Abstract
Generating new kidneys using tissue engineering technologies is an innovative strategy for overcoming the shortage of donor organs for transplantation. Here we report how to efficiently engineer the kidney vasculature of decellularized rat kidney scaffolds by using human induced pluripotent stem cell (hiPSCs)-derived endothelial cells (hiPSC-ECs). In vitro, hiPSC-ECs responded to flow stress by acquiring an alignment orientation, and attached to and proliferated on the acellular kidney sections, maintaining their phenotype. The hiPSC-ECs were able to self-organize into chimeric kidney organoids to form vessel-like structures. Ex vivo infusion of hiPSC-ECs through the renal artery and vein of acellular kidneys resulted in the uniform distribution of the cells in all the vasculature compartments, from glomerular capillaries to peritubular capillaries and small vessels. Ultrastructural analysis of repopulated scaffolds through transmission and scanning electron microscopy demonstrated the presence of continuously distributed cells along the vessel wall, which was also confirmed by 3D reconstruction of z-stack images showing the continuity of endothelial cell coverage inside the vessels. Notably, the detection of fenestrae in the endothelium of glomerular capillaries but not in the vascular capillaries was clear evidence of site-specific endothelial cell specialisation.
Highlights
Chronic kidney disease (CKD) is a global problem – more than half a million patients reach end-stage renal disease (ESRD) every year, and it causes over 700.000 deaths[1]
In the last few years major efforts have been made to optimize techniques to generate biological scaffolds, which make it possible to maintain the native composition of the extracellular matrix (ECM) and preserve the appropriate three-dimensional (3D) architecture and regional-specific cues needed for cellular adhesion
This data was in line with previously reported data that described the generation of a mixed cell population, which included both CD144 and perivascular α-smooth muscle actin (α-SMA) positive cells[14] as well as being confirmed by immunofluorescence analysis for both CD144 and α-SMA (Fig. 1b)
Summary
Chronic kidney disease (CKD) is a global problem – more than half a million patients reach end-stage renal disease (ESRD) every year, and it causes over 700.000 deaths[1]. Regenerative medicine has exhibited the potential to increase the number of donor organs for transplantation purposes by generating bioengineered organs[3,4] These strategies are based on the use of natural organ scaffolds and their repopulation with appropriate cells. Pioneering studies by Ross et al showed that mES injected into the renal artery (RA) of an acellular rat kidney were able to adhere to vascular structures and were induced to differentiate toward the endothelial lineage[9,10]. Induced pluripotent stem cells are the ideal cell source for many biomedical applications, including tissue engineering By virtue of their capacity for self-renewal and pluripotent differentiation, these cells can be used to generate progenitors and mature cells to repopulate the organ scaffolds and, ideally, regenerate a patient-specific organ. After phenotypic and functional characterization in vitro and ex vivo, we studied their ability to repopulate acellular rat kidney scaffolds
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