles of the nucleus in leukocyte migration. J Leukoc Biol, 2022, 112(4): 771-783.
14. Venturini V, Pezzano F, Català Castro F, et al. The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior. Science, 2020, 370(6514): eaba2644.
15. Lautscham L A, Kämmerer C, Lange J R, et al. Migration in confined 3D environments is determined by a combination of adhesiveness, nuclear volume, contractility, and cell stiffness. Biophys J, 2015, 109(5): 900-913.
16. Fracchia A, Asraf T, Salmon-Divon M, et al. Increased Lamin B1 levels promote cell migration by altering perinuclear actin organization. Cells, 2020, 9(10): 2161.
17. Roberts A B, Zhang J, Raj Singh V, et al. Tumor cell nuclei soften during transendothelial migration. J Biomech, 2021, 121: 110400.
18. Xu Zichen, Li Keming, Xin Ying, et al. Fluid shear stress regulates the survival of circulating tumor cells via nuclear expansion. J Cell Sci, 2022, 135(10): jcs259586.
19. Shah P, Hobson C M, Cheng S, et al. Nuclear deformation causes DNA damage by increasing replication stress. Curr Biol, 2021, 31(4): 753-765.
20. Bone C R, Chang Y T, Cain N E, et al. Nuclei migrate through constricted spaces using microtubule motors and actin networks in C. elegans hypodermal cells. Development, 2016, 143(22): 4193-4202.
21. Strouhalova K, Přechová M, Gandalovičová A, et al. Vimentin intermediate filaments as potential target for cancer treatment. Cancers, 2020, 12(1): 184.
22. Pogoda K, Byfield F, Deptuła P, et al. Unique role of vimentin networks in compression stiffening of cells and protection of nuclei from compressive stress. Nano Lett, 2022, 22(12): 4725-4732.
23. Cruz V E, Esra D F, Schwartz T U. Structural analysis of different LINC complexes reveals distinct binding modes. J Mol Biol, 2020, 432(23): 6028-6041.
24. Funkhouser C M, Sknepnek R, Shimi T, et al. Mechanical model of blebbing in nuclear lamin meshworks. Proc Natl Acad Sci U S A, 2013, 110(9): 3248–3253.
25. Bell E S, Shah P, Zuela-Sopilniak N, et al. Low lamin A levels enhance confined cell migration and metastatic capacity in breast cancer. Oncogene, 2022, 41(36): 4211-4230.
26. Vortmeyer-Krause M, Lindert M T, Riet J T, et al. Lamin B2 follows lamin A/C-mediated nuclear mechanics and cancer cell invasion efficacy. Cold Spring Harbor Laboratory, 2020. DOI: 10.1101/2020.04.07.028969.
27. Katiyar A, Zhang J, Antani J D, et al. The nucleus bypasses obstacles by deforming like a drop with surface tension mediated by lamin A/C. Adv Sci, 2022, 9(23): e2201248.
28. Fernandez A, Bautista M, Wu L, et al. Emerin self-assembly and nucleoskeletal coupling regulate nuclear envelope mechanics against stress. J Cell Sci, 2022, 135(6): jcs258969.
29. Niethammer P. Components and mechanisms of nuclear mechanotransduction. Annu Rev Cell Dev Biol, 2021, 37:233-256.
30. Stephens A D, Liu P Z, Banigan E J, et al. Chromatin histone modifications and rigidity affect nuclear morphology independent of lamins. Mol Biol Cell, 2018, 29(2): 220-233.
31. Sun J, Chen J, Mohagheghian E, et al. Force-induced gene up-regulation does not follow the weak power law but depends on H3K9 demethylation. Sci Adv, 2020, 6(14): eaay9095.
32. Hansen J C, Maeshima K, Hendzel M J. The solid and liquid states of chromatin. Epigenetics Chromatin, 2021, 14(1): 50.
33. Antmen E, Ermis M, Kuren O, et al. Nuclear deformability of breast cells analyzed from patients with malignant and benign breast diseases. ACS Biomater Sci Eng, 2023, 9(3): 1629-1643.
34. Antmen E, Demirci U, Hasirci V. Amplification of nuclear deformation of breast cancer cells by seeding on micropatterned surfaces to better distinguish their malignancies. Colloids Surf B Biointerfaces, 2019, 183: 110402.
35. Stowers R S, Shcherbina A, Israeli J, et al. Matrix stiffness induces a tumorigenic phenotype in mammary epithelium through changes in chromatin accessibility. Nat Biomed Eng, 2019, 3(12): 1009-1019.
36. Ribeiro A J, Khanna P, Sukumar A, et al. Nuclear stiffening inhibits migration of invasive melanoma cells. Cell Mol Bioeng. 2014, 7(4): 544-551.
37. Senigagliesi B, Penzo C, Severino L U, et al. The high mobility group A1 (HMGA1) chromatin architectural factor modulates nuclear stiffness in breast cancer cells. Int J Mol Sci, 2019, 20(11): 2733.
38. Tusamda Wakhloo N, Anders S, Badique F, et al. Actomyosin, vimentin and LINC complex pull on osteosarcoma nuclei to deform on micropillar topography. Biomaterials, 2020, 234: 119746.
39. Fischer T, Hayn A, Mierke C T. Effect of nuclear stiffness on cell mechanics and migration of human breast cancer cells. Front Cell Dev Biol, 2020, 8: 393.

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