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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.


Cell localization in myocardial tissue. Increased cell numbers were found in peptide-targeted (BioCAR, CRPPR, CRKDKC, and KSTRKS) MSCs than in untargeted MSCs (MSCs only). Means of n ≥ 3 ± S.D. Total targeted versus untargeted means are 3.1 versus 1.4, P < 0.05 one tailed Student's t-test.
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fig3: Cell localization in myocardial tissue. Increased cell numbers were found in peptide-targeted (BioCAR, CRPPR, CRKDKC, and KSTRKS) MSCs than in untargeted MSCs (MSCs only). Means of n ≥ 3 ± S.D. Total targeted versus untargeted means are 3.1 versus 1.4, P < 0.05 one tailed Student's t-test.

Mentions: To our knowledge, we are the only group, to date, that has investigated peptide-directed cell therapy. There has, however, been considerable interest in peptide-targeted drugs for some time, especially in the field of anticancer therapies [134]. Targeting peptides can be derived from endogenous binding proteins, or novel ligands can be identified by combinatorial chemistry libraries or using phage display [134]. Phage display is a powerful method where in vivo biopanning experiments can be performed to isolate tissue-specific peptides [135, 136]. This phage display method was utilized by our group with a limited phage “play-off” screen, where several previously identified binding phage peptides were analyzed for their ability to bind to infarcted myocardial tissue [137]. The most successful of these peptides were then synthesized as lipidated derivatives and used to coat MSCs, these were then systemically injected via the left ventricle of MI/reperfusion mice and achieved greater MSC numbers in all peptide-targeted groups than with uncoated MSCs (Figure 3) [137]. However, this increased binding to cardiac tissue was not seen in a permanent ligation model (unpublished results). Peptide-based delivery has several advantages over antibody-, gene-, or selectin-directed techniques: peptide manufacture is scalable, and the products have high purity and are relatively inexpensive to produce. Ligands can be highly specific for tissues or cells of interest and multiple ligands can be attached to the cell surface or drug delivery vehicle. However, in contrast to antibody-based therapies, no peptide-targeted therapeutic has yet made it to market [138].


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

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

Cell localization in myocardial tissue. Increased cell numbers were found in peptide-targeted (BioCAR, CRPPR, CRKDKC, and KSTRKS) MSCs than in untargeted MSCs (MSCs only). Means of n ≥ 3 ± S.D. Total targeted versus untargeted means are 3.1 versus 1.4, P < 0.05 one tailed Student's t-test.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

fig3: Cell localization in myocardial tissue. Increased cell numbers were found in peptide-targeted (BioCAR, CRPPR, CRKDKC, and KSTRKS) MSCs than in untargeted MSCs (MSCs only). Means of n ≥ 3 ± S.D. Total targeted versus untargeted means are 3.1 versus 1.4, P < 0.05 one tailed Student's t-test.
Mentions: To our knowledge, we are the only group, to date, that has investigated peptide-directed cell therapy. There has, however, been considerable interest in peptide-targeted drugs for some time, especially in the field of anticancer therapies [134]. Targeting peptides can be derived from endogenous binding proteins, or novel ligands can be identified by combinatorial chemistry libraries or using phage display [134]. Phage display is a powerful method where in vivo biopanning experiments can be performed to isolate tissue-specific peptides [135, 136]. This phage display method was utilized by our group with a limited phage “play-off” screen, where several previously identified binding phage peptides were analyzed for their ability to bind to infarcted myocardial tissue [137]. The most successful of these peptides were then synthesized as lipidated derivatives and used to coat MSCs, these were then systemically injected via the left ventricle of MI/reperfusion mice and achieved greater MSC numbers in all peptide-targeted groups than with uncoated MSCs (Figure 3) [137]. However, this increased binding to cardiac tissue was not seen in a permanent ligation model (unpublished results). Peptide-based delivery has several advantages over antibody-, gene-, or selectin-directed techniques: peptide manufacture is scalable, and the products have high purity and are relatively inexpensive to produce. Ligands can be highly specific for tissues or cells of interest and multiple ligands can be attached to the cell surface or drug delivery vehicle. However, in contrast to antibody-based therapies, no peptide-targeted therapeutic has yet made it to market [138].

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.