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Allometric Scaling and Cell Ratios in Multi-Organ in vitro Models of Human Metabolism.

Ucciferri N, Sbrana T, Ahluwalia A - Front Bioeng Biotechnol (2014)

Bottom Line: The theoretical scaling studies illustrate that the design and hence relevance of multi-organ models is principally determined by experimental constraints.Two experimentally feasible model configurations are then implemented in a multi-compartment organ-on-a-plate device.An analysis of the metabolic response of the two configurations demonstrates that their glucose and lipid balance is quite different, with only one of the two models recapitulating physiological-like homeostasis.

View Article: PubMed Central - PubMed

Affiliation: CNR Institute of Clinical Physiology , Pisa , Italy ; Interdepartmental Research Center "E. Piaggio", University of Pisa , Pisa , Italy.

ABSTRACT
Intelligent in vitro models able to recapitulate the physiological interactions between tissues in the body have enormous potential as they enable detailed studies on specific two-way or higher order tissue communication. These models are the first step toward building an integrated picture of systemic metabolism and signaling in physiological or pathological conditions. However, the rational design of in vitro models of cell-cell or cell-tissue interaction is difficult as quite often cell culture experiments are driven by the device used, rather than by design considerations. Indeed, very little research has been carried out on in vitro models of metabolism connecting different cell or tissue types in a physiologically and metabolically relevant manner. Here, we analyze the physiological relationship between cells, cell metabolism, and exchange in the human body using allometric rules, downscaling them to an organ-on-a-plate device. In particular, in order to establish appropriate cell ratios in the system in a rational manner, two different allometric scaling models (cell number scaling model and metabolic and surface scaling model) are proposed and applied to a two compartment model of hepatic-vascular metabolic cross-talk. The theoretical scaling studies illustrate that the design and hence relevance of multi-organ models is principally determined by experimental constraints. Two experimentally feasible model configurations are then implemented in a multi-compartment organ-on-a-plate device. An analysis of the metabolic response of the two configurations demonstrates that their glucose and lipid balance is quite different, with only one of the two models recapitulating physiological-like homeostasis. In conclusion, not only do cross-talk and physical stimuli play an important role in in vitro models, but the numeric relationship between cells is also crucial to recreate in vitro interactions, which can be extrapolated to the in vivo reality.

No MeSH data available.


Related in: MedlinePlus

(A) Glucose uptake and (B) Lactate release in the two allometric model configurations. Static samples were the same type and number of cells cultivated in a petridish. Mean ± SD, *p < 0.05, **p < 0.01, n = 3.
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Figure 4: (A) Glucose uptake and (B) Lactate release in the two allometric model configurations. Static samples were the same type and number of cells cultivated in a petridish. Mean ± SD, *p < 0.05, **p < 0.01, n = 3.

Mentions: Carbohydrates are the primary source of energy and metabolic intermediates. Glucose is the main carbohydrate used by the cell in both aerobic and anaerobic respiration. Hepatocytes are able to store or release glucose through glycogen synthesis or glycolysis pathways. Glucose dosing in the media showed a higher uptake in the MSSM configuration. In both static and dynamic conditions, the higher consumption of glucose can be attributed to the higher number of cells with respect to the CNSM model (approximately threefold more). Significant (p < 0.01) differences were observed between the two models in static conditions (Figure 4A). Lactate levels are a function of both glycolysis and gluconeogenesis in hepatocytes (Phillips et al., 1995), and are known to be down regulated by circulating (in vivo) or media FFAs (in vitro) (Morand et al., 1993). A significant (p < 0.05) decrease of lactate release in dynamic conditions was observed. No difference was found between the two models even when relating lactate release with glucose uptake: similar concentrations of lactate were found in both configurations despite the lower uptake of glucose in the CNSM (Figure 4B).


Allometric Scaling and Cell Ratios in Multi-Organ in vitro Models of Human Metabolism.

Ucciferri N, Sbrana T, Ahluwalia A - Front Bioeng Biotechnol (2014)

(A) Glucose uptake and (B) Lactate release in the two allometric model configurations. Static samples were the same type and number of cells cultivated in a petridish. Mean ± SD, *p < 0.05, **p < 0.01, n = 3.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4269269&req=5

Figure 4: (A) Glucose uptake and (B) Lactate release in the two allometric model configurations. Static samples were the same type and number of cells cultivated in a petridish. Mean ± SD, *p < 0.05, **p < 0.01, n = 3.
Mentions: Carbohydrates are the primary source of energy and metabolic intermediates. Glucose is the main carbohydrate used by the cell in both aerobic and anaerobic respiration. Hepatocytes are able to store or release glucose through glycogen synthesis or glycolysis pathways. Glucose dosing in the media showed a higher uptake in the MSSM configuration. In both static and dynamic conditions, the higher consumption of glucose can be attributed to the higher number of cells with respect to the CNSM model (approximately threefold more). Significant (p < 0.01) differences were observed between the two models in static conditions (Figure 4A). Lactate levels are a function of both glycolysis and gluconeogenesis in hepatocytes (Phillips et al., 1995), and are known to be down regulated by circulating (in vivo) or media FFAs (in vitro) (Morand et al., 1993). A significant (p < 0.05) decrease of lactate release in dynamic conditions was observed. No difference was found between the two models even when relating lactate release with glucose uptake: similar concentrations of lactate were found in both configurations despite the lower uptake of glucose in the CNSM (Figure 4B).

Bottom Line: The theoretical scaling studies illustrate that the design and hence relevance of multi-organ models is principally determined by experimental constraints.Two experimentally feasible model configurations are then implemented in a multi-compartment organ-on-a-plate device.An analysis of the metabolic response of the two configurations demonstrates that their glucose and lipid balance is quite different, with only one of the two models recapitulating physiological-like homeostasis.

View Article: PubMed Central - PubMed

Affiliation: CNR Institute of Clinical Physiology , Pisa , Italy ; Interdepartmental Research Center "E. Piaggio", University of Pisa , Pisa , Italy.

ABSTRACT
Intelligent in vitro models able to recapitulate the physiological interactions between tissues in the body have enormous potential as they enable detailed studies on specific two-way or higher order tissue communication. These models are the first step toward building an integrated picture of systemic metabolism and signaling in physiological or pathological conditions. However, the rational design of in vitro models of cell-cell or cell-tissue interaction is difficult as quite often cell culture experiments are driven by the device used, rather than by design considerations. Indeed, very little research has been carried out on in vitro models of metabolism connecting different cell or tissue types in a physiologically and metabolically relevant manner. Here, we analyze the physiological relationship between cells, cell metabolism, and exchange in the human body using allometric rules, downscaling them to an organ-on-a-plate device. In particular, in order to establish appropriate cell ratios in the system in a rational manner, two different allometric scaling models (cell number scaling model and metabolic and surface scaling model) are proposed and applied to a two compartment model of hepatic-vascular metabolic cross-talk. The theoretical scaling studies illustrate that the design and hence relevance of multi-organ models is principally determined by experimental constraints. Two experimentally feasible model configurations are then implemented in a multi-compartment organ-on-a-plate device. An analysis of the metabolic response of the two configurations demonstrates that their glucose and lipid balance is quite different, with only one of the two models recapitulating physiological-like homeostasis. In conclusion, not only do cross-talk and physical stimuli play an important role in in vitro models, but the numeric relationship between cells is also crucial to recreate in vitro interactions, which can be extrapolated to the in vivo reality.

No MeSH data available.


Related in: MedlinePlus