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Peer-reviewedCC BY-NC-NDBioactive Materials

Spatial mechanopriming of multicellular interfaces drives cytoskeletal-to-nuclear remodeling to boost therapeutic efficacy of stem cells

  • Oyunchimeg Bayaraa1
  • Na-Hyun Lee2
  • Sang-Hyun Kim3
  • Hwalim Lee4
  • Chen Ji Li2
  • Xiangting Fu2
  • Jeongeun Hyun5
  • Goeun Choi6
  • Jin-Ho Choy6
  • Hye Sung Kim
  • Hae-Won Kim
6 affiliations
  1. 1Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea; Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan, 31116, Republic of Korea; Drug Research Institute, Mongolian University of Pharmaceutical Sciences, 14250, Mongolia
  2. 2Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea; Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan, 31116, Republic of Korea
  3. 3Industry-academic Cooperation, Dankook University, Cheonan, 31116, Republic of Korea
  4. 4Institute of Tissue Regeneration Engineering (ITREN), Dankook University, Cheonan, 31116, Republic of Korea; Mechanobiology Dental Medicine Research Center, Dankook University, Cheonan, 31116, Republic of Korea; Department of Biomaterials Science, College of Dentistry, Dankook University, Cheonan, 31116, Republic of Korea
  5. 5Department of Biomedical Sciences & Biosystems, College of Bio-convergence, Dankook University, Cheonan, 31116, Republic of Korea; Department of Nanobiomedical Science and BK21 NBM Global Research Center for Regenerative Medicine, Dankook University, Cheonan, 31116, Republic of Korea
  6. 6Intelligent Nanohybrid Materials Laboratory (INML), Department of Chemistry, College of Science and Technology, Dankook University, Cheonan, 31116, Republic of Korea; Institute for Convergence Science (ICS), Global Chemical Convergence Research Institute (GCCRI), Dankook University, Cheonan, 31116, Republic of Korea
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Abstract

Engineering multicellular constructs through biophysical cues, independent of soluble biochemical factors, is a promising strategy to boost the therapeutic potential of stem cells for regenerative medicine. However, the mechanisms by which spatially organized cell-cell and cell-matrix interfaces govern multicellular signaling and subsequent behavioral outcomes remain poorly understood. Here, we elucidate these mechanistic events by introducing 2D nanoplates (∼350 nm) compartmentalized within the intercellular space of mesenchymal stem cell (MSC) spheroids to form de novo cell-matrix spatial interfaces. These interfaces redistribute internal stress across the spheroid, amplifying integrin-cytoskeleton-nucleus force transmission and restoring YAP-dependent mechanotransduction to achieve spatial mechanopriming. Cells within these mechanoprimed spheroids exhibit profound nuclear deformation, epigenetic remodeling, and spatially patterned metabolic activation. Finite element modeling and spatial transcriptomic analyses further reveal a spheroid-wide reorganization of cytoskeletal and transcriptional networks. Mechanistically, elevated cytoskeletal tension across the reorganized interfaces is associated with a putative, tension-associated pseudo-hypoxic signature involving HIF-1α-related signaling, establishing a mechanometabolic niche that robustly enhances angiogenic secretion. Consequently, mechanoprimed spheroids demonstrate superior engraftment, accelerated vascular regeneration, and improved perfusion recovery in a murine ischemia model. Collectively, this work establishes spatial mechanopriming as an effective strategy to remodel cytoskeletal-to-nuclear mechanics and enhance the therapeutic potential of 3D multicellular systems.

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Cite

BibTeXRIS
BibTeX
@article{bayaraa2026spatial,
  title = {{Spatial mechanopriming of multicellular interfaces drives cytoskeletal-to-nuclear remodeling to boost therapeutic efficacy of stem cells}},
  author = {Oyunchimeg Bayaraa and Na-Hyun Lee and Sang-Hyun Kim and Hwalim Lee and Chen Ji Li and Xiangting Fu and Jeongeun Hyun and Goeun Choi and Jin-Ho Choy and Hye Sung Kim and Hae-Won Kim},
  journal = {Bioactive Materials},
  year = {2026},
  month = oct,
  doi = {10.1016/j.bioactmat.2026.09.042},
  url = {https://doi.org/10.1016/j.bioactmat.2026.09.042},
  note = {CC BY-NC-ND},
}
RIS
TY  - JOUR
TI  - Spatial mechanopriming of multicellular interfaces drives cytoskeletal-to-nuclear remodeling to boost therapeutic efficacy of stem cells
AU  - Oyunchimeg Bayaraa
AU  - Na-Hyun Lee
AU  - Sang-Hyun Kim
AU  - Hwalim Lee
AU  - Chen Ji Li
AU  - Xiangting Fu
AU  - Jeongeun Hyun
AU  - Goeun Choi
AU  - Jin-Ho Choy
AU  - Hye Sung Kim
AU  - Hae-Won Kim
PY  - 2026
DA  - 2026/10/22
JO  - Bioactive Materials
DO  - 10.1016/j.bioactmat.2026.09.042
UR  - https://doi.org/10.1016/j.bioactmat.2026.09.042
AB  - Engineering multicellular constructs through biophysical cues, independent of soluble biochemical factors, is a promising strategy to boost the therapeutic potential of stem cells for regenerative medicine. However, the mechanisms by which spatially organized cell-cell and cell-matrix interfaces govern multicellular signaling and subsequent behavioral outcomes remain poorly understood. Here, we elucidate these mechanistic events by introducing 2D nanoplates (∼350 nm) compartmentalized within the intercellular space of mesenchymal stem cell (MSC) spheroids to form de novo cell-matrix spatial interfaces. These interfaces redistribute internal stress across the spheroid, amplifying integrin-cytoskeleton-nucleus force transmission and restoring YAP-dependent mechanotransduction to achieve spatial mechanopriming. Cells within these mechanoprimed spheroids exhibit profound nuclear deformation, epigenetic remodeling, and spatially patterned metabolic activation. Finite element modeling and spatial transcriptomic analyses further reveal a spheroid-wide reorganization of cytoskeletal and transcriptional networks. Mechanistically, elevated cytoskeletal tension across the reorganized interfaces is associated with a putative, tension-associated pseudo-hypoxic signature involving HIF-1α-related signaling, establishing a mechanometabolic niche that robustly enhances angiogenic secretion. Consequently, mechanoprimed spheroids demonstrate superior engraftment, accelerated vascular regeneration, and improved perfusion recovery in a murine ischemia model. Collectively, this work establishes spatial mechanopriming as an effective strategy to remodel cytoskeletal-to-nuclear mechanics and enhance the therapeutic potential of 3D multicellular systems.
SN  - 2452-199X
ER  -