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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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Related in: MedlinePlus

In the ABM of hASC trafficking during ischemia, circulating cells were able to undergo complex adhesive interactions under flow.These included secondary capture: clumping, firmly adhering other circulating cells, and rolling on circulating cells. Rolling along and firm adhesion to the endothelium is present in this model, as well. All of these interactions are of potential importance.
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pcbi-1000294-g011: In the ABM of hASC trafficking during ischemia, circulating cells were able to undergo complex adhesive interactions under flow.These included secondary capture: clumping, firmly adhering other circulating cells, and rolling on circulating cells. Rolling along and firm adhesion to the endothelium is present in this model, as well. All of these interactions are of potential importance.

Mentions: Types of interactions between circulating cells and the endothelium in silico included secondary capture and rolling on already adherent circulating cells (Figure 11). Table 3 lists adhesion molecules and binding pairs present within the model. Of note, there were expanded rules governing selectin binding, as this was the primary scope of interest within the ABM. For example, rules governing CD15s [38], CD34 [39], and CD65 [40] expression were instituted in addition to PSGL-1 (CD162) expression because these have been shown to facilitate selectin-mediated rolling. PSGL-1, in silico and in vivo, is constitutively expressed on monocytes and absent on hASCs. This molecule, or more importantly, the ability to roll via selectins, has been identified as critical for circulating cell homing. Because hASCs do not express PSGL-1, we hypothesized that an additional adhesion molecule (currently unknown) must be capable of supporting slowly rolling on selectins, in addition to any levels supported by CD15s, CD34, E-selectin, P-selectin, and CD65. This hypothesized adhesion molecule was termed “SBM-X” and we assigned identical rules to those that governed PSGL-1 behavior.


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)

In the ABM of hASC trafficking during ischemia, circulating cells were able to undergo complex adhesive interactions under flow.These included secondary capture: clumping, firmly adhering other circulating cells, and rolling on circulating cells. Rolling along and firm adhesion to the endothelium is present in this model, as well. All of these interactions are of potential importance.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000294-g011: In the ABM of hASC trafficking during ischemia, circulating cells were able to undergo complex adhesive interactions under flow.These included secondary capture: clumping, firmly adhering other circulating cells, and rolling on circulating cells. Rolling along and firm adhesion to the endothelium is present in this model, as well. All of these interactions are of potential importance.
Mentions: Types of interactions between circulating cells and the endothelium in silico included secondary capture and rolling on already adherent circulating cells (Figure 11). Table 3 lists adhesion molecules and binding pairs present within the model. Of note, there were expanded rules governing selectin binding, as this was the primary scope of interest within the ABM. For example, rules governing CD15s [38], CD34 [39], and CD65 [40] expression were instituted in addition to PSGL-1 (CD162) expression because these have been shown to facilitate selectin-mediated rolling. PSGL-1, in silico and in vivo, is constitutively expressed on monocytes and absent on hASCs. This molecule, or more importantly, the ability to roll via selectins, has been identified as critical for circulating cell homing. Because hASCs do not express PSGL-1, we hypothesized that an additional adhesion molecule (currently unknown) must be capable of supporting slowly rolling on selectins, in addition to any levels supported by CD15s, CD34, E-selectin, P-selectin, and CD65. This hypothesized adhesion molecule was termed “SBM-X” and we assigned identical rules to those that governed PSGL-1 behavior.

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