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

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 HeRussell R. Reid, Bin Jiang, Hariharan Subramanian, Vadim Backman^*, Guillermo A. Ameer^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

23 Scopus citations

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.

Original language	English (US)
Pages (from-to)	1514-1529
Number of pages	16
Journal	Nature Biomedical Engineering
Volume	7
Issue number	11
DOIs	https://doi.org/10.1038/s41551-023-01053-x
State	Published - Nov 2023

Funding

This work was supported by the National Science Foundation (NSF) Emerging Frontiers in Research and Innovation (EFRI) (no. 1830968 to G.A.A.), the National Cancer Institute (NCI) (no. R00CA188293, no. R01CA248770 and no.U54CA193419 to P.N.), National Institutes of Health (NIH) grants U54CA268084 and R01CA228272, NSF grant EFMA-1830961 (to V.B.) and philanthropic support from K. Hudson and R. Goldman, S. Brice and J. Esteve, M. E. Holliday and I. Schneider, the Christina Carinato Charitable Foundation, and D. Sachs. This work was performed as a collaboration between the Center for Advanced Regenerative Engineering (CARE) and the Center for Physical Genomics and Engineering (CPGE) at Northwestern University. This work made use of the EPIC facility, the NUFAB facility, and the BioCryo facility of Northwestern University’s NUANCE Center, which has received support from the SHyNE Resource (NSF ECCS-2025633), the International Institute for Nanotechnology (IIN) and Northwestern’s MRSEC programme (NSF DMR-1720139). This work also made use of the Northwestern University NUSeq Core and the Biological Imaging Facility (BIF). We also thank S. Blythe (Molecular Biosciences, Northwestern University) for his guidance in ATAC-seq data analysis. This work was supported by the National Science Foundation (NSF) Emerging Frontiers in Research and Innovation (EFRI) (no. 1830968 to G.A.A.), the National Cancer Institute (NCI) (no. R00CA188293, no. R01CA248770 and no.U54CA193419 to P.N.), National Institutes of Health (NIH) grants U54CA268084 and R01CA228272, NSF grant EFMA-1830961 (to V.B.) and philanthropic support from K. Hudson and R. Goldman, S. Brice and J. Esteve, M. E. Holliday and I. Schneider, the Christina Carinato Charitable Foundation, and D. Sachs. This work was performed as a collaboration between the Center for Advanced Regenerative Engineering (CARE) and the Center for Physical Genomics and Engineering (CPGE) at Northwestern University. This work made use of the EPIC facility, the NUFAB facility, and the BioCryo facility of Northwestern University’s NUANCE Center, which has received support from the SHyNE Resource (NSF ECCS-2025633), the International Institute for Nanotechnology (IIN) and Northwestern’s MRSEC programme (NSF DMR-1720139). This work also made use of the Northwestern University NUSeq Core and the Biological Imaging Facility (BIF). We also thank S. Blythe (Molecular Biosciences, Northwestern University) for his guidance in ATAC-seq data analysis.

ASJC Scopus subject areas

Biotechnology
Bioengineering
Medicine (miscellaneous)
Biomedical Engineering
Computer Science Applications

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Wang, X., Agrawal, V., Dunton, C. L., Liu, Y., Virk, R. K. A., Patel, P. A., Carter, L., Pujadas, E. M., Li, Y., Jain, S., Wang, H., Ni, N., Tsai, H. M., Rivera-Bolanos, N., Frederick, J., Roth, E., Bleher, R., Duan, C., Ntziachristos, P., ... Ameer, G. A. (2023). Chromatin reprogramming and bone regeneration in vitro and in vivo via the microtopography-induced constriction of cell nuclei. Nature Biomedical Engineering, 7(11), 1514-1529. https://doi.org/10.1038/s41551-023-01053-x

@article{14e198a0efb647afb5b5d4445b074490,

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

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{\textquoteright} 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{\textquoteright} 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{\textquoteright} 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.",

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

note = "Funding Information: This work was supported by the National Science Foundation (NSF) Emerging Frontiers in Research and Innovation (EFRI) (no. 1830968 to G.A.A.), the National Cancer Institute (NCI) (no. R00CA188293, no. R01CA248770 and no.U54CA193419 to P.N.), National Institutes of Health (NIH) grants U54CA268084 and R01CA228272, NSF grant EFMA-1830961 (to V.B.) and philanthropic support from K. Hudson and R. Goldman, S. Brice and J. Esteve, M. E. Holliday and I. Schneider, the Christina Carinato Charitable Foundation, and D. Sachs. This work was performed as a collaboration between the Center for Advanced Regenerative Engineering (CARE) and the Center for Physical Genomics and Engineering (CPGE) at Northwestern University. This work made use of the EPIC facility, the NUFAB facility, and the BioCryo facility of Northwestern University{\textquoteright}s NUANCE Center, which has received support from the SHyNE Resource (NSF ECCS-2025633), the International Institute for Nanotechnology (IIN) and Northwestern{\textquoteright}s MRSEC programme (NSF DMR-1720139). This work also made use of the Northwestern University NUSeq Core and the Biological Imaging Facility (BIF). We also thank S. Blythe (Molecular Biosciences, Northwestern University) for his guidance in ATAC-seq data analysis. Publisher Copyright: {\textcopyright} 2023, The Author(s), under exclusive licence to Springer Nature Limited.",

year = "2023",

month = nov,

doi = "10.1038/s41551-023-01053-x",

language = "English (US)",

volume = "7",

pages = "1514--1529",

journal = "Nature Biomedical Engineering",

issn = "2157-846X",

publisher = "Nature Research",

number = "11",

}

Wang, X, Agrawal, V, Dunton, CL, Liu, Y, Virk, RKA, Patel, PA, Carter, L, Pujadas, EM, Li, Y, Jain, S, Wang, H, Ni, N, Tsai, HM, Rivera-Bolanos, N, Frederick, J, Roth, E, Bleher, R, Duan, C, Ntziachristos, P, He, TC, Reid, RR, Jiang, B, Subramanian, H, Backman, V & Ameer, GA 2023, 'Chromatin reprogramming and bone regeneration in vitro and in vivo via the microtopography-induced constriction of cell nuclei', Nature Biomedical Engineering, vol. 7, no. 11, pp. 1514-1529. https://doi.org/10.1038/s41551-023-01053-x

TY - JOUR

T1 - Chromatin reprogramming and bone regeneration in vitro and in vivo via the microtopography-induced constriction of cell nuclei

AU - Wang, Xinlong

AU - Agrawal, Vasundhara

AU - Dunton, Cody L.

AU - Liu, Yugang

AU - Virk, Ranya K.A.

AU - Patel, Priyam A.

AU - Carter, Lucas

AU - Pujadas, Emily M.

AU - Li, Yue

AU - Jain, Surbhi

AU - Wang, Hao

AU - Ni, Na

AU - Tsai, Hsiu Ming

AU - Rivera-Bolanos, Nancy

AU - Frederick, Jane

AU - Roth, Eric

AU - Bleher, Reiner

AU - Duan, Chongwen

AU - Ntziachristos, Panagiotis

AU - He, Tong Chuan

AU - Reid, Russell R.

AU - Jiang, Bin

AU - Subramanian, Hariharan

AU - Backman, Vadim

AU - Ameer, Guillermo A.

N1 - Funding Information: This work was supported by the National Science Foundation (NSF) Emerging Frontiers in Research and Innovation (EFRI) (no. 1830968 to G.A.A.), the National Cancer Institute (NCI) (no. R00CA188293, no. R01CA248770 and no.U54CA193419 to P.N.), National Institutes of Health (NIH) grants U54CA268084 and R01CA228272, NSF grant EFMA-1830961 (to V.B.) and philanthropic support from K. Hudson and R. Goldman, S. Brice and J. Esteve, M. E. Holliday and I. Schneider, the Christina Carinato Charitable Foundation, and D. Sachs. This work was performed as a collaboration between the Center for Advanced Regenerative Engineering (CARE) and the Center for Physical Genomics and Engineering (CPGE) at Northwestern University. This work made use of the EPIC facility, the NUFAB facility, and the BioCryo facility of Northwestern University’s NUANCE Center, which has received support from the SHyNE Resource (NSF ECCS-2025633), the International Institute for Nanotechnology (IIN) and Northwestern’s MRSEC programme (NSF DMR-1720139). This work also made use of the Northwestern University NUSeq Core and the Biological Imaging Facility (BIF). We also thank S. Blythe (Molecular Biosciences, Northwestern University) for his guidance in ATAC-seq data analysis. Publisher Copyright: © 2023, The Author(s), under exclusive licence to Springer Nature Limited.

PY - 2023/11

Y1 - 2023/11

N2 - 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.

AB - 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.

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U2 - 10.1038/s41551-023-01053-x

DO - 10.1038/s41551-023-01053-x

M3 - Article

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AN - SCOPUS:85161690705

SN - 2157-846X

VL - 7

SP - 1514

EP - 1529

JO - Nature Biomedical Engineering

JF - Nature Biomedical Engineering

IS - 11

ER -

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

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