Plastic Surgery Research Council
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FIBROMODULIN REPROGRAMMED CELLS FOR BONE AND SKELETAL MUSCLE REGENERATION
Presenter: Zhong Zheng, PhD
Co-Authors: Jian J; Zhang X; Velasco O; Chung G; Hourfar A; Zhang K; Lee K; Ting K; Soo C
University of California Los Angeles Los Angeles

Musculoskeletal is the most commonly injured organ system in the U.S. Available clinical strategies do not fully regenerate musculoskeletal injuries. Stem cell-based therapies are promising for restorative repair, but significant drawbacks remain. Mesenchymal stem cells are hampered by low stem cell availability, high donor site morbidity, and/or lack of defined cell potency, purity, and identity. Meanwhile, induced pluripotent stem cells (iPSCs) are tumorigenic due to genomic changes and oncogenic genes introduced during cellular reprogramming. We report an exciting, protein-based technique using fibromodulin (FMOD), an extracellular matrix protein associated with scarless fetal skin repair and stem cell niche microenvironment, to directly reprogram human fibroblasts. FMOD reprogrammed (FReP) cells resemble iPSCs by possessing an embryonic stem cell (ESC)-like morphology, pluripotency marker elevation, and sustained SMAD3 signaling activation. Like iPSCs, FReP cells can differentiate into ectoderm, endoderm, and mesoderm cell lineage derivatives. However, FReP cells exhibit distinctly different proliferative, tumorigenic, and molecular phenotypes from iPSCs and do not form teratomas in combined immunodeficiency (SCID) mice teratoma assays. Because protein-based FReP cell generation avoids genome sequence alteration, teratoma tumorigenesis risks are significantly reduced. To demonstrate regenerative efficacy, we show that implanted human FReP cells (after 3 days in vitro osteogenic pre-differentiation) were able to engraft and differentiate into new bone in both SCID mice gluteofemoral muscle pocket and calvarial defect models. In a separate study, human FReP cells (after 3 days in vitro myogenic pre-differentiation) formed skeletal muscle tissue after implantation in normal and damaged muscle pockets of SCID mice. These data demonstrate the in vivo multipotency of FReP cells. Overall, we present a novel method of generating FReP multipotent cells with low tumorigenicity and highlight their potential usefulness for cell-based tissue engineering for the musculoskeletal system.


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