Repair of Full-Thickness Tendon Injury Using Connective Tissue Progenitors Efficiently Derived from Human Embryonic Stem Cells and Fetal Tissues

Sohnis and Forman Families Center for Stem Cell and Tissue Regeneration Research, Faculty of Medicine, Technion, Haifa, Israel.
Tissue Engineering Part A (Impact Factor: 4.64). 10/2010; 16(10):3119-37. DOI: 10.1089/ten.TEA.2009.0716
Source: PubMed


The use of stem cells for tissue engineering (TE) encourages scientists to design new platforms in the field of regenerative and reconstructive medicine. Human embryonic stem cells (hESC) have been proposed to be an important cell source for cell-based TE applications as well as an exciting tool for investigating the fundamentals of human development. Here, we describe the efficient derivation of connective tissue progenitors (CTPs) from hESC lines and fetal tissues. The CTPs were significantly expanded and induced to generate tendon tissues in vitro, with ultrastructural characteristics and biomechanical properties typical of mature tendons. We describe a simple method for engineering tendon grafts that can successfully repair injured Achilles tendons and restore the ankle joint extension movement in mice. We also show the CTP's ability to differentiate into bone, cartilage, and fat both in vitro and in vivo. This study offers evidence for the possibility of using stem cell-derived engineered grafts to replace missing tissues, and sets a basic platform for future cell-based TE applications in the fields of orthopedics and reconstructive surgery.

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    • "Characterization of molecular mechanisms responsible for differences in embryonic TPC and adult MSC response to factors may identify pathways that can be controlled to enhance the tenogenic capacity of MSCs. In addition to MSCs, a variety of other stem cells have been explored for tendon tissue engineering, including adipose-derived stem cells, embryonic stem cells, induced pluripotent stem cells, and even adult tendon-derived stem/progenitor cells (Bi et al., 2007; Cohen et al., 2010; James et al., 2011; Xu et al., 2013; Yin et al., 2013; Zhang and Wang, 2010). It is possible that specific stem cell types possess greater tenogenic potential. "
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    ABSTRACT: Tendon is a strong connective tissue that transduces muscle-generated forces into skeletal motion. In fulfilling this role, tendons are subjected to repeated mechanical loading and high stress, which may result in injury. Tissue engineering with stem cells offers the potential to replace injured/damaged tissue with healthy, new living tissue. Critical to tendon tissue engineering is the induction and guidance of stem cells towards the tendon phenotype. Typical strategies have relied on adult tissue homeostatic and healing factors to influence stem cell differentiation, but have yet to achieve tissue regeneration. A novel paradigm is to use embryonic developmental factors as cues to promote tendon regeneration. Embryonic tendon progenitor cell differentiation in vivo is regulated by a combination of mechanical and chemical factors. We propose that these cues will guide stem cells to recapitulate critical aspects of tenogenesis and effectively direct the cells to differentiate and regenerate new tendon. Here, we review recent efforts to identify mechanical and chemical factors of embryonic tendon development to guide stem/progenitor cell differentiation toward new tendon formation, and discuss the role this work may have in the future of tendon tissue engineering.
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    • "The use of pluripotent stem cells may circumvent such issues, as these cells cannot only be expanded to large quantities in vitro, but they can also be directed to differentiate into a vast array of specific progenitor or terminally differentiated cell types. Evidence of success using such cell-based therapies has recently been reported [23]. These authors engineered tendon grafts that effectively repaired injured Achilles tendons in mice. "
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