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Agent-based model of therapeutic adipose-derived stromal cell trafficking during ischemia predicts ability to roll on P-selectin.

Bailey AM, Lawrence MB, Shang H, Katz AJ, Peirce SM - PLoS Comput. Biol. (2009)

Bottom Line: In silico, trafficking phenomena within cell populations emerged as a result of the dynamic interactions between adhesion molecule expression, chemokine secretion, integrin affinity states, hemodynamics and microvascular network architectures.In vitro experiments confirmed this prediction; a subpopulation of hASCs slowly rolled on immobilized P-selectin at speeds as low as 2 microm/s.Thus, our work led to a fundamentally new understanding of hASC biology, which may have important therapeutic implications.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.

ABSTRACT
Intravenous delivery of human adipose-derived stromal cells (hASCs) is a promising option for the treatment of ischemia. After delivery, hASCs that reside and persist in the injured extravascular space have been shown to aid recovery of tissue perfusion and function, although low rates of incorporation currently limit the safety and efficacy of these therapies. We submit that a better understanding of the trafficking of therapeutic hASCs through the microcirculation is needed to address this and that selective control over their homing (organ- and injury-specific) may be possible by targeting bottlenecks in the homing process. This process, however, is incredibly complex, which merited the use of computational techniques to speed the rate of discovery. We developed a multicell agent-based model (ABM) of hASC trafficking during acute skeletal muscle ischemia, based on over 150 literature-based rules instituted in Netlogo and MatLab software programs. In silico, trafficking phenomena within cell populations emerged as a result of the dynamic interactions between adhesion molecule expression, chemokine secretion, integrin affinity states, hemodynamics and microvascular network architectures. As verification, the model reasonably reproduced key aspects of ischemia and trafficking behavior including increases in wall shear stress, upregulation of key cellular adhesion molecules expressed on injured endothelium, increased secretion of inflammatory chemokines and cytokines, quantified levels of monocyte extravasation in selectin knockouts, and circulating monocyte rolling distances. Successful ABM verification prompted us to conduct a series of systematic knockouts in silico aimed at identifying the most critical parameters mediating hASC trafficking. Simulations predicted the necessity of an unknown selectin-binding molecule to achieve hASC extravasation, in addition to any rolling behavior mediated by hASC surface expression of CD15s, CD34, CD62e, CD62p, or CD65. In vitro experiments confirmed this prediction; a subpopulation of hASCs slowly rolled on immobilized P-selectin at speeds as low as 2 microm/s. Thus, our work led to a fundamentally new understanding of hASC biology, which may have important therapeutic implications.

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Graphical representation of the adhesion cascade during acute skeletal muscle ischemia, as instituted in the ABM.The adhesion cascade generally proceeds sequentially before incorporation, and is mediated by the interplay between adhesion molecule expression, chemokines and cytokines, hemodynamics, and survey behavior. Interactions are complex spatially and temporally, and cell phenotypes accounted for within simulations are tissue macrophages, endothelial cells making up the blood vessel wall, circulating monocytes, and circulating human adipose-derived stromal cells.
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pcbi-1000294-g001: Graphical representation of the adhesion cascade during acute skeletal muscle ischemia, as instituted in the ABM.The adhesion cascade generally proceeds sequentially before incorporation, and is mediated by the interplay between adhesion molecule expression, chemokines and cytokines, hemodynamics, and survey behavior. Interactions are complex spatially and temporally, and cell phenotypes accounted for within simulations are tissue macrophages, endothelial cells making up the blood vessel wall, circulating monocytes, and circulating human adipose-derived stromal cells.

Mentions: The process by which endogenous circulating cells traffic to sites of general injury and gain access to the extravascular tissue space is referred to as the adhesion cascade [2]. Most often studied in leukocyte subpopulations (e.g., neutrophils and monocytes), it is applicable to the mobilization of circulating stem cells to sites of injury [3]. Depicted in Figure 1, the adhesion cascade consists of a series of sequential events including margination, rolling, integrin activation, firm adhesion, and trans-endothelial migration (extravasation). This complex process is mediated by the interplay between cellular adhesion molecule (CAM) expression, chemokines and cytokines, and hemodynamics [4]–[14].


Agent-based model of therapeutic adipose-derived stromal cell trafficking during ischemia predicts ability to roll on P-selectin.

Bailey AM, Lawrence MB, Shang H, Katz AJ, Peirce SM - PLoS Comput. Biol. (2009)

Graphical representation of the adhesion cascade during acute skeletal muscle ischemia, as instituted in the ABM.The adhesion cascade generally proceeds sequentially before incorporation, and is mediated by the interplay between adhesion molecule expression, chemokines and cytokines, hemodynamics, and survey behavior. Interactions are complex spatially and temporally, and cell phenotypes accounted for within simulations are tissue macrophages, endothelial cells making up the blood vessel wall, circulating monocytes, and circulating human adipose-derived stromal cells.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2636895&req=5

pcbi-1000294-g001: Graphical representation of the adhesion cascade during acute skeletal muscle ischemia, as instituted in the ABM.The adhesion cascade generally proceeds sequentially before incorporation, and is mediated by the interplay between adhesion molecule expression, chemokines and cytokines, hemodynamics, and survey behavior. Interactions are complex spatially and temporally, and cell phenotypes accounted for within simulations are tissue macrophages, endothelial cells making up the blood vessel wall, circulating monocytes, and circulating human adipose-derived stromal cells.
Mentions: The process by which endogenous circulating cells traffic to sites of general injury and gain access to the extravascular tissue space is referred to as the adhesion cascade [2]. Most often studied in leukocyte subpopulations (e.g., neutrophils and monocytes), it is applicable to the mobilization of circulating stem cells to sites of injury [3]. Depicted in Figure 1, the adhesion cascade consists of a series of sequential events including margination, rolling, integrin activation, firm adhesion, and trans-endothelial migration (extravasation). This complex process is mediated by the interplay between cellular adhesion molecule (CAM) expression, chemokines and cytokines, and hemodynamics [4]–[14].

Bottom Line: In silico, trafficking phenomena within cell populations emerged as a result of the dynamic interactions between adhesion molecule expression, chemokine secretion, integrin affinity states, hemodynamics and microvascular network architectures.In vitro experiments confirmed this prediction; a subpopulation of hASCs slowly rolled on immobilized P-selectin at speeds as low as 2 microm/s.Thus, our work led to a fundamentally new understanding of hASC biology, which may have important therapeutic implications.

View Article: PubMed Central - PubMed

Affiliation: Department of Biomedical Engineering, University of Virginia, Charlottesville, Virginia, USA.

ABSTRACT
Intravenous delivery of human adipose-derived stromal cells (hASCs) is a promising option for the treatment of ischemia. After delivery, hASCs that reside and persist in the injured extravascular space have been shown to aid recovery of tissue perfusion and function, although low rates of incorporation currently limit the safety and efficacy of these therapies. We submit that a better understanding of the trafficking of therapeutic hASCs through the microcirculation is needed to address this and that selective control over their homing (organ- and injury-specific) may be possible by targeting bottlenecks in the homing process. This process, however, is incredibly complex, which merited the use of computational techniques to speed the rate of discovery. We developed a multicell agent-based model (ABM) of hASC trafficking during acute skeletal muscle ischemia, based on over 150 literature-based rules instituted in Netlogo and MatLab software programs. In silico, trafficking phenomena within cell populations emerged as a result of the dynamic interactions between adhesion molecule expression, chemokine secretion, integrin affinity states, hemodynamics and microvascular network architectures. As verification, the model reasonably reproduced key aspects of ischemia and trafficking behavior including increases in wall shear stress, upregulation of key cellular adhesion molecules expressed on injured endothelium, increased secretion of inflammatory chemokines and cytokines, quantified levels of monocyte extravasation in selectin knockouts, and circulating monocyte rolling distances. Successful ABM verification prompted us to conduct a series of systematic knockouts in silico aimed at identifying the most critical parameters mediating hASC trafficking. Simulations predicted the necessity of an unknown selectin-binding molecule to achieve hASC extravasation, in addition to any rolling behavior mediated by hASC surface expression of CD15s, CD34, CD62e, CD62p, or CD65. In vitro experiments confirmed this prediction; a subpopulation of hASCs slowly rolled on immobilized P-selectin at speeds as low as 2 microm/s. Thus, our work led to a fundamentally new understanding of hASC biology, which may have important therapeutic implications.

Show MeSH
Related in: MedlinePlus