Hypoxia impacts human MSC response to substrate stiffness during chondrogenic differentiation

Foyt, Daniel; Taheem, Dheraj K.; Ferreira, Sandra Reis; Norman, Michael D. A.; Petzold, Jonna; Jell, Gavin; Grigoriadis, Agamemnon E.; Gentleman, Eileen

doi:10.1016/j.actbio.2019.03.002

Cited by 49 publications

(56 citation statements)

References 55 publications

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“…It has been reported that exposing MSCs to hypoxia (2% O 2 ) induces condensation‐like effects and another study demonstrated the favorable effect of transient hypoxia where the initial hypoxia‐activated cell proliferation and normoxia enhanced matrix synthesis . And the phenomenon of cell‐cell clustering is contributed by the mechanical traction forces generated in the cytoskeletal arrangement that in turn leads to the cross talk of other mechanical elements resulting in changes in cell shape and polarity finally governing the cell fate . The condensation of mesenchymal cells is often mediated through the interactions of cell adhesion molecules including N‐CAM and N‐cadherin Condensation leads to the activation of multiple transcription factors and is thought to promote a cell shape suitable for initiating chondrocyte differentiation by cytoskeletal rearrangement …”

Section: Discussionmentioning

confidence: 99%

“…This portrays the complexity of the mechanotransduction process in cells, which involves not only activation of mechanosensitive membrane receptors but also the cascade of intracellular signaling events which are subsequently activated. It has been reported that human umbilical cord matrix stem cells can undergo chondrogenic differentiation in presence of specific chondrogenic growth factors . Nair et al have demonstrated that dynamic biomechanical stimuli induces expression of chondrogenic genes even in the absence of soluble biochemical cues/growth factors and enhances growth factor‐induced chondrogenesis of umbilical cord MSCs under three‐dimensional culture conditions .…”

Section: Introductionmentioning

confidence: 99%

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Matrix remodeling and mechanotransduction in in vitro chondrogenesis: Implications towards functional stem cell‐based cartilage tissue engineering

Remya

Nair

2020

Engineering Reports

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Stem cell-based cartilage regeneration strategies take benefits from functional tissue engineering concepts that effectively exploit cells native mechanotransduction phenomenon for the development of in vitro cartilage constructs. In the present study, stem cell-seeded constructs were subjected to a dynamic compression of 10% strain, 1 Hz, 4 hours/1 hour each for 7 days. Integrin and Integrin-associated protein expression was evaluated using real-time PCR to elucidate the possible mechanotransduction pathway. Matrix remodeling was analyzed by evaluating chondrocyte-specific extracellular matrix genes as well as by expression of matrix metalloproteinases. The results suggest that dynamic compression significantly influences chondrogenesis by enhancing the expression of chondrocyte-specific extracellular matrix genes. The results also propose the involvement of Integrin-mediated signaling pathways in the mechanotransduction events on biomechanical stimuli-assisted chondrogenesis of stem cells.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Matrix remodeling and mechanotransduction in in vitro chondrogenesis: Implications towards functional stem cell‐based cartilage tissue engineering

Remya

Nair

2020

Engineering Reports

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“…28 Hypoxia has also been shown to increase cartilage-like ECM production in MSCs. 29 Indeed, delivery of a HIF-1a expression vector enhances the expression of genes for both collagen type II and the proteoglycan aggrecan, as well as a panel of chondrogenic transcription factors. 26 Moreover, stabilization of HIF-1a promotes the formation of cartilage-specific ECM by both upregulating the expression of SOX9 and through post-translational modifications to collagen type II.…”

Section: The Role Of Hif-1a In Differentiation Of Oc Progenitor Cellsmentioning

confidence: 99%

Hypoxia Inducible Factor-1α in Osteochondral Tissue Engineering

Taheem

Jell

Gentleman

2020

Tissue Engineering Part B: Reviews

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Damage to osteochondral (OC) tissues can lead to pain, loss of motility, and progress to osteoarthritis. Tissue engineering approaches offer the possibility of replacing damaged tissues and restoring joint function; however, replicating the spatial and functional heterogeneity of native OC tissue remains a pressing challenge. Chondrocytes in healthy cartilage exist in relatively low-oxygen conditions, while osteoblasts in the underlying bone experience higher oxygen pressures. Such oxygen gradients also exist in the limb bud, where they influence OC tissue development. The cellular response to these spatial variations in oxygen pressure, which is mediated by the hypoxia inducible factor (HIF) pathway, plays a central role in regulating osteo-and chondrogenesis by directing progenitor cell differentiation and promoting and maintaining appropriate extracellular matrix production. Understanding the role of the HIF pathway in OC tissue development may enable new approaches to engineer OC tissue. In this review, we discuss strategies to spatially and temporarily regulate the HIF pathway in progenitor cells to create functional OC tissue for regenerative therapies.

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“…In physiological conditions, MSC reside in hypoxic niches and are exposed to oxygen level ranging from 2% to 7% 7 . Thus, many studies have investigated the role of hypoxia on MSC functions focusing mainly on their proliferation and differentiation potential 8 . Hypoxic culture conditions enhance the survival and proliferation rate of MSC and stabilize their karyotype.…”

Section: Introductionmentioning

confidence: 99%

HIF1α‐dependent metabolic reprogramming governs mesenchymal stem/stromal cell immunoregulatory functions

et al. 2020

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Hypoxia‐inducible factor 1 α (HIF1α), a regulator of metabolic change, is required for the survival and differentiation potential of mesenchymal stem/stromal cells (MSC). Its role in MSC immunoregulatory activity, however, has not been completely elucidated. In the present study, we evaluate the role of HIF1α on MSC immunosuppressive potential. We show that HIF1α silencing in MSC decreases their inhibitory potential on Th1 and Th17 cell generation and limits their capacity to generate regulatory T cells. This reduced immunosuppressive potential of MSC is associated with a metabolic switch from glycolysis to OXPHOS and a reduced capacity to express or produce some immunosuppressive mediators including Intercellular Adhesion Molecule (ICAM), IL‐6, and nitric oxide (NO). Moreover, using the Delayed‐Type Hypersensitivity murine model (DTH), we confirm, in vivo, the critical role of HIF1α on MSC immunosuppressive effect. Indeed, we show that HIF1α silencing impairs MSC capacity to reduce inflammation and inhibit the generation of pro‐inflammatory T cells. This study reveals the pivotal role of HIF1α on MSC immunosuppressive activity through the regulation of their metabolic status and identifies HIF1α as a novel mediator of MSC immunotherapeutic potential.

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Hypoxia impacts human MSC response to substrate stiffness during chondrogenic differentiation

Abstract: Graphical abstract

Cited by 49 publications

References 55 publications

Matrix remodeling and mechanotransduction in in vitro chondrogenesis: Implications towards functional stem cell‐based cartilage tissue engineering

Matrix remodeling and mechanotransduction in in vitro chondrogenesis: Implications towards functional stem cell‐based cartilage tissue engineering

Hypoxia Inducible Factor-1α in Osteochondral Tissue Engineering

HIF1α‐dependent metabolic reprogramming governs mesenchymal stem/stromal cell immunoregulatory functions

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