Engineered cell homing

Abstract

One of the greatest challenges in cell therapy is to minimally invasively deliver a large quantity of viable cells to a tissue of interest with high engraftment efficiency. Low and inefficient homing of systemically delivered mesenchymal stem cells (MSCs), for example, is thought to be a major limitation of existing MSC-based therapeutic approaches, caused predominantly by inadequate expression of cell surface adhesion receptors. Using a platform approach that preserves the MSC phenotype and does not require genetic manipulation, we modified the surface of MSCs with a nanometer-scale polymer construct containing sialyl Lewisx (sLex) that is found on the surface of leukocytes and mediates cell rolling within inflamed tissue. The sLex engineered MSCs exhibited a robust rolling response on inflamed endothelium in vivo and homed to inflamed tissue with higher efficiency compared with native MSCs. The modular approach described herein offers a simple method to potentially target any cell type to specific tissues via the circulation.

Synthetic control of mammalian-cell motility by engineering chemotaxis to an orthogonal bioinert chemical signal

“…Other groups have described interesting approaches, including the chemical or enzymatic modification of the cell surface with specific adhesion molecules (45), materials engineering of artificial scaffolds and tunable matrices to direct cell adhesion and migration (46), expression or direct injection of natural homing ligands such as chemokines into sites where increased cell migration is desired (47,48), and the expression in therapeutic cells of natural receptors such as chemokine receptors whose ligands are up-regulated in inflammation or cancer (8,7,16,17). These strategies rely on naturally existing homing receptors and ligands, and they are powerful because they tap into cells' native migration axes.…”

mRNA-engineered mesenchymal stem cells for targeted delivery of interleukin-10 to sites of inflammation

“…This process is characterized by the upregulation of multiple adhesion ligands on the inflamed endothelium, including P-and E-selectin. 15,26 Twenty-four hours later, native and PSGL-1/SLeX MSCs, stained with different vibrant membrane dyes, were co-injected retroorbitally and imaged in the inflamed ear vasculature using dynamic real-time intravital confocal microscopy. As shown in the representative time-lapsed images ( Figure 3C), PSGL-1/SLeX MSCs exhibited a robust rolling behavior on LPS-induced inflamed endothelium in vivo.…”

“…11 Key ligands that are required for homing, such as adhesion ligands (eg, P-selectin glycoprotein ligand-1 [PSGL-1], Sialyl Lewis X [SLeX]) or chemokine receptors, are minimally expressed by MSCs, 15,16 or their expression is lost during culture expansion. 17 Moreover, though cell phenotype can be accurately controlled within in vitro settings, it is challenging to control cell properties after transplantation because cells are at the mercy of the biological milieu.…”

Effect of local bone marrow stromal cell administration on ligature-induced periodontitis in mice

“…Of these, intravenous injection is the most widely used because of the following advantages: 1) intravenous injection is minimally invasive, 2) BMSC infusions are reproducible, and 3) administered cells remain close to the oxygen-and nutrient-rich vasculature of the target tissue (27). However, many infused BMSCs may be trapped by some organs after intravenous injection, interrupting the homing of BMSCs to the target tissues.…”

“…Furthermore, some studies suggest that MSCs have the ability to engraft damaged tissues, integrate into tubular cells, and differentiate into mesangial cells (28,29). Nevertheless, directly administered BMSCs may exhibit diminished survival by the lack of available oxygen or nutrients in some target tissues (27). In this study, the locally administered DiI-labeled BMSCs were detected at 4 days after cell administration in ligature-induced progression of periodontitis in conjunction with the diminished periodontal bone resorption level, indicating that this method was potent in preventing periodontitis progression.…”