Discarded human kidneys as a source of ECM scaffold for kidney regeneration technologies

Orlando, Giuseppe; Booth, Christopher; Zhan, Wei; Totonelli, Giorgia; Ross, Christina; Moran, Emma; Salvatori, Marcus; Maghsoudlou, Panagiotis; Turmaine, Mark; DeLario, Ginger T.; Al-Shraideh, Yousef; Farooq, Umar; Farney, Alan C.; Rogers, Jeffrey; Iskandar, Samy S.; Burns, Alan J.; Marini, Frank C.; Coppi, Paolo De; Stratta, Robert J.; Söker, Shay

doi:10.1016/j.biomaterials.2013.04.033

Cited by 174 publications

(128 citation statements)

References 39 publications

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“…This observed reduction in DP following decellularization is in line with previous observations by Orlando et al for human kidney decellularization, providing proof-of-concept for this smallerscale model system for rodent scaffolds, which are more advantageous for future repopulation with stem or progenitor cells due to the limited availability of these cell populations. 8 We then went further to evaluate the influence of scaffold recellularization on DP. We first assessed a subset of acellular scaffolds perfused within the bioreactor at 37°C for 7 days without cells to evaluate matrix architecture and the effect on DP during maintenance culture.…”

Section: Pressure Drop Measurement At Defined Flow Ratesmentioning

confidence: 99%

“…Decellularization of livers and kidneys through perfusion of detergent solutions through the vasculature has been well documented 3,4 -with technical feasibility demonstrated using both large animal and humanscale organs [5][6][7][8] as well as small animal organs for repopulation with stem or immature progenitor cells. 7,[9][10][11][12][13] The current challenges and limitations to organ and tissue engineering have shifted to the cellular repopulation phase of tissue development where donor cells are reintroduced into wholeorgan ECM scaffolds; however, very little detail is typically provided describing bioreactor construction despite the identification of specific design features that are critical to optimize scaffold recellularization and overall function.…”

Section: Introductionmentioning

confidence: 99%

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Dual-Purpose Bioreactors to Monitor Noninvasive Physical and Biochemical Markers of Kidney and Liver Scaffold Recellularization

Uzarski

Bijonowski

Wang

et al. 2015

Tissue Engineering Part C: Methods

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Analysis of perfusion-based bioreactors for organ engineering and a detailed evaluation of physical and biochemical parameters that measure dynamic changes within maturing cell-laden scaffolds are critical components of ex vivo tissue development that remain understudied topics in the tissue and organ engineering literature. Intricately designed bioreactors that house developing tissue are critical to properly recapitulate the in vivo environment, deliver nutrients within perfused media, and monitor physiological parameters of tissue development. Herein, we provide an in-depth description and analysis of two dual-purpose perfusion bioreactors that improve upon current bioreactor designs and enable comparative analyses of ex vivo scaffold recellularization strategies and cell growth performance during long-term maintenance culture of engineered kidney or liver tissues. Both bioreactors are effective at maximizing cell seeding of small-animal organ scaffolds and maintaining cell survival in extended culture. We further demonstrate noninvasive monitoring capabilities for tracking dynamic changes within scaffolds as the native cellular component is removed during decellularization and model parenchymal cells are introduced into the scaffold during recellularization and proliferate in maintenance culture. We found that hydrodynamic pressure drop (DP) across the retained scaffold vasculature is a noninvasive measurement of scaffold integrity. We further show that DP, and thus resistance to fluid flow through the scaffold, decreases with cell loss during decellularization and correspondingly increases to near normal values for whole organs following recellularization of the kidney or liver scaffolds. Perfused media may be further sampled in real time to measure soluble biomarkers (e.g., resazurin, albumin, or kidney injury molecule-1) that indicate degree of cellular metabolic activity, synthetic function, or engraftment into the scaffold. Cell growth within bioreactors is validated for primary and immortalized cells, and the design of each bioreactor is scalable to accommodate any three-dimensional scaffold (e.g., synthetic or naturally derived matrix) that contains conduits for nutrient perfusion to deliver media to growing cells and monitor noninvasive parameters during scaffold repopulation, broadening the applicability of these bioreactor systems.

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Section: Pressure Drop Measurement At Defined Flow Ratesmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Dual-Purpose Bioreactors to Monitor Noninvasive Physical and Biochemical Markers of Kidney and Liver Scaffold Recellularization

Uzarski

Bijonowski

Wang

et al. 2015

Tissue Engineering Part C: Methods

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“…13 Thus, this approach does not provide robust evidence for cell seeding and proliferation in a setting that more closely mimics the in vivo exposure of innate ECM scaffold to renal precursors. More recently, renal ECM scaffolds were also successfully produced from porcine, 14 monkey 15 , and human 16 kidneys as a platform for renal bioengineering investigations, but no attempt to repopulate the whole-kidney scaffolds with cells was pursued in this investigation.…”

Section: Introductionmentioning

confidence: 99%

Recellularization of Well-Preserved Acellular Kidney Scaffold Using Embryonic Stem Cells

Bonandrini

Figliuzzi²,

Papadimou³

et al. 2014

Tissue Engineering Part A

184

146

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For chronic kidney diseases, there is little chance that the vast majority of world's population will have access to renal replacement therapy with dialysis or transplantation. Tissue engineering would help to address this shortcoming by regeneration of damaged kidney using naturally occurring scaffolds seeded with precursor renal cells. The aims of the present study were to optimize the production of three-dimensional (3D) rat whole-kidney scaffolds by shortening the duration of organ decellularization process using detergents that avoid nonionic compounds, to investigate integrity of extracellular matrix (ECM) structure and to enhance the efficacy of scaffold cellularization using physiological perfusion method. Intact rat kidneys were successfully decellularized after 17 h perfusion with sodium dodecyl sulfate. The whole-kidney scaffolds preserved the 3D architecture of blood vessels, glomeruli, and tubuli as shown by transmission and scanning electron microscopy. Microcomputerized tomography (micro-CT) scan confirmed integrity, patency, and connection of the vascular network. Collagen IV, laminin, and fibronectin staining of decellularized scaffolds were similar to those of native kidney tissues. After infusion of whole-kidney scaffolds with murine embryonic stem (mES) cells through the renal artery, and pressure-controlled perfusion with recirculating cell medium for 24 and 72 h, seeded cells were almost completely retained into the organ and uniformly distributed in the vascular network and glomerular capillaries without major signs of apoptosis. Occasionally, mES cells reached peritubular capillary and tubular compartment. We observed the loss of cell pluripotency and the start of differentiation toward meso-endodermal lineage. Our findings indicate that, with the proposed optimized protocol, rat kidneys can be efficiently decellularized to produce renal ECM scaffolds in a relatively short time, and rapid recellularization of vascular structures and glomeruli. This experimental setup may open the possibility to obtain differentiation of stem cells with long lasting in vitro perfusion.

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“…A specialized form of ECM, the basement membrane, underlies a layer of polarized cells, forming a basic architectural feature of animal tissues. Basement membranes serve as scaffolds for cell migration and adhesion, delineate apical-basal polarity, and modulate cell differentiation during development (1)(2)(3)(4)(5)(6)(7), and in the form of decellularized scaffolds, they guide pluripotent cells to partially regenerate whole organs (8)(9)(10)(11)(12). A major component is a collagen IV scaffold that is essential for tissue genesis and dysfunctional in several diseases (13)(14)(15)(16).…”

mentioning

confidence: 99%

A unique covalent bond in basement membrane is a primordial innovation for tissue evolution

Fidler

Vanacore

Chetyrkin

et al. 2013

Proc. Natl. Acad. Sci. U.S.A.

137

140

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Basement membrane, a specialized ECM that underlies polarized epithelium of eumetazoans, provides signaling cues that regulate cell behavior and function in tissue genesis and homeostasis. A collagen IV scaffold, a major component, is essential for tissues and dysfunctional in several diseases. Studies of bovine and Drosophila tissues reveal that the scaffold is stabilized by sulfilimine chemical bonds (S = N) that covalently cross-link methionine and hydroxylysine residues at the interface of adjoining triple helical protomers. Peroxidasin, a heme peroxidase embedded in the basement membrane, produces hypohalous acid intermediates that oxidize methionine, forming the sulfilimine cross-link. We explored whether the sulfilimine cross-link is a fundamental requirement in the genesis and evolution of epithelial tissues by determining its occurrence and evolutionary origin in Eumetazoa and its essentiality in zebrafish development; 31 species, spanning 11 major phyla, were investigated for the occurrence of the sulfilimine cross-link by electrophoresis, MS, and multiple sequence alignment of de novo transcriptome and available genomic data for collagen IV and peroxidasin. The results show that the cross-link is conserved throughout Eumetazoa and arose at the divergence of Porifera and Cnidaria over 500 Mya. Also, peroxidasin, the enzyme that forms the bond, is evolutionarily conserved throughout Metazoa. Morpholino knockdown of peroxidasin in zebrafish revealed that the cross-link is essential for organogenesis. Collectively, our findings establish that the triad-a collagen IV scaffold with sulfilimine cross-links, peroxidasin, and hypohalous acids-is a primordial innovation of the ECM essential for organogenesis and tissue evolution.

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Discarded human kidneys as a source of ECM scaffold for kidney regeneration technologies

Cited by 174 publications

References 39 publications

Dual-Purpose Bioreactors to Monitor Noninvasive Physical and Biochemical Markers of Kidney and Liver Scaffold Recellularization

Dual-Purpose Bioreactors to Monitor Noninvasive Physical and Biochemical Markers of Kidney and Liver Scaffold Recellularization

Recellularization of Well-Preserved Acellular Kidney Scaffold Using Embryonic Stem Cells

A unique covalent bond in basement membrane is a primordial innovation for tissue evolution

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