Z. Liu1, B. Wang1, D. M. Castilla1, Y. Li1, R. Tian1, L. Kovalski1, O. C. Velazquez1 1University Of Miami,Surgery/Sylvester Comprehensive Cancer Center,Miami, FL, USA
Introduction: Mesenchymal stem cells (MSC) carry high therapeutic potential for tissue regeneration. However, targeted delivery of therapeutic MSC to injured tissue remains a challenge. We are aimed to develop a safe and targeted cell delivery method for therapeutic administration of MSC to injured tissues to achieve enhanced wound healing and neovascularization. Herein, we present a novel cell delivery platform by coating the surface of MSC with nanocarriers composed of nanoparticle–adhesion molecule complex (NAMC). These nanocarriers guide the coated MSC to their destination via molecular recognition and association with their counterpart adhesion molecules, which are highly or selectively expressed on the injured tissue, and execute their therapeutic roles.
Methods: Murine bone marrow-derived MSC, which were obtained from ROSA 26-LacZ+ mice and pre-labeled with Luciferase 2 (Luc2+) gene, were coated with nanocarriers (NAMC) or control nanoparticle-albumin complex (NAC). 1x 106 NAMC- versus NAC-decorated MSC were administrated through either systemic (i.v.) or local (wound tissue injection) approach to recipient mice on which 6-mm full thickness dorsal skin wounds were created (n=6/group). An extra group of wounded mice were treated with saline as baseline control. Bio-distribution and selective wound tissue homing of administrated Luc2+ MSC were detected by IVIS (In Vitro Image System) at various time points. Increased homing of infused circulating NAMC-decorated MSC to wound tissues was validated by X-gal staining of LacZ+ MSC in wound tissues. Wound healing rate was calculated based upon daily digital photograph of wounds. Neovascularization was assessed by either Dil-perfusion and wound tissue confocal microscopy (for local administration) or immunohistochemistry analysis of wound tissue sections (for systemic administration).
Results:Whole-body IVIS scan showed significantly increased Luc2+ NAMC-decorated MSC within wound tissues, particularly on day 8 (~10-fold increased bioluminescence signal, p=0.029). Intravenously infused NAMC-decorated MSC selectively homed to wound tissues, but not other organs. Increased homing of intravenously infused NAMC-decorated MSC to wound tissues was demonstrated by X-gal staining of wound tissues. Wound healing rate and neovascularization were significantly increased by both systemic (p≤0.01) and local (p<0.01) administration of NAMC-decorated MSC in comparison with NAC-decorated control MSC.
Conclusion:We demonstrated the feasibility and efficacy of a novel form of nanocarrier for targeted delivery of therapeutic stem cells to wound tissues in mouse models for enhanced wound healing and neovascularization. This nanocarrier cell surface decoration method is suited for targeted delivery of virtually any type of therapeutic cells and holds promise to be developed as a clinically-relevant cell-based therapy for regenerative medicine and beyond.