A Three Dimensional Environment for Skeletal Muscle Stem Cell Transplantation

Principal Investigator: Kathryn Wagner

The purpose of this collaborative project is to develop and test and injectable scaffold embedded with muscle stem cells and a Pfizer drug to facilitate muscle regeneration. Cell based therapies lag behind the development of other approaches to chronic muscle disease including gene therapy and pharmacological therapies. However, it is commonly believed that cell therapies will provide the eventual cures to chronic inherited and acquired muscle disease such as muscular dystrophy and sarcopenia. Skeletal muscle is composed of syncytial multinucleated myofibers in a fairly simple cellular organization suggesting that stem cell therapy should be quite feasible. Indeed, animal studies have shown engraftment of muscle stem cells and amelioration of disease phenotype. However, previous clinical trials in disease patients have been disappointing. Recognizing that the environment as well as the stem cells needs to be optimized, a collaborative team, composed of muscle biologist and neuromuscular clinician, bioengineer, and stem cell biologist, proposes to develop a three dimensional environment for muscle stem cell transplantation. The Specific Aims of the proposal are to 1) optimize an injectable, biosynthetic scaffold for skeletal muscle stem cell transplantation, 2) embed novel myostatin inhibitors obtained by a collaboration with Pfizer in the biosynthetic scaffold to stimulate muscle stem cells to proliferate and differentiate into myofibers and 3) isolate and derive various human muscle stem cells including satellite cells, pericytes and skeletal muscle cells derived from hiPSCs from human volunteers. The human muscle stem cells will then be seeded on optimized scaffold with embedded myostatin blocker and transplantation efficiency will be assessed in immunodeficient mice. These experiments will provide important knowledge on requirements of biosynthetic scaffolds, properties of various human muscle stem cells and the growth conditions needed to facilitate their transplantation and engraftment to achieve effective skeletal muscle regeneration.