Osteochondral Tissue Engineering with Induced Pluripotent Stem Cells

Abstract

With growing numbers of increasingly younger patients suffering debilitating arthropathies, the need for simple models that recapitulate the complex interplay between distinct joint tissues, and grafts that emulate these joint structures in their biological properties and their strength have become more urgent. The objective of this study is to engineer constructs of multiple tissue types by controlling the morphogenetic factors that direct stem cell differentiation and tissue formation either exogenously or via transduction of expression vectors. Our hypothesis is that sequential changes in exogenous growth factor delivery and also scaffold-mediated inducible regulation of morphogenetic gene expression and signaling in 3D-constructs of murine iPSCs will lead to the formation of both bone and cartilage tissue types, both as separate tissues, and as osteochondral constructs. In the first study, osteochondral organoids were grown in a scaffold-free system from a single iPSC cell source, creating tissues containing a distinct core with the genetic and extracellular matrix profile of articular cartilage surrounded by a shell with the genetic and extracellular matrix profile of bone. In the second study, chondrogenic, osteogenic, and osteochondral tissue grafts were grown by scaffold-mediated lentiviral delivery of differentiation factors expressed both constitutively and in a temporally inducible manner. These constructs will provide an excellent platform to study diseases of the osteochondral junction, to screen pharmacologic therapies affecting both cartilage and bone tissue, and as a next step toward making an implantable osteochondral graft for the direct treatment of joint defects.