Exploring mesenchymal stem cells homing mechanisms and improvement strategies

Abstract

Mesenchymal stem cells (MSCs) are multipotent cells with high self-renewal and multilineage differentiation abilities, playing an important role in tissue healing. Recent advancements in stem cell-based technologies have offered new and promising therapeutic options in regenerative medicine. Upon tissue damage, MSCs are immediately mobilized from the bone marrow and move to the injury site via blood circulation. Notably, allogenically transplanted MSCs can also home to the damaged tissue site. Therefore, MSCs hold great therapeutic potential for curing various diseases. However, one major obstacle to this approach is attracting MSCs specifically to the injury site following systemic administration. In this review, we describe the molecular pathways governing the homing mechanism of MSCs and various strategies for improving this process, including targeted stem cell administration, target tissue modification, in vitro priming, cell surface engineering, genetic modifications, and magnetic guidance. These strategies are crucial for directing MSCs precisely to the injury site and, consequently, enhancing their migration and local tissue repair properties. Specifically, our review provides a guide to improving the therapeutic efficacy of clinical applications of MSCs through optimized in vivo administration and homing capacities.

Keywords: administration; homing; improvement strategies; mesenchymal stem cells; migration; priming; target tissue modification.

Graphical Abstract

Figure 1.

Overview of MSC homing mechanism. The systemic homing of MSCs comprises 5 distinct steps, including tethering and rolling, activation, arrest, diapedesis or transmigration, and migration. Tethering and rolling, which are the first steps of this mechanism, are facilitated by interactions of selectins and ligands. The second step activation is facilitated by G protein-coupled chemokine receptors, and the third step of cell arrest involves integrins. In the fourth step of diapedesis or transmigration, MSCs cross the endothelial cell layer and basement membrane by secreting matrix metalloproteinases (MMPs). In the final step, MSCs migrate to the injury site through the interstitium due to chemotactic signals released upon tissue damage. Modified from Ullah et al.

Figure 2.

Targeted administration of MSCs at or near the damaged tissue. This process is called nonsystemic homing. It is the chemokines which guide the MSCs toward damaged tissue when administered near the damaged tissue. Modified from Ullah et al.

Figure 3.

Target tissue modification for increasing MSCs homing efficiency. (A) Direct injection of homing factor, (B) target tissue genetic modification by direct injection of homing factor containing plasmid or by intravenous injection of homing factor containing microbubble injection followed by ultrasound-mediated microbubble destruction method, and (C) homing factor containing scaffold implantation. Modified from Ullah et al.

Figure 4.

Overview of cell surface engineering, genetic modifications, magnetic guidance, and radiotherapeutic (ultrasound) techniques for improving MSCs homing at the target tissue. Modified from Ullah et al.

Figure 5.

Overview of in vitro priming methods to enhance homing of MSCs modified from Ullah et al. These methods include CD44 upregulation at tethering stage, an increase in the expression of CXCR4, CXCR7, CCR2, CCR3, and CCR4 at activation step, an increase in matrix metalloproteinases (MMPs) expression at transmigration stage.

Figure 6.

Explaining MSCs homing mechanism along with various strategies used for enhancing homing efficiency of MSCs at the target site. This includes both systemic homing and nonsystemic homing mechanism improvement strategies.