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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 appropriate monocyte and hASC rolling distances in simulations of trafficking in both healthy and ischemic tissues.Data presented as the average across all the cells in the phenotype, as well as according to whether cells eventually extravasated. (A) In simulations of healthy microvascular networks, monocytes consistently rolled 200 µm on average. Despite similar rules governing their behavior, hASCs rolling distances varied depending on whether that cell eventually extravasated. (B) In simulations of ischemic microvascular networks, both monocytes and hASC rolling distances were less than levels seen in healthy networks.
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pcbi-1000294-g006: The ABM reproduced appropriate monocyte and hASC rolling distances in simulations of trafficking in both healthy and ischemic tissues.Data presented as the average across all the cells in the phenotype, as well as according to whether cells eventually extravasated. (A) In simulations of healthy microvascular networks, monocytes consistently rolled 200 µm on average. Despite similar rules governing their behavior, hASCs rolling distances varied depending on whether that cell eventually extravasated. (B) In simulations of ischemic microvascular networks, both monocytes and hASC rolling distances were less than levels seen in healthy networks.

Mentions: Consistent with an earlier ABM [23], monocyte extravasation was shown to be unaffected in E-selectin knockouts, P-selectin knockouts, and only marginally in double selectin knockouts (10% decrease). Triple-selectin knockouts virtually eliminated instances of rolling and extravasation (78% reduction; Figure 5). This agrees with experimental literature showing that monocytes are able to proceed through the adhesion cascade non-sequentially and incorporate into extravascular spaces without rolling on the selectins prior to firm adhesion (Table 2). Simulating a knockout of ICAM-1 significantly inhibited monocyte extravasation (55% reduction; Table 2), and it appears that rolling behavior was affected, as well (Figure 5). Average monocyte rolling distances ranged from 72.6±14.7 to 198±57.5 µm in injured and healthy tissue, respectively. The rolling distances of monocytes that eventually extravasated did not significantly differ from that of monocytes that failed to extravasate, in either healthy or ischemic tissue (Figure 6). In vivo, leukocyte rolling distances have been reported to range from 30–400 µm (Table 2).


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 appropriate monocyte and hASC rolling distances in simulations of trafficking in both healthy and ischemic tissues.Data presented as the average across all the cells in the phenotype, as well as according to whether cells eventually extravasated. (A) In simulations of healthy microvascular networks, monocytes consistently rolled 200 µm on average. Despite similar rules governing their behavior, hASCs rolling distances varied depending on whether that cell eventually extravasated. (B) In simulations of ischemic microvascular networks, both monocytes and hASC rolling distances were less than levels seen in healthy networks.
© Copyright Policy
Related In: Results  -  Collection

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

pcbi-1000294-g006: The ABM reproduced appropriate monocyte and hASC rolling distances in simulations of trafficking in both healthy and ischemic tissues.Data presented as the average across all the cells in the phenotype, as well as according to whether cells eventually extravasated. (A) In simulations of healthy microvascular networks, monocytes consistently rolled 200 µm on average. Despite similar rules governing their behavior, hASCs rolling distances varied depending on whether that cell eventually extravasated. (B) In simulations of ischemic microvascular networks, both monocytes and hASC rolling distances were less than levels seen in healthy networks.
Mentions: Consistent with an earlier ABM [23], monocyte extravasation was shown to be unaffected in E-selectin knockouts, P-selectin knockouts, and only marginally in double selectin knockouts (10% decrease). Triple-selectin knockouts virtually eliminated instances of rolling and extravasation (78% reduction; Figure 5). This agrees with experimental literature showing that monocytes are able to proceed through the adhesion cascade non-sequentially and incorporate into extravascular spaces without rolling on the selectins prior to firm adhesion (Table 2). Simulating a knockout of ICAM-1 significantly inhibited monocyte extravasation (55% reduction; Table 2), and it appears that rolling behavior was affected, as well (Figure 5). Average monocyte rolling distances ranged from 72.6±14.7 to 198±57.5 µm in injured and healthy tissue, respectively. The rolling distances of monocytes that eventually extravasated did not significantly differ from that of monocytes that failed to extravasate, in either healthy or ischemic tissue (Figure 6). In vivo, leukocyte rolling distances have been reported to range from 30–400 µm (Table 2).

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