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Substrate stiffness and oxygen as regulators of stem cell differentiation during skeletal tissue regeneration: a mechanobiological model.

Burke DP, Kelly DJ - PLoS ONE (2012)

Bottom Line: Rather than assuming mechanical signals act directly on stem cells to determine their differentiation pathway, it is postulated that they act indirectly to regulate angiogenesis and hence partially determine the local oxygen environment within a regenerating tissue.Chondrogenesis of MSCs was hypothesized to occur in low oxygen regions, while in well vascularised regions of the regenerating tissue a soft local substrate was hypothesised to facilitate adipogenesis while a stiff substrate facilitated osteogenesis.Predictions from the model were compared to both experimental data and to predictions of a well established computational mechanobiological model where tissue differentiation is assumed to be regulated directly by the local mechanical environment.

View Article: PubMed Central - PubMed

Affiliation: Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.

ABSTRACT
Extrinsic mechanical signals have been implicated as key regulators of mesenchymal stem cell (MSC) differentiation. It has been possible to test different hypotheses for mechano-regulated MSC differentiation by attempting to simulate regenerative events such as bone fracture repair, where repeatable spatial and temporal patterns of tissue differentiation occur. More recently, in vitro studies have identified other environmental cues such as substrate stiffness and oxygen tension as key regulators of MSC differentiation; however it remains unclear if and how such cues determine stem cell fate in vivo. As part of this study, a computational model was developed to test the hypothesis that substrate stiffness and oxygen tension regulate stem cell differentiation during fracture healing. Rather than assuming mechanical signals act directly on stem cells to determine their differentiation pathway, it is postulated that they act indirectly to regulate angiogenesis and hence partially determine the local oxygen environment within a regenerating tissue. Chondrogenesis of MSCs was hypothesized to occur in low oxygen regions, while in well vascularised regions of the regenerating tissue a soft local substrate was hypothesised to facilitate adipogenesis while a stiff substrate facilitated osteogenesis. Predictions from the model were compared to both experimental data and to predictions of a well established computational mechanobiological model where tissue differentiation is assumed to be regulated directly by the local mechanical environment. The model predicted all the major events of fracture repair, including cartilaginous bridging, endosteal and periosteal bony bridging and bone remodelling. It therefore provides support for the hypothesis that substrate stiffness and oxygen play a key role in regulating MSC fate during regenerative events such as fracture healing.

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Effect on healing Time of parameter variations.(a): Healing time versus angiogenic strain threshold, γangio (X signifies the prediction of non-union) (b): Healing time versus tissue formation rate, TFR. (c): Healing time versus angiogenic diffusion coefficient, H.
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pone-0040737-g007: Effect on healing Time of parameter variations.(a): Healing time versus angiogenic strain threshold, γangio (X signifies the prediction of non-union) (b): Healing time versus tissue formation rate, TFR. (c): Healing time versus angiogenic diffusion coefficient, H.

Mentions: A sensitivity analysis was performed to investigate the effect of modifying the angiogenic diffusion coefficient, H, the angiogenic strain threshold, γangio, and the tissue formation rate (TFR) (see Fig. 7). Models with the angiogenic threshold value increased to 8% deviatoric strain predicted slightly less cartilage and more bone formation in the early stages of healing in comparison to the baseline simulation. Models with the threshold value reduced to 4% deviatoric strain displayed slightly more cartilage and less bone formation in the early stages of healing in comparison to the baseline simulation. Healing, which we define as when the fracture gap is full of bone, occurred earlier for an increased angiogenic inhibition threshold (8%) and occurred later for a decreased angiogenic inhibition threshold (4%) (3 days earlier and 6 days later respectively, see Fig. 7c). Decreasing the threshold for angiogenic inhibition to 2% deviatoric strain resulted in a prediction of non-union (see Fig. 7a). Halving the angiogenic diffusion coefficient (0.25) resulted in slower healing (9 days later). Doubling the angiogenic diffusion coefficient (1.0) was predicted to only decrease the healing time by 1 day over the baseline simulation. Further increases in this coefficient appear to cause simulations to converge upon a minimum healing time and has no additional effect. In this case, the bone formation rate becomes the limiting factor. Increasing the bone formation rate, while the angiogenic diffusion coefficient remains constant, had a similar convergence upon a minimum healing time (see Fig. 7b).


Substrate stiffness and oxygen as regulators of stem cell differentiation during skeletal tissue regeneration: a mechanobiological model.

Burke DP, Kelly DJ - PLoS ONE (2012)

Effect on healing Time of parameter variations.(a): Healing time versus angiogenic strain threshold, γangio (X signifies the prediction of non-union) (b): Healing time versus tissue formation rate, TFR. (c): Healing time versus angiogenic diffusion coefficient, H.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3404068&req=5

pone-0040737-g007: Effect on healing Time of parameter variations.(a): Healing time versus angiogenic strain threshold, γangio (X signifies the prediction of non-union) (b): Healing time versus tissue formation rate, TFR. (c): Healing time versus angiogenic diffusion coefficient, H.
Mentions: A sensitivity analysis was performed to investigate the effect of modifying the angiogenic diffusion coefficient, H, the angiogenic strain threshold, γangio, and the tissue formation rate (TFR) (see Fig. 7). Models with the angiogenic threshold value increased to 8% deviatoric strain predicted slightly less cartilage and more bone formation in the early stages of healing in comparison to the baseline simulation. Models with the threshold value reduced to 4% deviatoric strain displayed slightly more cartilage and less bone formation in the early stages of healing in comparison to the baseline simulation. Healing, which we define as when the fracture gap is full of bone, occurred earlier for an increased angiogenic inhibition threshold (8%) and occurred later for a decreased angiogenic inhibition threshold (4%) (3 days earlier and 6 days later respectively, see Fig. 7c). Decreasing the threshold for angiogenic inhibition to 2% deviatoric strain resulted in a prediction of non-union (see Fig. 7a). Halving the angiogenic diffusion coefficient (0.25) resulted in slower healing (9 days later). Doubling the angiogenic diffusion coefficient (1.0) was predicted to only decrease the healing time by 1 day over the baseline simulation. Further increases in this coefficient appear to cause simulations to converge upon a minimum healing time and has no additional effect. In this case, the bone formation rate becomes the limiting factor. Increasing the bone formation rate, while the angiogenic diffusion coefficient remains constant, had a similar convergence upon a minimum healing time (see Fig. 7b).

Bottom Line: Rather than assuming mechanical signals act directly on stem cells to determine their differentiation pathway, it is postulated that they act indirectly to regulate angiogenesis and hence partially determine the local oxygen environment within a regenerating tissue.Chondrogenesis of MSCs was hypothesized to occur in low oxygen regions, while in well vascularised regions of the regenerating tissue a soft local substrate was hypothesised to facilitate adipogenesis while a stiff substrate facilitated osteogenesis.Predictions from the model were compared to both experimental data and to predictions of a well established computational mechanobiological model where tissue differentiation is assumed to be regulated directly by the local mechanical environment.

View Article: PubMed Central - PubMed

Affiliation: Trinity Centre for Bioengineering, Trinity Biomedical Sciences Institute, Trinity College Dublin, Dublin, Ireland.

ABSTRACT
Extrinsic mechanical signals have been implicated as key regulators of mesenchymal stem cell (MSC) differentiation. It has been possible to test different hypotheses for mechano-regulated MSC differentiation by attempting to simulate regenerative events such as bone fracture repair, where repeatable spatial and temporal patterns of tissue differentiation occur. More recently, in vitro studies have identified other environmental cues such as substrate stiffness and oxygen tension as key regulators of MSC differentiation; however it remains unclear if and how such cues determine stem cell fate in vivo. As part of this study, a computational model was developed to test the hypothesis that substrate stiffness and oxygen tension regulate stem cell differentiation during fracture healing. Rather than assuming mechanical signals act directly on stem cells to determine their differentiation pathway, it is postulated that they act indirectly to regulate angiogenesis and hence partially determine the local oxygen environment within a regenerating tissue. Chondrogenesis of MSCs was hypothesized to occur in low oxygen regions, while in well vascularised regions of the regenerating tissue a soft local substrate was hypothesised to facilitate adipogenesis while a stiff substrate facilitated osteogenesis. Predictions from the model were compared to both experimental data and to predictions of a well established computational mechanobiological model where tissue differentiation is assumed to be regulated directly by the local mechanical environment. The model predicted all the major events of fracture repair, including cartilaginous bridging, endosteal and periosteal bony bridging and bone remodelling. It therefore provides support for the hypothesis that substrate stiffness and oxygen play a key role in regulating MSC fate during regenerative events such as fracture healing.

Show MeSH
Related in: MedlinePlus