The Role of Chemokines in Mesenchymal Stem Cell Homing to Wounds

Abstract

Significance: Mesenchymal stem cells (MSCs) are being administered to cutaneous wounds with the goal of accelerating wound closure and promoting regeneration instead of scar formation. An ongoing challenge for cell-based therapies is achieving effective and optimal targeted delivery and engraftment at the site of injury. Contributing to this challenge is our incomplete understanding of endogenous MSC homing to sites of injury. Recent Advances: Chemokines and their receptors are now recognized as important mediators of stem cell homing. To date, the most studied chemokinechemokine receptor axis in MSC homing to wounds is CXCL12-CXCR4 but recent work suggests that CCL27-CCR10 and CCL21-CCR7 may also be involved. Critical Issues: Strategies to enhance chemokine-mediated MSC homing to wounds are using a variety of approaches to amplify the chemokine signal at the wound site and/or overexpress specific chemokine receptors on the surface of the MSC. Future Directions: Harnessing chemokine signaling may enhance the therapeutic effects of stem cell therapy by increasing the number of both exogenous and endogenous stem cells recruited to the site of injury. Alternatively, chemokine-based therapies directly targeting endogenous stem cells may circumvent the need for the time-consuming and costly isolation and expansion of autologous stem cells prior to therapeutic administration. SCOPE AND SIGNIFICANCEMesenchymal stem cells (MSCs) are being administered to cutaneous wounds with the goal of accelerating wound closure and promoting regeneration instead of scar formation.1 An ongoing challenge for cell-based therapies is achieving effective and optimal targeted delivery and engraftment at the site of injury. Contributing to this challenge is our incomplete understanding of endogenous MSC homing to sites of injury.2 This review will summarize our current knowledge about the role of chemokines in MSC recruitment to wounds. TRANSLATIONAL RELEVANCEThe translational relevance for research defining the chemokines responsible for stem cell homing is significant with a direct impact on stem cell therapy. Harnessing chemokine signaling may enhance the therapeutic effects of stem cell therapy by increasing the number of both exogenous and endogenous stem cells recruited to the site of injury. Alternatively, chemokine-based therapies directly targeting endogenous stem cells may circumvent the need for the time-consuming and costly isolation and expansion of autologous stem cells prior to therapeutic administration. CLINICAL RELEVANCEOngoing clinical trials are investigating the safety and efficacy of MSC therapy for the treatment of

A microfluidic device for measuring cell migration towards substrate-bound and soluble chemokine gradients

“…An example for co-existing immobilized and soluble chemokine gradients is the mobilization of mesenchymal stem cells during tissue regeneration by soluble chemokines such as CCL19 on the one side and chemokines that bind to extracellular glycosaminoglycans such as CCL2, CXCL12 or CCL5 on the other side2627. Also, guided cell migration presumably mediated by chemotactic and haptotactic signals are of importance in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS)28.…”

Angiopellosis as an Alternative Mechanism of Cell Extravasation

“…The site of injury could be exuding signals that are recognized by the injected stem cells, which prompts them to attach to the blood vessel wall, which then stimulates the angiopellosis process to occur. Chemokines and their receptors have been reported as important mediators in the process of stem cell homing . Another possibility is that signals on the injected cell's membrane are interacting with the receptors on the blood vessel endothelial cells, asking for the cells removal from the lumen.…”

Minicircle microporation-based non-viral gene delivery improved the targeting of mesenchymal stem cells to an injury site

“…It has been known that MSCs have relatively weak homing ability [27,28]: the major reason is that the expression of CXCR4, the primary receptor for main chemokine (stromal cell-derived factor 1; SDF1), is not high on the surface of MSCs, especially in long-term expansion culture [27e31]. Therefore, many studies have reported on enhancement of the homing ability of MSCs through the increase of CXCR4 expression by viral In this study, CXCR4 gene was overexpressed in mBM-MSCs by minicircle microporation, and the resulting improvement of homing ability was confirmed by in vivo bioluminescence imaging.…”