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MSCs: Delivery Routes and Engraftment, Cell-Targeting Strategies, and Immune Modulation.

Kean TJ, Lin P, Caplan AI, Dennis JE - Stem Cells Int (2013)

Bottom Line: Several methodologies to target MSCs to specific organs are being developed.These cell targeting methodologies focus on the modification of cell surface molecules through chemical, genetic, and coating techniques to promote selective adherence to particular organs or tissues.Future improvements in targeting and delivery methodologies to improve engraftment are expected to improve therapeutic results, extend the duration of efficacy, and reduce the effective (MSC) therapeutic dose.

View Article: PubMed Central - PubMed

Affiliation: Benaroya Research Institute, Seattle, WA 98101, USA.

ABSTRACT
Mesenchymal stem cells (MSCs) are currently being widely investigated both in the lab and in clinical trials for multiple disease states. The differentiation, trophic, and immunomodulatory characteristics of MSCs contribute to their therapeutic effects. Another often overlooked factor related to efficacy is the degree of engraftment. When reported, engraftment is generally low and transient in nature. MSC delivery methods should be tailored to the lesion being treated, which may be local or systemic, and customized to the mechanism of action of the MSCs, which can also be local or systemic. Engraftment efficiency is enhanced by using intra-arterial delivery instead of intravenous delivery, thus avoiding the "first-pass" accumulation of MSCs in the lung. Several methodologies to target MSCs to specific organs are being developed. These cell targeting methodologies focus on the modification of cell surface molecules through chemical, genetic, and coating techniques to promote selective adherence to particular organs or tissues. Future improvements in targeting and delivery methodologies to improve engraftment are expected to improve therapeutic results, extend the duration of efficacy, and reduce the effective (MSC) therapeutic dose.

No MeSH data available.


Comparison of intravenous and intra-arterial cell delivery. Mice were irradiated unilaterally (white arrow) before injection IV (tail vein; a) or IA (aortic arch; b) with 1 × 106 BMC9 MSCs expressing a luciferase reporter.
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Related In: Results  -  Collection


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fig1: Comparison of intravenous and intra-arterial cell delivery. Mice were irradiated unilaterally (white arrow) before injection IV (tail vein; a) or IA (aortic arch; b) with 1 × 106 BMC9 MSCs expressing a luciferase reporter.

Mentions: The alternative method is to deliver the cells intravascularly. With this systemic injection methodology, there remain several hurdles to overcome in order to deliver cells to the target tissue and have them engraft. Intravascular injection has the advantage of being minimally invasive, and it allows for wide distribution of cells throughout the body. The most common method for accessing the circulatory system is IV and is historically the most common method for delivering MSCs. However, cells delivered IV have to first pass through the lungs before they can distribute throughout the body. This presents a major problem with what has been termed the pulmonary “first-pass” effect, which results in significant entrapment of cells [83]. This problem arises because MSCs have an estimated diameter of 20–30 μm [27, 83, 84] and experiments with microspheres have demonstrated that most particles of this size are filtered out by the lungs [83, 85]. While this may be an overestimation of the amount of entrapment, as microspheres are rigid and MSCs can deform, experimental data supports that a large proportion of MSCs are entrapped in the lung following IV administration [27] (Figure 1). Furthermore, it was observed that the number of trapped cells decreased with the administration of a vasodilator [27], lending support to the hypothesis that MSC size is a major contributor to the first-pass effect. In addition to size, it is possible that endothelial cell adhesion molecules contribute to lung entrapment. This hypothesis is supported by evidence showing that when the CD49d receptor was blocked, there was a small, but significant, decrease in the number of cells trapped in the lungs [83]. In a comparison between umbilical cord blood-derived MSCs (UCB-MSCs) and bone marrow-derived MSCs (BM-MSCs), a significant difference was found in the cell surface expression of adhesion molecules (significantly higher CD49f, CD49d, and cMET in UCB-MSCs) and glycolipid carbohydrate epitopes (significantly lower GD2 and SSEA4 in UCB-MSCs), and this cell surface profile correlated with lung clearance rates, with UCB-MSCs exiting the lungs faster than BM-MSCs [86].


MSCs: Delivery Routes and Engraftment, Cell-Targeting Strategies, and Immune Modulation.

Kean TJ, Lin P, Caplan AI, Dennis JE - Stem Cells Int (2013)

Comparison of intravenous and intra-arterial cell delivery. Mice were irradiated unilaterally (white arrow) before injection IV (tail vein; a) or IA (aortic arch; b) with 1 × 106 BMC9 MSCs expressing a luciferase reporter.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC3755386&req=5

fig1: Comparison of intravenous and intra-arterial cell delivery. Mice were irradiated unilaterally (white arrow) before injection IV (tail vein; a) or IA (aortic arch; b) with 1 × 106 BMC9 MSCs expressing a luciferase reporter.
Mentions: The alternative method is to deliver the cells intravascularly. With this systemic injection methodology, there remain several hurdles to overcome in order to deliver cells to the target tissue and have them engraft. Intravascular injection has the advantage of being minimally invasive, and it allows for wide distribution of cells throughout the body. The most common method for accessing the circulatory system is IV and is historically the most common method for delivering MSCs. However, cells delivered IV have to first pass through the lungs before they can distribute throughout the body. This presents a major problem with what has been termed the pulmonary “first-pass” effect, which results in significant entrapment of cells [83]. This problem arises because MSCs have an estimated diameter of 20–30 μm [27, 83, 84] and experiments with microspheres have demonstrated that most particles of this size are filtered out by the lungs [83, 85]. While this may be an overestimation of the amount of entrapment, as microspheres are rigid and MSCs can deform, experimental data supports that a large proportion of MSCs are entrapped in the lung following IV administration [27] (Figure 1). Furthermore, it was observed that the number of trapped cells decreased with the administration of a vasodilator [27], lending support to the hypothesis that MSC size is a major contributor to the first-pass effect. In addition to size, it is possible that endothelial cell adhesion molecules contribute to lung entrapment. This hypothesis is supported by evidence showing that when the CD49d receptor was blocked, there was a small, but significant, decrease in the number of cells trapped in the lungs [83]. In a comparison between umbilical cord blood-derived MSCs (UCB-MSCs) and bone marrow-derived MSCs (BM-MSCs), a significant difference was found in the cell surface expression of adhesion molecules (significantly higher CD49f, CD49d, and cMET in UCB-MSCs) and glycolipid carbohydrate epitopes (significantly lower GD2 and SSEA4 in UCB-MSCs), and this cell surface profile correlated with lung clearance rates, with UCB-MSCs exiting the lungs faster than BM-MSCs [86].

Bottom Line: Several methodologies to target MSCs to specific organs are being developed.These cell targeting methodologies focus on the modification of cell surface molecules through chemical, genetic, and coating techniques to promote selective adherence to particular organs or tissues.Future improvements in targeting and delivery methodologies to improve engraftment are expected to improve therapeutic results, extend the duration of efficacy, and reduce the effective (MSC) therapeutic dose.

View Article: PubMed Central - PubMed

Affiliation: Benaroya Research Institute, Seattle, WA 98101, USA.

ABSTRACT
Mesenchymal stem cells (MSCs) are currently being widely investigated both in the lab and in clinical trials for multiple disease states. The differentiation, trophic, and immunomodulatory characteristics of MSCs contribute to their therapeutic effects. Another often overlooked factor related to efficacy is the degree of engraftment. When reported, engraftment is generally low and transient in nature. MSC delivery methods should be tailored to the lesion being treated, which may be local or systemic, and customized to the mechanism of action of the MSCs, which can also be local or systemic. Engraftment efficiency is enhanced by using intra-arterial delivery instead of intravenous delivery, thus avoiding the "first-pass" accumulation of MSCs in the lung. Several methodologies to target MSCs to specific organs are being developed. These cell targeting methodologies focus on the modification of cell surface molecules through chemical, genetic, and coating techniques to promote selective adherence to particular organs or tissues. Future improvements in targeting and delivery methodologies to improve engraftment are expected to improve therapeutic results, extend the duration of efficacy, and reduce the effective (MSC) therapeutic dose.

No MeSH data available.