Mechanical memory stored through epigenetic remodeling reduces cell therapeutic potential.
Journal
Biophysical journal
ISSN: 1542-0086
Titre abrégé: Biophys J
Pays: United States
ID NLM: 0370626
Informations de publication
Date de publication:
18 04 2023
18 04 2023
Historique:
received:
20
09
2022
revised:
31
01
2023
accepted:
01
03
2023
pmc-release:
18
04
2024
medline:
21
4
2023
pubmed:
6
3
2023
entrez:
5
3
2023
Statut:
ppublish
Résumé
Understanding how cells remember previous mechanical environments to influence their fate, or mechanical memory, informs the design of biomaterials and therapies in medicine. Current regeneration therapies, such as cartilage regeneration procedures, require 2D cell expansion processes to achieve large cell populations critical for the repair of damaged tissues. However, the limit of mechanical priming for cartilage regeneration procedures before inducing long-term mechanical memory following expansion processes is unknown, and mechanisms defining how physical environments influence the therapeutic potential of cells remain poorly understood. Here, we identify a threshold to mechanical priming separating reversible and irreversible effects of mechanical memory. After 16 population doublings in 2D culture, expression levels of tissue-identifying genes in primary cartilage cells (chondrocytes) are not recovered when transferred to 3D hydrogels, while expression levels of these genes were recovered for cells only expanded for eight population doublings. Additionally, we show that the loss and recovery of the chondrocyte phenotype correlates with a change in chromatin architecture, as shown by structural remodeling of the trimethylation of H3K9. Efforts to disrupt the chromatin architecture by suppressing or increasing levels of H3K9me3 reveal that only with increased levels of H3K9me3 did the chromatin architecture of the native chondrocyte phenotype partially return, along with increased levels of chondrogenic gene expression. These results further support the connection between the chondrocyte phenotype and chromatin architecture, and also reveal the therapeutic potential of inhibitors of epigenetic modifiers as disruptors of mechanical memory when large numbers of phenotypically suitable cells are required for regeneration procedures.
Identifiants
pubmed: 36871159
pii: S0006-3495(23)00157-1
doi: 10.1016/j.bpj.2023.03.004
pmc: PMC10147835
pii:
doi:
Substances chimiques
Chromatin
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
1428-1444Subventions
Organisme : NIAMS NIH HHS
ID : R01 AR063712
Pays : United States
Organisme : NIGMS NIH HHS
ID : R35 GM142884
Pays : United States
Organisme : NIGMS NIH HHS
ID : T32 GM065103
Pays : United States
Informations de copyright
Copyright © 2023 Biophysical Society. Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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