Abstract
Advances in the fields of stem cell biology, biomaterials, and tissue engineering over the last decades have brought the possibility of constructing tissue substitutes with a broad range of applications in regenerative medicine, disease modeling, and drug discovery. Different types of human stem cells have been used, each presenting a unique set of advantages and limitations with regard to the desired research goals. Whereas adult stem cells are at the frontier of research for tissue and organ regeneration, pluripotent stem cells represent a more challenging cell source for clinical translation. However, with their unlimited growth and wide differentiation potential, pluripotent stem cells represent an unprecedented resource for the construction of advanced human tissue models for biological studies and drug discovery. At the heart of these applications lies the challenge to reproducibly expand, differentiate, and organize stem cells into mature, stable tissue structures. In this review, we focus on the derivation of mesenchymal tissue progenitors from human pluripotent stem cells and the control of their osteogenic differentiation and maturation by modulation of the biophysical culture environment. Similarly to enhancing bone development, the described principles can be applied to the construction of other mesenchymal tissues for basic and applicative studies.
Highlights
Engineering of viable human tissue substitutes has been pursued as a promising alternative to the transplantation of tissue grafts and alloplastic materials [1]
We evaluated global molecular changes occurring during bioreactor culture of hESCand Human induced pluripotent stem cell (hiPSC)-derived Mesenchymal progenitor (MP) [51] and found that all lines exhibited extensive alteration in gene expression profile after perfusion culture and that a comparable number of genes were significantly upregulated or downregulated between Human embryonic stem cell (hESC)- and hiPSC-derived MPs
Deyle and colleagues [78] isolated mesenchymal cells from osteogenesis imperfecta patients, inactivated their mutant collagen genes, and derived hiPSCs that were expanded and differentiated into MPs. These genetargeted MPs produced normal collagen and formed bone in vivo, demonstrating that the combination of gene targeting and hiPSC derivation could be used to produce potentially therapeutic cells from patients with genetic disease [78]. These studies demonstrate how Pluripotent stem cell (PSC) could be used in conjunction with tissue engineering (TE) strategies to construct advanced tissue models, holding the potential to greatly improve the process of drug discovery by testing the substances/biologics directly on the cell types affected by a particular condition
Summary
Engineering of viable human tissue substitutes has been pursued as a promising alternative to the transplantation of tissue grafts and alloplastic materials [1]. There are a number of remaining challenges, including reproducibility of osteogenic induction protocols from different PSC lines; the influences of genetic background, source tissue, and methods of reprogramming on regenerative potential; and development of defined differentiation protocols Another concern is that the current TE approaches involving ‘custom-made’ bioreactors, which differ in maintenance and running requirements [24,71,73], limit broad implementation of specific strategies, compared with the universality of well-plate culture designs for both experimentation and analytics. These genetargeted MPs produced normal collagen and formed bone in vivo, demonstrating that the combination of gene targeting and hiPSC derivation could be used to produce potentially therapeutic cells from patients with genetic disease [78] Together, these studies demonstrate how PSCs could be used in conjunction with TE strategies to construct advanced tissue models, holding the potential to greatly improve the process of drug discovery by testing the substances/biologics directly on the cell types affected by a particular condition
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