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Potency of Human Urine-Derived Stem Cells for Renal Lineage Differentiation

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Tissue Engineering and Regenerative Medicine Aims and scope

Abstract

Kidney is one of the most difficult organs for regeneration. Several attempts have been performed to regenerate renal tissue using stem cells, the results were not satisfactory. Urine is major product of kidney and contains cells from renal components. Moreover, urine-derived stem cells (USCs) can be easily obtained without any health risks throughout a patient’s entire life. Here, we evaluated the utility of USCs for renal tissue regeneration. In this study, the ability of USCs to differentiate into renal lineage cells was compared with that of adipose tissue-derived stem cells (ADSCs) and amniotic fluid-derived stem cells (AFSCs), with respect to surface antigen expression, morphology, immunocytochemistry, renal lineage gene expression, secreted factors, immunomodulatory marker expression, in vivo safety, and renal differentiation potency. Undifferentiated USCs were positive for CD44 and CD73, negative for CD34 and CD45, and formed aggregates after 3 weeks of renal differentiation. Undifferentiated USCs showed high SSEA4 expression, while renal-differentiated cells expressed PAX2, WT1, and CADHERIN 6. In the stem/renal lineage-associated gene analysis, OCT4, SSEA4, and CD117 were significantly downregulated over time, while PAX2, LIM1, PDGFRA, E-CADHERIN, CD24, ACTB, AQP1, OCLN, and NPHS1 were gradually upregulated. In the in vivo safety evaluation, renal-differentiated USCs did not show abnormal histology. These findings demonstrated that USCs have a similar MSC potency, renal lineage-differentiation ability, immunomodulatory effects, and in vivo safety as ADSCs and AFSCs, and showed higher levels of growth factor secretion for paracrine effects. Therefore, urine and USCs can be one of good cell sources for kidney regeneration.

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References

  1. Flaquer M, Romagnani P, Cruzado JM. Growth factors and renal regeneration. Nefrologia. 2010;30:385–93.

    CAS  PubMed  Google Scholar 

  2. Yokote S, Yokoo T. Organogenesis for kidney regeneration. Curr Opin Organ Transplant. 2013;18:186–90.

    Article  CAS  PubMed  Google Scholar 

  3. Hauser PV, De Fazio R, Bruno S, Sdei S, Grange C, Bussolati B, et al. Stem cells derived from human amniotic fluid contribute to acute kidney injury recovery. Am J Pathol. 2010;177:2011–21.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Breymann C, Schmidt D, Hoerstrup SP. Umbilical cord cells as a source of cardiovascular tissue engineering. Stem Cell Rev. 2006;2:87–92.

    Article  PubMed  Google Scholar 

  5. Graziano A, d’Aquino R, Laino G, Papaccio G. Dental pulp stem cells: a promising tool for bone regeneration. Stem Cell Rev. 2008;4:21–6.

    Article  PubMed  Google Scholar 

  6. Murohara T, Shintani S, Kondo K. Autologous adipose-derived regenerative cells for therapeutic angiogenesis. Curr Pharm Des. 2009;15:2784–90.

    Article  CAS  PubMed  Google Scholar 

  7. Chun SY, Kim HT, Kwon SY, Kim J, Kim BS, Yoo ES, et al. The efficacy and safety of collagen-I and hypoxic conditions in urine-derived stem cell ex vivo culture. Tissue Eng Regen Med. 2016;13:403–15.

    Article  CAS  Google Scholar 

  8. Biazar E. Use of umbilical cord and cord blood-derived stem cells for tissue repair and regeneration. Expert Opin Biol Ther. 2014;14:301–10.

    Article  CAS  PubMed  Google Scholar 

  9. Gronthos S, Mankani M, Brahim J, Robey PG, Shi S. Postnatal human dental pulp stem cells (DPSCs) in vitro and in vivo. Proc Natl Acad Sci U S A. 2000;97:13625–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Zhang Y, McNeill E, Tian H, Soker S, Andersson KE, Yoo JJ, et al. Urine derived cells are a potential source for urological tissue reconstruction. J Urol. 2008;180:2226–33.

    Article  CAS  PubMed  Google Scholar 

  11. Chun SY, Kim HT, Lee JS, Kim MJ, Kim BS, Kim BW, et al. Characterization of urine-derived cells from upper urinary tract in patients with bladder cancer. Urology. 2012;79:1181.e1–7.

    Article  Google Scholar 

  12. Tögel F, Hu Z, Weiss K, Isaac J, Lange C, Westenfelder C. Administered mesenchymal stem cells protect against ischemic acute renal failure through differentiation-independent mechanisms. Am J Physiol Renal Physiol. 2005;289:F31–42.

    Article  PubMed  Google Scholar 

  13. Bi B, Schmitt R, Israilova M, Nishio H, Cantley LG. Stromal cells protect against acute tubular injury via an endocrine effect. J Am Soc Nephrol. 2007;18:2486–96.

    Article  PubMed  Google Scholar 

  14. Caplan AI, Dennis JE. Mesenchymal stem cells as trophic mediators. J Cell Biochem. 2006;98:1076–84.

    Article  CAS  PubMed  Google Scholar 

  15. Lv FJ, Tuan RS, Cheung KM, Leung VY. Concise review: the surface markers and identity of human mesenchymal stem cells. Stem Cells. 2014;32:1408–19.

    Article  CAS  PubMed  Google Scholar 

  16. Williams K, Motiani K, Giridhar PV, Kasper S. CD44 integrates signaling in normal stem cell, cancer stem cell and (pre)metastatic niches. Exp Biol Med (Maywood). 2013;238:324–38.

    Article  CAS  Google Scholar 

  17. Tögel F, Isaac J, Hu Z, Weiss K, Westenfelder C. Renal SDF-1 signals mobilization and homing of CXCR4-positive cells to the kidney after ischemic injury. Kidney Int. 2005;67:1772–84.

    Article  PubMed  Google Scholar 

  18. Herrera MB, Bussolati B, Bruno S, Morando L, Mauriello-Romanazzi G, Sanavio F, et al. Exogenous mesenchymal stem cells localize to the kidney by means of CD44 following acute tubular injury. Kidney Int. 2007;72:430–41.

    Article  CAS  PubMed  Google Scholar 

  19. Hunsucker SA, Mitchell BS, Spychala J. The 5′-nucleotidases as regulators of nucleotide and drug metabolism. Pharmacol Ther. 2005;107:1–30.

    Article  CAS  PubMed  Google Scholar 

  20. Barker TH, Hagood JS. Getting a grip on Thy-1 signaling. Biochim Biophys Acta. 2009;1793:921–3.

    Article  CAS  PubMed  Google Scholar 

  21. Sidney LE, Branch MJ, Dunphy SE, Dua HS, Hopkinson A. Concise review: evidence for CD34 as a common marker for diverse progenitors. Stem Cells. 2014;32:1380–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Hermiston ML, Xu Z, Weiss A. CD45: a critical regulator of signaling thresholds in immune cells. Annu Rev Immunol. 2003;21:107–37.

    Article  CAS  PubMed  Google Scholar 

  23. Kim D, Dressler GR. Nephrogenic factors promote differentiation of mouse embryonic stem cells into renal epithelia. J Am Soc Nephrol. 2005;16:3527–34.

    Article  CAS  PubMed  Google Scholar 

  24. Hosono S, Luo X, Hyink DP, Schnapp LM, Wilson PD, Burrow CR, et al. WT1 expression induces features of renal epithelial differentiation in mesenchymal fibroblasts. Oncogene. 1999;18:417–27.

    Article  CAS  PubMed  Google Scholar 

  25. Palmer RE, Kotsianti A, Cadman B, Boyd T, Gerald W, Haber DA. WT1 regulates the expression of the major glomerular podocyte membrane protein Podocalyxin. Curr Biol. 2001;11:1805–9.

    Article  CAS  PubMed  Google Scholar 

  26. Nishikawa M, Yanagawa N, Kojima N, Yuri S, Hauser PV, Jo OD, et al. Stepwise renal lineage differentiation of mouse embryonic stem cells tracing in vivo development. Biochem Biophys Res Commun. 2012;417:897–902.

    Article  CAS  PubMed  Google Scholar 

  27. Tsuji K, Kitamura S. Trophic factors from tissue stem cells for renal regeneration. Stem Cells Int. 2015;2015:537204.

    Article  PubMed  PubMed Central  Google Scholar 

  28. Chou YH, Pan SY, Yang CH, Lin SL. Stem cells and kidney regeneration. J Formos Med Assoc. 2014;113:201–9.

    Article  CAS  PubMed  Google Scholar 

  29. L Ramos T, Sánchez-Abarca LI, Muntión S, Preciado S, Puig N, López-Ruano G, et al. MSC surface markers (CD44, CD73, and CD90) can identify human MSC-derived extracellular vesicles by conventional flow cytometry. Cell Commun Signal. 2016;14:2.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Schrijvers BF, Flyvbjerg A, De Vriese AS. The role of vascular endothelial growth factor (VEGF) in renal pathophysiology. Kidney Int. 2004;65:2003–17.

    Article  CAS  PubMed  Google Scholar 

  31. Karavanova ID, Dove LF, Resau JH, Perantoni AO. Conditioned medium from a rat ureteric bud cell line in combination with bFGF induces complete differentiation of isolated metanephric mesenchyme. Development. 1996;122:4159–67.

    CAS  PubMed  Google Scholar 

  32. Colleoni S, Bottani E, Tessaro I, Mari G, Merlo B, Romagnoli N, et al. Isolation, growth and differentiation of equine mesenchymal stem cells: effect of donor, source, amount of tissue and supplementation with basic fibroblast growth factor. Vet Res Commun. 2009;33:811–21.

    Article  PubMed  Google Scholar 

  33. Kunz D, Walker G, Eberhardt W, Messmer UK, Huwiler A, Pfeilschifter J. Platelet-derived growth factor and fibroblast growth factor differentially regulate interleukin 1beta- and cAMP-induced nitric oxide synthase expression in rat renal mesangial cells. J Clin Invest. 1997;100:2800–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Charron D. Allogenicity & immunogenicity in regenerative stem cell therapy. Indian J Med Res. 2013;138:749–54.

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This research was supported by Biomedical Research Institute grant, Kyungpook National University Hospital (2014).

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Author notes

  1. Jae Young Choi and So Young Chun have contributed equally to this work.

Authors and Affiliations

  1. Department of Urology, College of Medicine, Yeungnam University, 170 Hyunchung-ro, Nam-gu, Daegu, 42415, Korea

    Jae Young Choi & Phil Hyun Song

  2. Biomedical Research Institute, Kyungpook National University Hospital, 130 Dongdeok-ro, Jung-gu, Daegu, 41944, Korea

    So Young Chun

  3. Department of Urology, School of Medicine, Kyungpook National University, 130 Dongdeok-ro, Jung-gu, Daegu, 41944, Korea

    Yun-Sok Ha, Hyun Tae Kim, Eun Sang Yoo, Bum Soo Kim & Tae Gyun Kwon

  4. Department of Laboratory Animal Research Support Team, Yeungnam University Medical Center, 170 Hyunchung-ro, Nam-gu, Daegu, 42415, Korea

    Dae Hwan Kim

  5. Department of Pathology, Central Hospital, 480 Munsu-ro, Nam-gu, Ulsan, 44667, Korea

    Jeongshik Kim

  6. Department of Urology, Kyungpook National University Chilgok Hospital, 807 Hogukro, Buk-gu, Daegu, 41404, Korea

    Tae Gyun Kwon

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  1. Jae Young Choi
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Correspondence to Bum Soo Kim or Tae Gyun Kwon.

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Ethical statement

All procedures involving animals were performed in accordance with the ethical standards of our institution and following an animal protocol approved by the Yeungnam University Institutional Animal Care and Use Committee (YUMC-AEC2016-003).

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Choi, J.Y., Chun, S.Y., Ha, YS. et al. Potency of Human Urine-Derived Stem Cells for Renal Lineage Differentiation. Tissue Eng Regen Med 14, 775–785 (2017). https://doi.org/10.1007/s13770-017-0081-y

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  • DOI: https://doi.org/10.1007/s13770-017-0081-y

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