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

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.

Figure 1

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.

Figure 2

Antibody- and peptide-based cell painting. Therapeutic cells are harvested and “painted” either by a two-step process where the cells are first coated with lipidated protein A (or G) and then incubated with targeting antibody, or a one-step process where the cells are coated with a peptide-targeting molecule that contains a lipid moiety. The coated cells are then reintroduced into the patient where the cells are directed towards specific tissues or organs.

Figure 3

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.