Engineering the Second Generation of Therapeutic Cells with Enhanced Targeting of Injured Tissues

Experimental approaches to improving tissue repair utilize cells and growth factors needed to restore the architecture and function of damaged tissues and organs. Key limitations of these approaches include poor delivery of therapeutic cells and growth factors into injury sites, as well as their short-term retention in target areas. In our earlier studies, we demonstrated that artificial collagen-specific anchor (ACSA) expressed on the surface of therapeutic cells directs them into collagen-rich sites of injury. Moreover, we demonstrated that the ACSA improves the retention of these cells in target sites, thereby promoting tissue repair. To advance the ACSA-based technology, we engineered the second generation of the ACSA-expressing cells able to deliver growth factors to target sites. In this study, we specifically focused on insulin growth factor 1 (IGF1), which enhances the repair of a number of collagen-rich connective tissues, including ligament and tendon. Utilizing gene engineering, we produced IGF1 in the ACSA-expressing cells. Using relevant experimental models, we demonstrated that recombinant IGF1 secreted by these cells maintains its specificity and biological activity. Moreover, our studies show that IGF1 produced by the ACSA-expressing cells cultured in three-dimensional environment promotes the formation of the collagen-rich fibrillar matrix. Furthermore, the engineered cells integrated well with the native collagen-rich tendon tissue. Our study provides strong evidence for the great potential of cells with rationally engineered target-specific receptors to restore damaged connective tissues. Future studies in relevant animal models will determine the utility of these cells in vivo.