Skip to main content

Advertisement

Log in

Biosynthetic Tubules: Multiscale Approaches to Kidney Engineering

  • Tissue Engineering and Regeneration (J Wertheim, Section Editor)
  • Published:
Current Transplantation Reports Aims and scope Submit manuscript

Abstract

Purpose of Review

There are over 700,000 cases of end-stage renal disease in the USA, resulting in more deaths per year than prostate or breast cancer. Many researchers have proposed the generation of in vitro kidney models or implantable therapeutic replacements using biomedical engineering strategies. Because the functional unit of the kidney—the nephron—is based on tubule structures, the formation of biosynthetic tubules is at the foundation of creating models or devices to recapitulate the kidney.

Recent Findings

Recent approaches to engineering kidney tubules involve both bioengineering (perfusable microfluidic proximal tubule chips, biomaterials as scaffolds to support engineered kidney tissue units) and biological (cellular aggregates differentiated from stem cells, self-assembled kidney tubule-like structures from epithelial cells) to model kidney cells and tissues.

Summary

In this review, we detail advances in the two main approaches—bioengineering and biological—for the generation of biosynthetic kidney tubules. Although many steps have been taken towards recapitulation of kidney function, no approach has been able to recreate multiple segments of the nephron in a functional scheme.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Hill NR, Fatoba ST, Oke JL, Hirst JA, O’Callaghan CA, Lasserson DS, et al. Global prevalence of chronic kidney disease - a systematic review and meta-analysis. PLoS One. 2016;11:e0158765.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. United States Renal Data System. 2018 USRDS annual data report: epidemiology of kidney disease in the United States. National institutes of health, national institute of diabetes and digestive and kidney diseases, Bethesda, MD; 2018.

  3. UNOS (2019) Transplant trends. https://unos.org/data/transplant-trends/. Accessed 3 Dec 2018.

  4. Hart A, Smith JM, Skeans MA, et al. OPTN/SRTR 2016 annual data report: kidney. Am J Transplant. 2018;18(Suppl 1):18–113.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Catapano G, Buscaroli A. Renal function replacement by hemodialysis: forty-year anniversary and a glimpse into the future at hand. Int J Artif Organs. 2017;40:313–22.

    Article  PubMed  Google Scholar 

  6. Sladen RN. In: Miller's anesth. New York: Elsvier. Ren. Physiol; 2012. p. 441–476.

  7. Gounden V, Jialal I. Renal function tests. StatPearls Publishing. 2019.

  8. Weinbaum S, Duan Y, Satlin LM, Wang T, Weinstein AM. Mechanotransduction in the renal tubule. Am J Physiol Physiol. 2010;299:F1220–36.

    Article  CAS  Google Scholar 

  9. Carrisoza-Gaytan R, Liu Y, Flores D, Else C, Lee HG, Rhodes G, et al. Effects of biomechanical forces on signaling in the cortical collecting duct (CCD). Am J Physiol Physiol. 2014;307:F195–204.

    Article  CAS  Google Scholar 

  10. Burg MB. Introduction: background and development of microperfusion technique. Kidney Int. 1982;22:417–424. https://doi.org/10.1038/ki.1982.194.

  11. Nagami GT. Ammonia production and secretion by isolated perfused proximal tubule segments. Miner Electrolyte Metab. 1990;16:259–63.

    CAS  PubMed  Google Scholar 

  12. Schafer JA, Barfuss DW. The study of pars recta function by the perfusion of isolated tubule segments. Kidney Int. 1982;22:434–48.

    Article  CAS  PubMed  Google Scholar 

  13. Weber HM, Tsurkan MV, Magno V, Freudenberg U, Werner C. Heparin-based hydrogels induce human renal tubulogenesis in vitro. Acta Biomater. 2017;57:59–69.

    Article  CAS  PubMed  Google Scholar 

  14. Subramanian B, Kaya O, Pollak MR, Yao G, Zhou J. Guided tissue organization and disease modeling in a kidney tubule array. Biomaterials. 2018;183:295–305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Batchelder CA, Martinez ML, Tarantal AF. Natural scaffolds for renal differentiation of human embryonic stem cells for kidney tissue engineering. PLoS One. 2015;10:e0143849.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. • Yamaguchi S, Morizane R, Homma K, et al. Generation of kidney tubular organoids from human pluripotent stem cells. Sci Rep. 2016;6:38353. This study describes methods developed for the generation of kidney tubular organoids from iPS cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. •• Takasato M, Er PX, Chiu HS, Maier B, Baillie GJ, Ferguson C, et al. Kidney organoids from human iPS cells contain multiple lineages and model human nephrogenesis. Nature. 2015;526:564–8. This study provides a thorough description of the methods developed for the generation of multilineage kidney organoids from iPS cells.

    Article  CAS  PubMed  Google Scholar 

  18. King SM, Higgins JW, Nino CR, et al. 3D proximal tubule tissues recapitulate key aspects of renal physiology to enable nephrotoxicity testing. Front Physiol. 2017;8:123.

    Article  PubMed  PubMed Central  Google Scholar 

  19. Weber EJ, Chapron A, Chapron BD, Voellinger JL, Lidberg KA, Yeung CK, et al. Development of a microphysiological model of human kidney proximal tubule function. Kidney Int. 2016;90:627–37.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Vedula EM, Alonso JL, Arnaout MA, Charest JL. A microfluidic renal proximal tubule with active reabsorptive function. PLoS One. 2017;12:e0184330.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. • Homan KA, Kolesky DB, Skylar-Scott MA, Herrmann J, Obuobi H, Moisan A, et al. Bioprinting of 3D hips. Sci Rep. 2016;6:34845. This work demonstrates the potential for 3D bioprinting to be used for the creation of tissue-on-chip models of organ function.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. •• Jansen J, De Napoli IE, Fedecostante M, et al. Human proximal tubule epithelial cells cultured on hollow fibers: living membranes that actively transport organic cations. Sci Rep. 2015;5:16702. This system demonstrates a scalable approach to generation of multiplexed kidney tubule-like structures that are able to perform some of the key functions of native proximal tubule.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. • Secker PF, Luks L, Schlichenmaier N, Dietrich DR. RPTEC/TERT1 cells form highly differentiated tubules when cultured in a 3D matrix. ALTEX. 2018;35:223–34. This study represents a key effort in the self-assembled approach to the production of polarized proximal tubules that demonstrate key functional markers.

    Article  PubMed  Google Scholar 

  24. Benedetti V, Brizi V, Guida P, Tomasoni S, Ciampi O, Angeli E, et al. Engineered kidney tubules for modeling patient-specific diseases and drug discovery. EBioMedicine. 2018;33:253–68.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Abolbashari M, Agcaoili SM, Lee M-K, Ko IK, Aboushwareb T, Jackson JD, et al. Repopulation of porcine kidney scaffold using porcine primary renal cells. Acta Biomater. 2016;29:52–61.

    Article  CAS  PubMed  Google Scholar 

  26. Vormann MK, Gijzen L, Hutter S, Boot L, Nicolas A, van den Heuvel A, et al. Nephrotoxicity and kidney transport assessment on 3D perfused proximal tubules. AAPS J. 2018;20:90.

    Article  CAS  PubMed  Google Scholar 

  27. Bajaj P, Rodrigues AD, Steppan CM, Engle SJ, Mathialagan S, Schroeter T. Human pluripotent stem cell-derived kidney model for nephrotoxicity studies. Drug Metab Dispos. 2018;46:1703–11.

    Article  CAS  PubMed  Google Scholar 

  28. Jansen J, Fedecostante M, Wilmer MJ, Peters JG, Kreuser UM, van den Broek PH, et al. Bioengineered kidney tubules efficiently excrete uremic toxins. Sci Rep. 2016;6:26715.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Suter-Dick L, Mauch L, Ramp D, Caj M, Vormann MK, Hutter S, et al. Combining extracellular miRNA determination with microfluidic 3D cell cultures for the assessment of nephrotoxicity: a proof of concept study. AAPS J. 2018;20:86.

    Article  CAS  PubMed  Google Scholar 

  30. Ardeshirylajimi A, Vakilian S, Salehi M, Mossahebi-Mohammadi M. Renal differentiation of mesenchymal stem cells seeded on nanofibrous scaffolds improved by human renal tubular cell lines-conditioned medium. ASAIO J. 2017;63:356–63.

    Article  PubMed  Google Scholar 

  31. • Wilmer MJ, Ng CP, Lanz HL, Vulto P, Suter-Dick L, Masereeuw R. Kidney-on-a-chip technology for drug-induced nephrotoxicity screening. Trends Biotechnol. 2016;34:156–70. This study demonstrates the use of a kidney-on-a-chip model for screening of drug-induced nephrotoxicity, which would enhance in vitro drug screenings capabilities and thus improve clinical trial outcomes.

    Article  CAS  PubMed  Google Scholar 

  32. Shanti A, Teo J, Stefanini C. In vitro immune organs-on-chip for drug development: a review. Pharmaceutics. 2018;10:278.

    Article  PubMed Central  Google Scholar 

  33. Nieskens TTG, Wilmer MJ. Kidney-on-a-chip technology for renal proximal tubule tissue reconstruction. Eur J Pharmacol. 2016;790:46–56.

    Article  CAS  PubMed  Google Scholar 

  34. Peattie RA, Fisher RJ. Perfusion effects and hydrodynamics. Adv Biochem Eng Biotechnol. 2007;103:75–156.

    PubMed  Google Scholar 

  35. Yonemura S. Differential sensitivity of epithelial cells to extracellular matrix in polarity establishment. PLoS One. 2014;9:e112922.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ruhfus B, Bauernschmitt HG, Kinne RK. Properties of a polarized primary culture from rat renal inner medullary collecting duct (IMCD) cells. In Vitro Cell Dev Biol Anim. 1998;34:227–31.

    Article  CAS  PubMed  Google Scholar 

  37. Minuth WW, Schumacher K, Strehl R. Renal epithelia in long term gradient culture for biomaterial testing and tissue engineering. Biomed Mater Eng. 2005;15:51–63.

    PubMed  Google Scholar 

  38. Fukuda Y, Kaishima M, Ohnishi T, Tohyama K, Chisaki I, Nakayama Y, et al. Fluid shear stress stimulates MATE2-K expression via Nrf2 pathway activation. Biochem Biophys Res Commun. 2017;484:358–64.

    Article  CAS  PubMed  Google Scholar 

  39. Montesano R, Schaller G, Orci L. Induction of epithelial tubular morphogenesis in vitro by fibroblast-derived soluble factors. Cell. 1991;66:697–711.

    Article  CAS  PubMed  Google Scholar 

  40. Maeshima A, Zhang YQ, Furukawa M, Naruse T, Kojima I. Hepatocyte growth factor induces branching tubulogenesis in MDCK cells by modulating the activin-follistatin system. Kidney Int. 2000;58:1511–22.

    Article  CAS  PubMed  Google Scholar 

  41. Hirashima T, Hoshuyama M, Adachi T. In vitro tubulogenesis of Madin–Darby canine kidney (MDCK) spheroids occurs depending on constituent cell number and scaffold gel concentration. J Theor Biol. 2017;435:110–5.

    Article  CAS  PubMed  Google Scholar 

  42. Caralt M, Uzarski JS, Iacob S, Obergfell KP, Berg N, Bijonowski BM, et al. Optimization and critical evaluation of decellularization strategies to develop renal extracellular matrix scaffolds as biological templates for organ engineering and transplantation. Am J Transplant. 2015;15:64–75.

    Article  CAS  PubMed  Google Scholar 

  43. Love HD, Ao M, Jorgensen S, et al (2018) Substrate elasticity governs differentiation of renal tubule cells in prolonged culture. Tissue Eng Part A. https://doi.org/10.1089/ten.tea.2018.0182.

  44. Takasato M, Little MH. Making a kidney organoid using the directed differentiation of human pluripotent stem cells. In: Methods Mol Biol. 2017;195–206. https://doi.org/10.1007/978-1-4939-6949-4_14.

  45. Gozalpour E, Fenner KS. Current State of in vitro cell-based renal models. Curr Drug Metab. 2018;19:310–26.

    Article  CAS  PubMed  Google Scholar 

  46. Takasato M, Er PX, Chiu HS, et al. Generation of kidney organoids from human pluripotent stem cells. Protoc Exch. 2015;11:1681–92.

    Article  CAS  Google Scholar 

Download references

Acknowledgments

We thank the members and administrators of the (Re) Building a Kidney consortium.

Funding

We thank the NIH (R24DK106743) for financial support.

Author information

Authors and Affiliations

Authors

Ethics declarations

Conflict of Interest

The authors declare that they have no conflict of interest.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Additional information

Publisher’s Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

This article is part of the Topical Collection on Tissue Engineering and Regeneration

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Szymkowiak, S., Kaplan, D. Biosynthetic Tubules: Multiscale Approaches to Kidney Engineering. Curr Transpl Rep 6, 214–220 (2019). https://doi.org/10.1007/s40472-019-00248-z

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40472-019-00248-z

Keywords

Navigation