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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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Iterative procedure for tissue differentiation hypothesis testing.
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pone-0040737-g003: Iterative procedure for tissue differentiation hypothesis testing.

Mentions: Tissue differentiation within the fracture callus was simulated via an iterative procedure similar to that described previously in the literature [7], [56] (Fig. 3). Within each iteration, a prediction of mechanical stimuli, cell density, substrate stiffness, blood supply and oxygen tension is made in order to enable the local phenotype to be determined based on the tissue differentiation algorithm. Firstly, a finite element model of a fracture callus is used to predict the spatial patterns of mechanical stimuli within the callus (see Finite Element Model Section). These mechanical stimuli influence angiogenic progression, which is inhibited in regions of high deviatoric strain. The oxygen tension is then dependent upon the initial oxygen environment, local blood supply, cell consumption rate and cell density (see Oxygen Transport Section). Local phenotype predictions are then made according to the tissue differentiation algorithm (Fig. 1). Cell proliferation and migration are modelled as a diffusive process (see Appendix S1) [56]. Tissue material properties are influenced by cell density according to the rule of mixtures as previously described (see Appendix S2) [7], [56], [57]. A temporal smoothing procedure is implemented to account for the delay between stimuli first acting on a cell and change of tissue type (see Appendix S3) [7], [56], [57]. Updated material properties are fed back into the finite element model for the next iteration of the cycle. This iterative process is continued until a solution is converged upon.


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

Burke DP, Kelly DJ - PLoS ONE (2012)

Iterative procedure for tissue differentiation hypothesis testing.
© Copyright Policy
Related In: Results  -  Collection

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

pone-0040737-g003: Iterative procedure for tissue differentiation hypothesis testing.
Mentions: Tissue differentiation within the fracture callus was simulated via an iterative procedure similar to that described previously in the literature [7], [56] (Fig. 3). Within each iteration, a prediction of mechanical stimuli, cell density, substrate stiffness, blood supply and oxygen tension is made in order to enable the local phenotype to be determined based on the tissue differentiation algorithm. Firstly, a finite element model of a fracture callus is used to predict the spatial patterns of mechanical stimuli within the callus (see Finite Element Model Section). These mechanical stimuli influence angiogenic progression, which is inhibited in regions of high deviatoric strain. The oxygen tension is then dependent upon the initial oxygen environment, local blood supply, cell consumption rate and cell density (see Oxygen Transport Section). Local phenotype predictions are then made according to the tissue differentiation algorithm (Fig. 1). Cell proliferation and migration are modelled as a diffusive process (see Appendix S1) [56]. Tissue material properties are influenced by cell density according to the rule of mixtures as previously described (see Appendix S2) [7], [56], [57]. A temporal smoothing procedure is implemented to account for the delay between stimuli first acting on a cell and change of tissue type (see Appendix S3) [7], [56], [57]. Updated material properties are fed back into the finite element model for the next iteration of the cycle. This iterative process is continued until a solution is converged upon.

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