A Bioartificial Renal Tubule Device Embedding Human Renal Stem/Progenitor Cells

We present a bio-inspired renal microdevice that resembles the in vivo structure of a kidney proximal tubule. For the first time, a population of tubular adult renal stem/progenitor cells (ARPCs) was embedded into a microsystem to create a bioengineered renal tubule. These cells have both multipotent differentiation abilities and an extraordinary capacity for injured renal cell regeneration. Therefore, ARPCs may be considered a promising tool for promoting regenerative processes in the kidney to treat acute and chronic renal injury. Here ARPCs were grown to confluence and exposed to a laminar fluid shear stress into the chip, in order to induce a functional cell polarization. Exposing ARPCs to fluid shear stress in the chip led the aquaporin-2 transporter to localize at their apical region and the Na+K+ATPase pump at their basolateral portion, in contrast to statically cultured ARPCs. A recovery of urea and creatinine of (20±5)% and (13±5)%, respectively, was obtained by the device. The microengineered biochip here-proposed might be an innovative “lab-on-a-chip” platform to investigate in vitro ARPCs behaviour or to test drugs for therapeutic and toxicological responses.

[1]  M. Carini,et al.  Isolation and characterization of multipotent progenitor cells from the Bowman's capsule of adult human kidneys. , 2006, Journal of the American Society of Nephrology : JASN.

[2]  Yoshinobu Sato,et al.  Evaluation of long-term transport ability of a bioartificial renal tubule device using LLC-PK1 cells. , 2004, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[3]  S. Sell Adult stem cell plasticity , 2007, Stem Cell Reviews.

[4]  Laurent Griscom,et al.  Development of a Renal Microchip for In Vitro Distal Tubule Models , 2007, Biotechnology progress.

[5]  John Greenman,et al.  Development of microfluidic devices for biomedical and clinical application , 2011 .

[6]  Hanry Yu,et al.  Stem cells in microfluidics , 2009, Biotechnology progress.

[7]  Irving L Weissman,et al.  Plasticity of Adult Stem Cells , 2004, Cell.

[8]  H D Humes,et al.  Tissue engineering of a bioartificial renal tubule assist device: in vitro transport and metabolic characteristics. , 1999, Kidney international.

[9]  F. Schena,et al.  TLR2 plays a role in the activation of human resident renal stem/progenitor cells , 2010, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[10]  F. Schena,et al.  Human renal stem/progenitor cells repair tubular epithelial cell injury through TLR2-driven inhibin-A and microvesicle-shuttled decorin. , 2013, Kidney international.

[11]  Yi Duan,et al.  Shear-induced reorganization of renal proximal tubule cell actin cytoskeleton and apical junctional complexes , 2008, Proceedings of the National Academy of Sciences.

[12]  F. Terzi,et al.  Mechanical strains induced by tubular flow affect the phenotype of proximal tubular cells. , 2001, American journal of physiology. Renal physiology.

[13]  D. Beebe,et al.  Cell culture models in microfluidic systems. , 2008, Annual review of analytical chemistry.

[14]  M. Bowser,et al.  Size selective DNA transport through a nanoporous membrane in a PDMS microfluidic device. , 2012, The Analyst.

[16]  M. Rotondi,et al.  Regenerative potential of embryonic renal multipotent progenitors in acute renal failure. , 2007, Journal of the American Society of Nephrology : JASN.

[17]  B. Mayer,et al.  The surface properties of nanocrystalline diamond and nanoparticulate diamond powder and their suitability as cell growth support surfaces. , 2008, Biomaterials.

[18]  F. Schena,et al.  AQP5 Is Expressed In Type-B Intercalated Cells in the Collecting Duct System of the Rat, Mouse and Human Kidney , 2011, Cellular Physiology and Biochemistry.

[19]  D. Ingber,et al.  Reconstituting Organ-Level Lung Functions on a Chip , 2010, Science.

[20]  Eli J. Weinberg,et al.  In vitro analysis of a hepatic device with intrinsic microvascular-based channels , 2008, Biomedical microdevices.

[21]  R. Zager,et al.  HK-2: an immortalized proximal tubule epithelial cell line from normal adult human kidney. , 1994, Kidney international.

[22]  N. Jeon,et al.  Microfluidic culture platform for neuroscience research , 2006, Nature Protocols.

[23]  L. Gesualdo,et al.  BMP-2 induces a profibrotic phenotype in adult renal progenitor cells through Nox4 activation. , 2012, American journal of physiology. Renal physiology.

[24]  H. Humes,et al.  Stem Cell Approaches for the Treatment of Renal Failure , 2005, Pharmacological Reviews.

[25]  Shuichi Takayama,et al.  Computer-controlled microcirculatory support system for endothelial cell culture and shearing. , 2005, Analytical chemistry.

[26]  J. Vacanti,et al.  Endothelialized Networks with a Vascular Geometry in Microfabricated Poly(dimethyl siloxane) , 2004 .

[27]  G. Camussi,et al.  Contribution of stem cells to kidney repair. , 2009, Current stem cell research & therapy.

[28]  T. Groth,et al.  Wettability of substrata controls cell-substrate and cell-cell adhesions. , 2007, Biochimica et biophysica acta.

[29]  Uwe Marx,et al.  Design and prototyping of a chip-based multi-micro-organoid culture system for substance testing, predictive to human (substance) exposure. , 2010, Journal of biotechnology.

[30]  P. Romagnani,et al.  Stem-cell approaches for kidney repair: choosing the right cells. , 2008, Trends in molecular medicine.

[31]  G. Whitesides The origins and the future of microfluidics , 2006, Nature.

[32]  M. Carini,et al.  Characterization of Renal Progenitors Committed Toward Tubular Lineage and Their Regenerative Potential in Renal Tubular Injury , 2012, Stem cells.

[33]  M. Barac-nieto,et al.  The relationship between renal metabolism and proximal tubule transport during ontogeny , 1988, Pediatric Nephrology.

[34]  Xin Zhang,et al.  The use of controlled surface topography and flow-induced shear stress to influence renal epithelial cell function. , 2012, Integrative biology : quantitative biosciences from nano to macro.

[35]  Shuichi Takayama,et al.  Leakage-free bonding of porous membranes into layered microfluidic array systems. , 2007, Analytical chemistry.

[36]  K. Suh,et al.  A multi-layer microfluidic device for efficient culture and analysis of renal tubular cells. , 2010, Lab on a chip.

[37]  G. Whitesides,et al.  Soft lithography in biology and biochemistry. , 2001, Annual review of biomedical engineering.

[38]  Kahp Yang Suh,et al.  Cell research with physically modified microfluidic channels: a review. , 2008, Lab on a chip.

[39]  J. Zahn,et al.  Glucose recovery in a microfluidic microdialysis biochip , 2005 .

[40]  G. Camussi,et al.  Isolation of renal progenitor cells from adult human kidney. , 2005, The American journal of pathology.

[41]  Paul Jennings,et al.  hTERT alone immortalizes epithelial cells of renal proximal tubules without changing their functional characteristics. , 2008, American journal of physiology. Renal physiology.

[42]  Norbert Lameire,et al.  Complications of dialysis , 2000 .

[43]  Kyung-Jin Jang,et al.  Fluid-shear-stress-induced translocation of aquaporin-2 and reorganization of actin cytoskeleton in renal tubular epithelial cells. , 2011, Integrative biology : quantitative biosciences from nano to macro.

[44]  T. Yokoo,et al.  Stem cells for kidney repair: useful tool for acute renal failure? , 2008, Kidney international.

[45]  Jong Hwan Sung,et al.  Prevention of air bubble formation in a microfluidic perfusion cell culture system using a microscale bubble trap , 2009, Biomedical microdevices.

[46]  Y Hirasawa [Complications of dialysis]. , 1995, Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine.

[47]  Felix Koberling,et al.  Precise measurement of diffusion by multi-color dual-focus fluorescence correlation spectroscopy , 2008 .

[48]  T. Terachi,et al.  Development of bioartificial renal tubule devices with lifespan-extended human renal proximal tubular epithelial cells. , 2011, Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association.

[49]  F. Smedts,et al.  The use of fibrous, supramolecular membranes and human tubular cells for renal epithelial tissue engineering: towards a suitable membrane for a bioartificial kidney. , 2010, Macromolecular bioscience.

[50]  Mandy B. Esch,et al.  Characterization of a gastrointestinal tract microscale cell culture analog used to predict drug toxicity , 2009, Biotechnology and bioengineering.

[51]  Niraj K Inamdar,et al.  Microfluidic cell culture models for tissue engineering. , 2011, Current opinion in biotechnology.

[52]  A. Berg,et al.  Organs-on-chips: breaking the in vitro impasse. , 2012, Integrative biology : quantitative biosciences from nano to macro.

[53]  K. Tiranathanagul,et al.  Bioartificial kidney in the treatment of acute renal failure associated with sepsis (Review Article) , 2006, Nephrology.

[54]  S. Quake,et al.  Microfluidics: Fluid physics at the nanoliter scale , 2005 .

[55]  Z. Gugala,et al.  Protein adsorption, attachment, growth and activity of primary rat osteoblasts on polylactide membranes with defined surface characteristics. , 2004, Biomaterials.

[56]  D. Ingber,et al.  Human kidney proximal tubule-on-a-chip for drug transport and nephrotoxicity assessment. , 2013, Integrative biology : quantitative biosciences from nano to macro.

[57]  Donald E Ingber,et al.  Microengineered physiological biomimicry: organs-on-chips. , 2012, Lab on a chip.