Abstract
Despite the enthusiasm for bioengineering of functional renal tissues for transplantation, many obstacles remain before the potential of this technology can be realized in a clinical setting. Viable tissue engineering strategies for the kidney require identification of the necessary cell populations, efficient scaffolds, and the 3D culture conditions to develop and support the unique architecture and physiological function of this vital organ. Our studies have previously demonstrated that decellularized sections of rhesus monkey kidneys of all age groups provide a natural extracellular matrix (ECM) with sufficient structural properties with spatial and organizational influences on human embryonic stem cell (hESC) migration and differentiation. To further explore the use of decellularized natural kidney scaffolds for renal tissue engineering, pluripotent hESC were seeded in whole- or on sections of kidney ECM and cell migration and phenotype compared with the established differentiation assays for hESC. Results of qPCR and immunohistochemical analyses demonstrated upregulation of renal lineage markers when hESC were cultured in decellularized scaffolds without cytokine or growth factor stimulation, suggesting a role for the ECM in directing renal lineage differentiation. hESC were also differentiated with growth factors and compared when seeded on renal ECM or a new biologically inert polysaccharide scaffold for further maturation. Renal lineage markers were progressively upregulated over time on both scaffolds and hESC were shown to express signature genes of renal progenitor, proximal tubule, endothelial, and collecting duct populations. These findings suggest that natural scaffolds enhance expression of renal lineage markers particularly when compared to embryoid body culture. The results of these studies show the capabilities of a novel polysaccharide scaffold to aid in defining a protocol for renal progenitor differentiation from hESC, and advance the promise of tissue engineering as a source of functional kidney tissue.
Highlights
The expanding field of tissue engineering provides hope for the creation of tissue and organs with functional properties and therapeutic potential for nearly every tissue of the human body
It is notable that the kidney which is in greatest demand is one of the most challenging tissues to engineer due to complex architecture, a spectrum of cell phenotypes, multiple functions, and a lack of an established stem/progenitor cell population in adults from which the kidney can be regenerated
Many obstacles remain before bioengineering of functional renal tissues for human transplantation can be realized
Summary
The expanding field of tissue engineering provides hope for the creation of tissue and organs with functional properties and therapeutic potential for nearly every tissue of the human body. Viable tissue engineering strategies for the kidney requires identification of necessary cell populations, suitable scaffolds to provide structural support and spatiotemporal organizational properties, as well as medium/growth factor/culture combinations to sustain growth and physiological function of the engineered tissue. One promising approach for renal tissue engineering involves the use of natural scaffolds produced by decellularization of donor kidneys. Our studies have previously demonstrated that decellularized rhesus monkey kidney sections of all age groups (fetal to aged) provide a natural ECM with sufficient structural properties to support migration of cells from kidney explants in an age-dependent manner [12, 13], and the utility of these scaffolds to provide spatial and organizational influences on human embryonic stem cell (hESC) migration and differentiation [22]. To evaluate the role of the scaffold in guiding hESC renal differentiation, cells were seeded on decellularized kidney sections and compared with the cellular phenotype of cells obtained when using an organic, physiologically inert polysaccharide scaffold
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