Chromatin reprogramming and bone regeneration in vitro and in vivo via the microtopography-induced constriction of cell nuclei

Xinlong Wang; Vasundhara Agrawal; Cody L Dunton; Yugang Liu; Ranya K A Virk; Priyam A Patel; Lucas Carter; Emily M Pujadas; Yue Li; Surbhi Jain; Hao Wang; Na Ni; Hsiu-Ming Tsai; Nancy Rivera-Bolanos; Jane Frederick; Eric Roth; Reiner Bleher; Chongwen Duan; Panagiotis Ntziachristos; Tong Chuan He; Russell R Reid; Bin Jiang; Hariharan Subramanian; Vadim Backman; Guillermo A Ameer

doi:10.1038/s41551-023-01053-x

Chromatin reprogramming and bone regeneration in vitro and in vivo via the microtopography-induced constriction of cell nuclei

Nat Biomed Eng. 2023 Nov;7(11):1514-1529. doi: 10.1038/s41551-023-01053-x. Epub 2023 Jun 12.

Authors

Xinlong Wang^#^{1

2}, Vasundhara Agrawal^#^{1

3}, Cody L Dunton^{1

3}, Yugang Liu^{1

2}, Ranya K A Virk^{1

3}, Priyam A Patel⁴, Lucas Carter^{1

3}, Emily M Pujadas^{1

3}, Yue Li^{1

3}, Surbhi Jain^{1

3}, Hao Wang⁵, Na Ni⁵, Hsiu-Ming Tsai⁶, Nancy Rivera-Bolanos^{1

2}, Jane Frederick^{1

3}, Eric Roth⁷, Reiner Bleher⁷, Chongwen Duan^{1

2}, Panagiotis Ntziachristos^{8

9

10

11}, Tong Chuan He^{2

5}, Russell R Reid^{2

12}, Bin Jiang^{1

2

8}, Hariharan Subramanian^{1

3}, Vadim Backman^{13

14

15

16}, Guillermo A Ameer^{17

18

19

20

21

22

23}

Affiliations

¹ Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA.
² Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA.
³ Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL, USA.
⁴ Quantitative Data Science Core, Center for Genetic Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁵ Molecular Oncology Laboratory, Department of Orthopedic Surgery and Rehabilitation Medicine, The University of Chicago Medical Center, Chicago, IL, USA.
⁶ Department of Radiology, The University of Chicago, Chicago, IL, USA.
⁷ Department of Materials Sciences and Engineering, Northwestern University, Evanston, IL, USA.
⁸ Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
⁹ Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA.
¹⁰ Simpson Querrey Center for Epigenetics, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
¹¹ Department of Biomolecular Medicine, Ghent University, Ghent, Belgium.
¹² Laboratory of Craniofacial Biology and Development, Section of Plastic and Reconstructive Surgery, Department of Surgery, The University of Chicago Medical Center, Chicago, IL, USA.
¹³ Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA. v-backman@northwestern.edu.
¹⁴ Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA. v-backman@northwestern.edu.
¹⁵ Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL, USA. v-backman@northwestern.edu.
¹⁶ Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA. v-backman@northwestern.edu.
¹⁷ Department of Biomedical Engineering, Northwestern University, Evanston, IL, USA. g-ameer@northwestern.edu.
¹⁸ Center for Advanced Regenerative Engineering, Northwestern University, Evanston, IL, USA. g-ameer@northwestern.edu.
¹⁹ Center for Physical Genomics and Engineering, Northwestern University, Evanston, IL, USA. g-ameer@northwestern.edu.
²⁰ Department of Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA. g-ameer@northwestern.edu.
²¹ Chemistry of Life Process Institute, Northwestern University, Chicago, IL, USA. g-ameer@northwestern.edu.
²² International Institute for Nanotechnology, Northwestern University, Evanston, IL, USA. g-ameer@northwestern.edu.
²³ Simpson Querrey Institute for Bionanotechnology, Northwestern University, Chicago, IL, USA. g-ameer@northwestern.edu.

^# Contributed equally.

Abstract

Topographical cues on cells can, through contact guidance, alter cellular plasticity and accelerate the regeneration of cultured tissue. Here we show how changes in the nuclear and cellular morphologies of human mesenchymal stromal cells induced by micropillar patterns via contact guidance influence the conformation of the cells' chromatin and their osteogenic differentiation in vitro and in vivo. The micropillars impacted nuclear architecture, lamin A/C multimerization and 3D chromatin conformation, and the ensuing transcriptional reprogramming enhanced the cells' responsiveness to osteogenic differentiation factors and decreased their plasticity and off-target differentiation. In mice with critical-size cranial defects, implants with micropillar patterns inducing nuclear constriction altered the cells' chromatin conformation and enhanced bone regeneration without the need for exogenous signalling molecules. Our findings suggest that medical device topographies could be designed to facilitate bone regeneration via chromatin reprogramming.

MeSH terms

Animals
Bone Regeneration
Chromatin
Constriction
Humans
Mesenchymal Stem Cells*
Mice
Osteogenesis*

Substances

Chromatin

Abstract

MeSH terms

Substances

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