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Cited by 16Cellular Mechanics and InteractionsHydrogels: synthesis, properties, applicationsMesenchymal stem cell research

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Matrix stiffness-dependent regulation of immunomodulatory genes in human MSCs is associated with the lncRNA CYTOR

Open access
Lim, Justin J., Vining, Kyle H., Mooney, David J., Blencowe, Benjamin J.·2024·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.2404146121PMC PMC11317610
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Abstract

Cell–matrix interactions in 3D environments significantly differ from those in 2D cultures. As such, mechanisms of mechanotransduction in 2D cultures are not necessarily applicable to cell-encapsulating hydrogels that resemble features of tissue architecture. Accordingly, the characterization of molecular pathways in 3D matrices is expected to uncover insights into how cells respond to their mechanical environment in physiological contexts, and potentially also inform hydrogel-based strategies in cell therapies. In this study, a bone marrow-mimetic hydrogel was employed to systematically investigate the stiffness-responsive transcriptome of mesenchymal stromal cells. High matrix rigidity impeded integrin-collagen adhesion, resulting in changes in cell morphology characterized by a contractile network of actin proximal to the cell membrane. This resulted in a suppression of extracellular matrix-regulatory genes involved in the remodeling of collagen fibrils, as well as the upregulation of secreted immunomodulatory factors. Moreover, an investigation of long noncoding RNAs revealed that the cytoskeleton regulator RNA (CYTOR) contributes to these 3D stiffness-driven changes in gene expression. Knockdown of CYTOR using antisense oligonucleotides enhanced the expression of numerous mechanoresponsive cytokines and chemokines to levels exceeding those achievable by modulating matrix stiffness alone. Taken together, our findings further our understanding of mechanisms of mechanotransduction that are distinct from canonical mechanotransductive pathways observed in 2D cultures.

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  • Mechanical cues modulate transcriptional programs related to cell adhesion, survival, and drug resistance, leading to gene expression profiles that diverge from ECM-free conditions.

    “These mechanical cues have been shown to modulate transcriptional programs related to cell adhesion, survival, and drug resistance, leading to gene expression profiles that diverge significantly from those observed in ECM-free conditions [213,217,218].”

    From Modeling Tumor Microenvironment Complexity In Vitro: Spheroids as Physiologically Relevant Tumor Models and Strategies for Their Analysis (2025) · cites this paper as [217]

    The Results section ('The Stiffness-Sensitive Transcriptome Is Enriched in ECM-Regulatory and Secreted Immunomodulatory Factors'; page unavailable) reports stiffness-dependent changes in adhesion-related and immunomodulatory gene expression in encapsulated MSCs. It does not establish transcriptional programs related to survival or drug resistance, and its gene-expression comparison is between different matrix stiffnesses, not between ECM-containing and ECM-free conditions. (LLM, conf=0.88)

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References 114 · Cited by 16

Research works printed but not linked: 108

  1. 10.1038/s41392-023-01501-9 · DOI
  2. 10.1038/nrm.2017.108 · DOI · Paper page
  3. 10.1016/j.tcb.2018.01.008 · DOI
  4. 10.1038/s41580-019-0134-2 · DOI · Paper page
  5. 10.1038/s41467-019-09755-0 · DOI
  6. 10.1016/j.bpj.2020.07.003 · DOI
  7. 10.1038/nmat2732 · DOI
  8. 10.1038/s41580-023-00583-1 · DOI
  9. 10.1038/s41586-020-2612-2 · DOI · Paper page
  10. 10.1038/s41580-022-00566-8 · DOI
  11. 10.1038/s41580-020-00315-9 · DOI · Paper page
  12. 10.3390/ncrna8020028 · DOI
  13. 10.1038/s41419-022-04650-x · DOI
  14. 10.1038/s41413-022-00191-3 · DOI
  15. 10.1038/s42003-020-0987-0 · DOI
  16. 10.1002/btm2.10158 · DOI
  17. 10.1126/sciadv.aba6884 · DOI · Paper page
  18. 10.1016/j.biopha.2023.114655 · DOI
  19. 10.1016/j.biomaterials.2018.07.039 · DOI
  20. 10.1073/pnas.1802568115 · DOI · Paper page
  21. 10.1039/C9BM01202H · DOI
  22. 10.1021/acsbiomaterials.9b00843 · DOI
  23. 10.1126/sciadv.aaw0158 · DOI
  24. 10.1016/j.actbio.2022.07.010 · DOI
  25. 10.1126/science.1064829 · DOI · Paper page
  26. 10.1016/j.biomaterials.2017.11.004 · DOI
  27. 10.1016/j.biomaterials.2018.10.013 · DOI
  28. 10.1039/C7BM00853H · DOI
  29. 10.1016/j.biomaterials.2021.120797 · DOI
  30. 10.1038/s41563-022-01293-3 · DOI
  31. 10.1016/j.jmbbm.2015.06.023 · DOI
  32. 10.1042/BSR20150025 · DOI
  33. 10.1159/000445096 · DOI
  34. 10.1038/s41467-018-06641-z · DOI
  35. 10.1083/jcb.201201124 · DOI
  36. 10.1016/j.devcel.2021.02.017 · DOI
  37. 10.1038/s41467-019-08465-x · DOI
  38. 10.1002/cm.20041 · DOI · Paper page
  39. 10.1016/j.cell.2017.10.008 · DOI · Paper page
  40. 10.1242/jcs.050724 · DOI
  41. 10.1016/j.celrep.2023.112338 · DOI
  42. 10.1073/pnas.1505421112 · DOI
  43. 10.1101/gr.177790.114 · DOI · Paper page
  44. 10.1016/j.molcel.2017.01.011 · DOI
  45. 10.1101/gr.220962.117 · DOI
  46. 10.1186/s13059-014-0550-8 · DOI · Paper page
  47. 10.1074/mcp.M111.014647 · DOI · Paper page
  48. 10.1074/jbc.M115.641670 · DOI
  49. 10.1186/s12933-022-01626-1 · DOI
  50. 10.1046/j.1365-2567.2000.00997.x · DOI
  51. 10.3389/fimmu.2018.01930 · DOI
  52. 10.1038/s41467-019-14263-2 · DOI
  53. 10.1038/s41598-021-87153-7 · DOI
  54. 10.1016/j.jaci.2014.12.1926 · DOI
  55. 10.5966/sctm.2015-0166 · DOI
  56. 10.1182/blood-2010-12-327353 · DOI
  57. 10.1016/j.cellimm.2008.06.002 · DOI
  58. 10.1038/s41419-021-03524-y · DOI
  59. 10.1167/iovs.19-27493 · DOI
  60. 10.1038/s41392-020-00303-7 · DOI · Paper page
  61. 10.1016/j.bpj.2020.06.026 · DOI
  62. 10.1016/j.cell.2021.04.048 · DOI · Paper page
  63. 10.7554/eLife.81656 · DOI
  64. 10.15283/ijsc22101 · DOI
  65. 10.3390/cells9020497 · DOI
  66. 10.1016/j.stemcr.2023.10.015 · DOI
  67. 10.1155/2014/803237 · DOI
  68. 10.1038/ncomms14344 · DOI
  69. 10.1186/1471-2105-14-128 · DOI · Paper page
  70. 10.1093/nar/gkw377 · DOI · Paper page
  71. 10.1093/bioadv/vbac016 · DOI
  72. 10.1038/s41525-020-00151-y · DOI
  73. 10.1038/nmat4489 · DOI · Paper page
  74. 10.1038/nrm1549 · DOI
  75. 10.1083/jcb.107.3.1241 · DOI
  76. 10.1242/jcs.188672 · DOI
  77. 10.1016/j.cellsig.2021.109984 · DOI
  78. 10.1002/ijc.27475 · DOI
  79. Y. Liu, M. Li, H. Yu, H. Piao, lncRNA CYTOR promotes tamoxifen resistance in breast cancer cells via sponging miR-125a-5p. Int. J. Mol. Med. 45, 497–509 (2019), 10.3892/ijmm.2019.4428. · DOI
  80. 10.1016/j.gendis.2021.08.012 · DOI
  81. 10.3390/cells11091528 · DOI
  82. 10.1126/scitranslmed.abc7367 · DOI
  83. 10.1126/sciadv.aba1972 · DOI · Paper page
  84. 10.1042/BSR20181599 · DOI
  85. 10.1016/j.drudis.2017.09.018 · DOI
  86. 10.1016/j.mtbio.2022.100537 · DOI
  87. 10.1038/s41467-018-02906-9 · DOI
  88. 10.1155/2016/5246584 · DOI
  89. 10.3390/polym14050876 · DOI
  90. 10.1074/jbc.M115.702571 · DOI
  91. 10.1038/ni.2060 · DOI
  92. 10.1007/s12185-022-03373-1 · DOI
  93. 10.1182/blood.V122.21.1946.1946 · DOI
  94. 10.1038/s41551-023-01052-y · DOI
  95. 10.1016/j.yexcr.2013.09.018 · DOI
  96. 10.1038/ncb2074 · DOI
  97. 10.1096/fj.02-1148com · DOI
  98. 10.1074/jbc.M115.707174 · DOI
  99. 10.1038/ncb3525 · DOI
  100. 10.1083/jcb.200207130 · DOI
  101. 10.1038/nature19346 · DOI
  102. 10.1016/j.biopha.2017.11.015 · DOI
  103. 10.1074/jbc.270.45.27348 · DOI · Paper page
  104. 10.1038/s41423-023-00974-6 · DOI
  105. 10.1136/jitc-2019-000308 · DOI
  106. 10.1096/fj.202201982RRR · DOI
  107. 10.1136/gutjnl-2018-316324 · DOI
  108. 10.1093/nar/30.1.207 · DOI · Paper page

Metadata

Authors
Lim, J. J., Vining, K. H., Mooney, D. J., & Blencowe, B. J.
Affiliations
  • University of Toronto (CA)
  • University of Pennsylvania (US)
  • Harvard University (US)
Corresponding author
  • Lim, Justin J.
  • Blencowe, Benjamin J.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2024-07-29
Volume
121
Issue
32
Pages
e2404146121-e2404146121
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.2404146121
PMC
PMC11317610
OpenAlex
W4401071020
Cited by
16
References
114
Citations by year
2026: 11 · 2025: 5
FWCI
3.60
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
Funders
Canadian Government | Canadian Institutes of Health Research (FDN 353947)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Physical Sciences › Materials Science › Biomaterials › Hydrogels: synthesis, properties, applications
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Mesenchymal stem cell research
Keywords
extracellular matrix stiffness, mechanotransduction, mesenchymal stem cells, CYTOR, long non-coding RNA, immunomodulatory genes, 3D hydrogels, actin cytoskeleton, cytokines and chemokines, antisense oligonucleotide knockdown, cell therapy
MeSH terms
Cells, Cultured, Collagen, Extracellular Matrix, Gene Expression Regulation, Humans, Hydrogels, Mechanotransduction, Cellular, Immunomodulation, Mesenchymal Stem Cells, RNA, Long Noncoding

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