Mechanical memory stored through epigenetic remodeling reduces cell therapeutic potential

Scott, Adrienne K.; Casas, Eduard; Schneider, Stephanie; Swearingen, Alison R.; Elzen, Courtney L. Van Den; Seelbinder, Benjamin; Barthold, Jeanne E.; Kugel, Jennifer F.; Stern, Josh Lewis; Foster, Kyla; Emery, Nancy C.; Brumbaugh, Justin; Neu, Corey P.

doi:10.1016/j.bpj.2023.03.004

Cited by 16 publications

(12 citation statements)

References 72 publications

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“…Previous studies demonstrated that proper mechanical dosing induced mechanical memory to regulate MSC fate 5,7,37 . Our study revealed that repetitive stretch stimulation promoted proliferation and SMC differentiation in MSCs.…”

Section: Discussionsupporting

confidence: 59%

“…Mechanical memory has been observed in various mechanical environments and cell lines, 5,8,37,38 yet the understanding of the key mechanisms that explain this biological phenomenon is limited. Our work demonstrates that MSCs exhibited mechanical memory in response to intermittent stretch, as evidenced by cell reorientation, alignment of F-actin, nuclear deformation, transcriptional activity, condensed chromatin, and active metabolism.…”

Section: Discussionmentioning

confidence: 99%

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Mechanical memory based on chromatin and metabolism remodeling promotes proliferation and smooth muscle differentiation in mesenchymal stem cells

Na,

Shi,

Yang

et al. 2024

The FASEB Journal

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Stem cells respond and remember mechanical cues from the microenvironment, which modulates their therapeutic effects. Chromatin organization and energy metabolism regulate the stem cell fate induced by mechanical cues. However, the mechanism of mechanical memory is still unclear. This study aimed to investigate the effects of mechanical amplitude, frequency, duration, and stretch cycle on mechanical memory in mesenchymal stem cells. It showed that the amplitude was the dominant parameter to the persistence of cell alignment. F‐actin, paxillin, and nuclear deformation are more prone to be remolded than cell alignment. Stretching induces transcriptional memory, resulting in greater transcription upon subsequent reloading. Cell metabolism displays mechanical memory with sustained mitochondrial fusion and increased ATP production. The mechanical memory of chromatin condensation is mediated by histone H3 lysine 27 trimethylation, leading to much higher smooth muscle differentiation efficiency. Interestingly, mechanical memory can be transmitted based on direct cell–cell interaction, and stretched cells can remodel the metabolic homeostasis of static cells. Our results provide insight into the underlying mechanism of mechanical memory and its potential benefits for stem cell therapy.

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Section: Discussionsupporting

confidence: 59%

Section: Discussionmentioning

confidence: 99%

Mechanical memory based on chromatin and metabolism remodeling promotes proliferation and smooth muscle differentiation in mesenchymal stem cells

Na,

Shi,

Yang

et al. 2024

The FASEB Journal

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“…4,23 In chondrocytes, it has been demonstrated that monolayer expansion results in altered chromatin structure that prevents redifferentiation. 41 The ability to redifferentiate chondrocytes has been shown to be influenced by methylation of histone, H3K9. It was determined that increasing the H3K9me3 level reorganizes chromatin in passaged cells, leading to native chromatin conformations that allow for redifferentiation.…”

Section: Discussionmentioning

confidence: 99%

Passaged Articular Chondrocytes From the Superficial Zone and Deep Zone Can Regain Zone-Specific Properties After Redifferentiation

Davis,

Manzoni,

Bianchi

et al. 2024

Am J Sports Med

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Background: Bioengineered cartilage is a developing therapeutic to repair cartilage defects. The matrix must be rich in collagen type II and aggrecan and mechanically competent, withstanding compressive and shearing loads. Biomechanical properties in native articular cartilage depend on the zonal architecture consisting of 3 zones: superficial, middle, and deep. The superficial zone chondrocytes produce lubricating proteoglycan-4, whereas the deep zone chondrocytes produce collagen type X, which allows for integration into the subchondral bone. Zonal and chondrogenic expression is lost after cell number expansion. Current cell-based therapies have limited capacity to regenerate the zonal structure of native cartilage. Hypothesis: Both passaged superficial and deep zone chondrocytes at high density can form bioengineered cartilage that is rich in collagen type II and aggrecan; however, only passaged superficial zone–derived chondrocytes will express superficial zone–specific proteoglycan-4, and only passaged deep zone–derived chondrocytes will express deep zone–specific collagen type X. Study Design: Controlled laboratory study. Methods: Superficial and deep zone chondrocytes were isolated from bovine joints, and zonal subpopulations were separately expanded in 2-dimensional culture. At passage 2, superficial and deep zone chondrocytes were seeded, separately, in scaffold-free 3-dimensional culture within agarose wells and cultured in redifferentiation media. Results: Monolayer expansion resulted in loss of expression for proteoglycan-4 and collagen type X in passaged superficial and deep zone chondrocytes, respectively. By passage 2, superficial and deep zone chondrocytes had similar expression for dedifferentiated molecules collagen type I and tenascin C. Redifferentiation of both superficial and deep zone chondrocytes led to the expression of collagen type II and aggrecan in both passaged chondrocyte populations. However, only redifferentiated deep zone chondrocytes expressed collagen type X, and only redifferentiated superficial zone chondrocytes expressed and secreted proteoglycan-4. Additionally, redifferentiated deep zone chondrocytes produced a thicker and more robust tissue compared with superficial zone chondrocytes. Conclusion: The recapitulation of the primary phenotype from passaged zonal chondrocytes introduces a novel method of functional bioengineering of cartilage that resembles the zone-specific biological properties of native cartilage. Clinical Relevance: The recapitulation of the primary phenotype in zonal chondrocytes could be a possible method to tailor bioengineered cartilage to have zone-specific expression.

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“…100,123 In noninvasive cancer cells, mechanical priming on stiff substrates increased the migration speed and invasion potential in a similar way in 2D and 3D matrices. 71 However, in chondrocytes, 3D culture was found to better maintain differentiated phenotype compared to 2D TCPS, 89 the combined effect of low stiffness and 3D environment helping to limit any mechanical memory effect. To further confirm the occurrence of mechanical memory in 3D, more experiments are required in which mechanical stress or substrate stiffness are modulated after cell or organoid encapsulation.…”

Section: Discussionmentioning

confidence: 99%

Implications of Cellular Mechanical Memory in Bioengineering

Dudaryeva,

Bernhard,

Tibbitt

et al. 2023

ACS Biomater. Sci. Eng.

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The ability to maintain and differentiate cells in vitro is critical to many advances in the field of bioengineering. However, on traditional, stiff (E ≈ GPa) culture substrates, cells are subjected to sustained mechanical stress that can lead to phenotypic changes. Such changes may remain even after transferring the cells to another scaffold or engrafting them in vivo and bias the outcomes of the biological investigation or clinical treatment. This persistenceor mechanical memorywas initially observed for sustained myofibroblast activation of pulmonary fibroblasts after culturing them on stiff (E ≈ 100 kPa) substrates. Aspects of mechanical memory have now been described in many in vitro contexts. In this Review, we discuss the stiffness-induced effectors of mechanical memory: structural changes in the cytoskeleton and activity of transcription factors and epigenetic modifiers. We then focus on how mechanical memory impacts cell expansion and tissue regeneration outcomes in bioengineering applications relying on prolonged 2D plastic culture, such as stem cell therapies and disease models. We propose that alternatives to traditional cell culture substrates can be used to mitigate or erase mechanical memory and improve the efficiency of downstream cell-based bioengineering applications.

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Mechanical memory stored through epigenetic remodeling reduces cell therapeutic potential

Cited by 16 publications

References 72 publications

Mechanical memory based on chromatin and metabolism remodeling promotes proliferation and smooth muscle differentiation in mesenchymal stem cells

Mechanical memory based on chromatin and metabolism remodeling promotes proliferation and smooth muscle differentiation in mesenchymal stem cells

Passaged Articular Chondrocytes From the Superficial Zone and Deep Zone Can Regain Zone-Specific Properties After Redifferentiation

Implications of Cellular Mechanical Memory in Bioengineering

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