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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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The ABM reproduced increased exposure of circulating monocytes to inflammatory chemokines and cytokines.Prior to ischemic insult, circulating monocyte exposure to soluble and surface-bound chemokines was relatively low (t = 300 seconds; chemokines secreted by monocytes, ECs, tissue macrophages at baseline and WSS-induced changes). After ischemic insult and for duration of simulations (t = 300–2400 seconds), a higher percentage of monocytes encountered chemokines and cytokines, a hallmark of ischemic injury in humans. This led to additional surveying, rolling, firm adhesion, and extravasation by circulating cells. Reported are mean values+standard deviation (n = 5).
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pcbi-1000294-g004: The ABM reproduced increased exposure of circulating monocytes to inflammatory chemokines and cytokines.Prior to ischemic insult, circulating monocyte exposure to soluble and surface-bound chemokines was relatively low (t = 300 seconds; chemokines secreted by monocytes, ECs, tissue macrophages at baseline and WSS-induced changes). After ischemic insult and for duration of simulations (t = 300–2400 seconds), a higher percentage of monocytes encountered chemokines and cytokines, a hallmark of ischemic injury in humans. This led to additional surveying, rolling, firm adhesion, and extravasation by circulating cells. Reported are mean values+standard deviation (n = 5).

Mentions: Acute ischemic injuries are characterized by alterations in circulating chemokine and cytokine levels in animal models and in humans. Implicated chemokines and cytokines during vascular injury include stromal cell-derived factor-1alpha (SDF-1α), interleukin-1beta (IL-1β), interleukin-8 (IL-8), interleukin-10 (IL-10), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), and nitric oxide (NO), which formed the basis for their inclusion in the rule-sets [4],[5],[30] (Text S1). In ABM simulations, the secretion of inflammatory chemokines and cytokines by ECs was increased (Figure 3). Furthermore, circulating monocytes were increasingly exposed to circulating chemokines and cytokines (Figure 4), as expected. Unfortunately, in vivo data for the absolute amount of inflammatory chemokines and cytokines being secreted by ECs during ischemia is inconsistently reported in the literature, and so it could not serve as comparison here. Rather, their increased (relative) presence serves as verification (Text S1).


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)

The ABM reproduced increased exposure of circulating monocytes to inflammatory chemokines and cytokines.Prior to ischemic insult, circulating monocyte exposure to soluble and surface-bound chemokines was relatively low (t = 300 seconds; chemokines secreted by monocytes, ECs, tissue macrophages at baseline and WSS-induced changes). After ischemic insult and for duration of simulations (t = 300–2400 seconds), a higher percentage of monocytes encountered chemokines and cytokines, a hallmark of ischemic injury in humans. This led to additional surveying, rolling, firm adhesion, and extravasation by circulating cells. Reported are mean values+standard deviation (n = 5).
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000294-g004: The ABM reproduced increased exposure of circulating monocytes to inflammatory chemokines and cytokines.Prior to ischemic insult, circulating monocyte exposure to soluble and surface-bound chemokines was relatively low (t = 300 seconds; chemokines secreted by monocytes, ECs, tissue macrophages at baseline and WSS-induced changes). After ischemic insult and for duration of simulations (t = 300–2400 seconds), a higher percentage of monocytes encountered chemokines and cytokines, a hallmark of ischemic injury in humans. This led to additional surveying, rolling, firm adhesion, and extravasation by circulating cells. Reported are mean values+standard deviation (n = 5).
Mentions: Acute ischemic injuries are characterized by alterations in circulating chemokine and cytokine levels in animal models and in humans. Implicated chemokines and cytokines during vascular injury include stromal cell-derived factor-1alpha (SDF-1α), interleukin-1beta (IL-1β), interleukin-8 (IL-8), interleukin-10 (IL-10), monocyte chemoattractant protein-1 (MCP-1), tumor necrosis factor-alpha (TNF-α), transforming growth factor-beta (TGF-β), and nitric oxide (NO), which formed the basis for their inclusion in the rule-sets [4],[5],[30] (Text S1). In ABM simulations, the secretion of inflammatory chemokines and cytokines by ECs was increased (Figure 3). Furthermore, circulating monocytes were increasingly exposed to circulating chemokines and cytokines (Figure 4), as expected. Unfortunately, in vivo data for the absolute amount of inflammatory chemokines and cytokines being secreted by ECs during ischemia is inconsistently reported in the literature, and so it could not serve as comparison here. Rather, their increased (relative) presence serves as verification (Text S1).

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