journal article·2019-12-11Open access

Volume Adaptation Controls Stem Cell Mechanotransduction

Luke G. Major, Andrew W. Holle, Jennifer L. Young, Matt S. Hepburn, Kwanghee Jeong, Ian L. Chin, Rowan W. Sanderson, Ji Hoon Jeong, Zachary M. Aman, Brendan F. Kennedy, Yongsung Hwang, Dong-Wook Han, Hyun Woo Park, Kun-Liang Guan, Joachim P. Spatz, Yu Suk Choi

ACS Applied Materials & Interfaces· Volume 11· Issue 49

Abstract

Recent studies have found discordant mechanosensitive outcomes when comparing 2D and 3D, highlighting the need for tools to study mechanotransduction in 3D across a wide spectrum of stiffness. A gelatin methacryloyl (GelMA) hydrogel with a continuous stiffness gradient ranging from 5 to 38 kPa was developed to recapitulate physiological stiffness conditions. Adipose-derived stem cells (ASCs) were encapsulated in this hydrogel, and their morphological characteristics and expression of both mechanosensitive proteins (Lamin A, YAP, and MRTFa) and differentiation markers (PPARγ and RUNX2) were analyzed. Low-stiffness regions (∼8 kPa) permitted increased cellular and nuclear volume and enhanced mechanosensitive protein localization in the nucleus. This trend was reversed in high stiffness regions (∼30 kPa), where decreased cellular and nuclear volumes and reduced mechanosensitive protein nuclear localization were observed. Interestingly, cells in soft regions exhibited enhanced osteogenic RUNX2 expression, while those in stiff regions upregulated the adipogenic regulator PPARγ, suggesting that volume, not substrate stiffness, is sufficient to drive 3D stem cell differentiation. Inhibition of myosin II (Blebbistatin) and ROCK (Y-27632), both key drivers of actomyosin contractility, resulted in reduced cell volume, especially in low-stiffness regions, causing a decorrelation between volume expansion and mechanosensitive protein localization. Constitutively active and inactive forms of the canonical downstream mechanotransduction effector TAZ were stably transfected into ASCs. Activated TAZ resulted in higher cellular volume despite increasing stiffness and a consistent, stiffness-independent translocation of YAP and MRTFa into the nucleus. Thus, volume adaptation as a function of 3D matrix stiffness can control stem cell mechanotransduction and differentiation.
Source: openalex_inverted_index · Quality: baseline

Research context

OpenAlex topics: Cellular Mechanics and Interactions · 3D Printing in Biomedical Research · Hippo pathway signaling and YAP/TAZ

SciVX discovery tags are terminology-based. OpenAlex topics are source-provided classifications.

Affiliations

School of Human Sciences, University of Western Australia, Perth, Western Australia 6009, Australia

Department of Cellular Biophysics, Max Planck Institute for Medical Research, 69120 Heidelberg, Germany

Department of Biophysical Chemistry, University of Heidelberg, D-69117 Heidelberg, Germany

BRITElab, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands and Centre for Medical Research, University of Western Australia, Perth, Western Australia 6009, Australia

Department of Electrical, Electronic & Computer Engineering, School of Engineering, University of Western Australia, Perth, Western Australia, 6009, Australia

Fluid Science and Resources, Department of Chemical Engineering, School of Engineering, University of Western Australia, Perth, Western Australia 6009, Australia

Soonchunhyang Institute of Medi-bio Science, Soonchunhyang University, Cheonan-si, Chungcheongnam-do 31151, Korea

Australian Research Council Centre for Personalised Therapeutics Technologies, Perth, Western Australia 6009, Australia

Department of CognoMechatronics Engineering, College of Nanoscience & Nanotechnology, Pusan National University, Busan 46241, Korea

Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Korea

Department of Pharmacology and Moores Cancer Center, University of California San Diego, La Jolla, California 92093, United States

Funding

Deutscher Akademischer Austauschdienst · Department of Health, Government of Western Australia · University of Western Australia · National Health and Medical Research Council · National Heart Foundation of Australia

References (37)

Show source-provided references
1. 10.1016/j.cell.2006.06.04410.1016/j.cell.2006.06.044 ↗
2. 10.1073/pnas.161823911410.1073/pnas.1618239114 ↗
3. 10.1016/S1534-5807(04)00075-910.1016/S1534-5807(04)00075-9 ↗
4. 10.1073/pnas.090326910710.1073/pnas.0903269107 ↗
5. 10.1016/j.biomaterials.2015.05.03010.1016/j.biomaterials.2015.05.030 ↗
6. 10.1016/j.biomaterials.2016.05.01610.1016/j.biomaterials.2016.05.016 ↗
7. 10.1016/j.jbiomech.2009.09.00910.1016/j.jbiomech.2009.09.009 ↗
8. 10.1016/j.biomaterials.2010.10.02010.1016/j.biomaterials.2010.10.020 ↗
9. 10.1242/jcs.02967810.1242/jcs.029678 ↗
10. 10.1016/j.biomaterials.2011.12.00410.1016/j.biomaterials.2011.12.004 ↗
11. 10.1002/term.273610.1002/term.2736 ↗
12. 10.1016/S0006-3495(00)76279-510.1016/S0006-3495(00)76279-5 ↗
13. 10.1016/j.biomaterials.2016.06.06110.1016/j.biomaterials.2016.06.061 ↗
14. 10.1038/nature1013710.1038/nature10137 ↗
15. 10.1038/s41467-019-08465-x10.1038/s41467-019-08465-x ↗
16. 10.1021/acs.nanolett.7b0498210.1021/acs.nanolett.7b04982 ↗
17. 10.1016/j.actbio.2014.08.01010.1016/j.actbio.2014.08.010 ↗
18. 10.1016/j.cell.2015.07.01310.1016/j.cell.2015.07.013 ↗
19. 10.1038/nmat405110.1038/nmat4051 ↗
20. 10.1038/srep1553810.1038/srep15538 ↗
21. Drexler W. · 201510.1007/978-3-319-06419-2 ↗
22. 10.1063/1.272492010.1063/1.2724920 ↗
23. 10.1093/bioinformatics/btr09510.1093/bioinformatics/btr095 ↗
24. Colthup N. · 1990
25. 10.1146/annurev.anchem.1.031207.11281410.1146/annurev.anchem.1.031207.112814 ↗
26. 10.1098/rspb.2010.037710.1098/rspb.2010.0377 ↗
27. 10.1016/j.biomaterials.2018.10.02510.1016/j.biomaterials.2018.10.025 ↗
28. 10.1016/S0006-3495(04)74140-510.1016/S0006-3495(04)74140-5 ↗
29. 10.1038/s41467-019-08465-x10.1038/s41467-019-08465-x ↗
30. 10.1038/ncomms166810.1038/ncomms1668 ↗
31. 10.1126/science.124010410.1126/science.1240104 ↗
32. 10.1074/jbc.RA118.00271510.1074/jbc.RA118.002715 ↗
33. 10.1038/ncomms1532110.1038/ncomms15321 ↗
34. 10.1016/j.jbiomech.2015.12.05110.1016/j.jbiomech.2015.12.051 ↗
35. 10.1073/pnas.170517911410.1073/pnas.1705179114 ↗
36. 10.1016/j.cell.2014.02.05210.1016/j.cell.2014.02.052 ↗
37. 10.1021/acs.nanolett.8b0472010.1021/acs.nanolett.8b04720 ↗