Annals of Nephrology

ISSN: 2642-4827

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COMMENTARY | VOLUME 3 | ISSUE 1 OPEN ACCESS

Autologous Urine-derived Stem Cells for Kidney Tissue Repair

Deying Zhang, Geng Xing, Li Tao, Mengjia Gong, Wenjun Ma, Jiaqiang Chu, Dawei He, Guanghui Wei and Yuanyuan Zhang

  • Deying Zhang 1
  • Geng Xing 1
  • Mengjia Gong 1
  • Wenjun Ma 1
  • Jiaqiang Chu 1
  • Dawei He 1
  • Guanghui Wei 1
  • Yuanyuan Zhang 2*
  • Department of Urology, Children's Hospital of Chongqing Medical University, China
  • Institute for Regeneration Medicine, Wake Forest University, USA

Zhang D, Xing G, Tao L, et al. (2018) Autologous Urine-derived Stem Cells for Kidney Tissue Repair. Ann Nephrol 3(1):28-30.

Accepted: August 23, 2018 | Published Online: August 25, 2018

Autologous Urine-derived Stem Cells for Kidney Tissue Repair

Stem cell-based therapy offers an alternative treatment for chronic kidney diseases, including acute or chronic renal failure, diabetic nephropathy, polycystic kidney diseases and renal transplantation. Most studies have focused on endothelial progenitor cells or mesenchymal stem cells (MSCs), not embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs) [1] because the concern of teratoma formation or ethical issues hamper the further clinical application potential of ESCs or iPSCs. Available experimental evidences confirm that MSCs contribute to cellular repair and ameliorate renal injury in chronic renal failure via anti-inflammatory, anti-fibrotic, anti-apoptotic and pro-angiogenic potentials [2-4]. However, to obtain MSCs from bone marrow, fat, and other tissues, invasive tissue biopsies are usually required. In addition, stem cells often used in preclinical studies are isolated from healthy donors, not from patient tissues. For eventual clinical use, autologous stem cells would be the optimal cell source, to avoid immune rejection [5] and other adverse events associated with allogeneic or exogenous sources. Thus, autologous stem cells conveniently obtained from a non-invasive, safe, reproducible, and low-cost approach would be highly desirable as an alternative cell source for improve renal tissue regeneration for the patients with various kidney diseases.

Ideal cell candidate for cell therapy in the treatment of kidney dysfunction should be: i) The cells are easily accessible from a patient's own cells; ii) They could survive and exert the reparative function under diseases-stress after implanted; iii) They are able to potential in inhibiting inflammatory response, fibrosis and oxidative stress, and giving rise into podoctyes and renal tubule epithelial cells; iv) They are safe to use in vivo without any risk of oncogenicity. We were the first to discover a subpopulation of cells isolated from urine that possess biological characteristics of stem cells: Clonogenicity, cell growth patterns, expansion capacity, migration, cell surface marker expression profiles of mesenchymal stem cells, pro-angiogenic paracrine effects, immunomodulatory properties, easily-induced pluripotent stem (iPS) cells, and multipotent differentiation capacity [6,7]. We demonstrated that USCs originate from parietal epithelial cells in kidney glomeruli [8], because the USCs obtained from women receiving a sex-mismatched kidney transplant (male) contained the Y chromosome, expressed parietal epithelial cell markers (Pax2, Pax8, CD24, CD133 and claudin-1) [9,10] Importantly, USCs can differentiate into renal cells, such as podocytes and renal tubular epithelial cells besides giving rise to osteogenic, adipogenic chondrogenic, myogenic, and neurogenic cell lineages and endothelial cells in vitro, and formed relevant tissues in vivo [6,11,12]. USCs expressed podocyte markers (WT1, synaptopodin, podocalyxin and podocin) [11,13] after induction at a rate similar to that seen in parietal epithelial cells and podocytes that populate glomeruli. USCs displayed epithelial markers of renal tubular epithelial cells and tight junctions, and displayed barrier junctions after the induced medium. Furthermore, USCs secrete bioactive trophic factors in vitro; those factors significantly improved tissue regeneration via increasing implanted cell viability and recruited the resident stem cells participating in endogenous tissue regeneration in vivo [14].

Although there are several cell types in urine, our culture system can easily isolate stem cells from other somatic cells [15]. A single USC clone can generate large numbers of pure stem cells [6,7]. Cell viability is better protected [7,16] because isolation of USCs does not require tissue dissociation procedures (such as digestive enzymes). USCs possess potent proliferation capacity. Up to 75% of USCs collected from middle-aged donors expressed telomerase activity (USCs-TA+) and retained telomere length [17]. USCs-TA+ possessed higher proliferative capacities and were maintained for up to 67 population doublings after 16-20 passages, indicating that a single USC can generate up to 267 cells within 14 weeks [6]. After optimizing our methods, 100-140 USC clones/24 hr urine were consistently obtained from each individual [7]. Thus, a 24 hr urine sample can provide ample cells (> 100 × 106) in 3 weeks for the purposes of cell implantation. Importantly, although USCs do display telomerase activity, these cells do not form teratomas or tumors after subcutaneous implantation or under the renal capsule for up to 3 months, indicating they have high proliferation potential but are a safe source for cell therapy [2,17]. In short, our data suggest that USCs with potent regeneration capacity are an optimal cell source for cell-based therapy in the treatment of kidney diseases, compared to other adult stem cells.

USCs obtained from healthy human donors have been used for tissue regeneration in various in vivo models. We recently tested the protective effects of USCs on pancreatic islets, the myocardium, the renal glomerulus, and the bladder detrusor muscle in high fat diet/streptozotocin-induced Type 2 diabetic rat models. USCs significantly inhibited fibrosis and apoptosis of the myocardium, glomerulus, and detrusor, but did not decrease fasting blood glucose significantly, suggesting that USCs may be most useful in treating complications of diabetes [2]. Our most recent study showed that human USCs significantly improved renal function in a rat model of chronic renal insufficiency induced by gentamicin combined with renal ischemic insult, with a 50% decline in serum creatinine at 2 weeks post-cell injection (5 × 106 cells/kidney) maintained over 9 weeks, compared to controls. The implanted USCs were detected around the glomerulus and interstitial area. Numbers of macrophages and amount of collagen deposited significantly decreased in renal tissue (unpublished data). Furthermore, use of implanted USCs restored erectile function in a rodent model of diabetic erectile dysfunction [18], and improved urethral sphincter function in a rat model of vaginal distention injury [19]. Our procedures with USCs have been successfully repeated by other [4,12,20-32]. They used human USCs for kidney [4,12,33], bladder, [29] cardiomyotic tissue [2], corpora cavernosa [34], bone [26,35], lungs [31], skin [13], neurogenic [11] and other types of tissue regeneration [13,35]. Importantly, our more recent studies that up to 30% of USCs from the patients with chronic diseases (such as diabetic nephropathy) possess normal regenerative function in cell proliferation, differentiation, and paracrine factor section (unpublished data). Taken together, these data show that patients-sourced USCs have therapeutic effects on tissue regeneration, particularly for renal tissue repair. In addition, these cells could be useful in assessment of renal function, and in the diagnosis and prognosis of different types of renal disease and renal failures.

References


  1. Osafune K (2012) Ips cell technology-based research for the treatment of diabetic nephropathy. Semin Nephrol 32: 479-485.
  2. Dong X, Zhang T, Liu Q, et al. (2016) Beneficial effects of urine-derived stem cells on fibrosis and apoptosis of myocardial, glomerular and bladder cells. Mol Cell Endocrinol 427: 21-32.
  3. Griffin TP, Martin WP, Islam N, et al. (2016) The promise of mesenchymal stem cell therapy for diabetic kidney disease. Curr Diab Rep 16: 42.
  4. Jiang ZZ, Liu YM, Niu X, et al. (2016) Exosomes secreted by human urine-derived stem cells could prevent kidney complications from type I diabetes in rats. Stem Cell Res Ther 7: 24.
  5. Eliopoulos N, Stagg J, Lejeune L, et al. (2005) Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice. Blood 106: 4057-4065.
  6. Bharadwaj S, Liu G, Shi Y, et al. (2013) Multipotential differentiation of human urine-derived stem cells: Potential for therapeutic applications in urology. Stem Cells 31: 1840-1856.
  7. Lang R, Liu G, Shi Y, et al. (2013) Self-renewal and differentiation capacity of urine-derived stem cells after urine preservation for 24 hours. PLoS One 8: E53980.
  8. Wu RP, Liu G, Shi YA, et al. (2014) Human urine-derived stem cells originate from parietal stem cells. J Urol 191: e1-e958.
  9. Shankland SJ, Smeets B, Pippin JW, et al. (2014) The emergence of the glomerular parietal epithelial cell. Nat Rev Nephrol 10: 158-173.
  10. Kietzmann L, Guhr SS, Meyer TN, et al. (2015) MicroRNA-193a regulates the transdifferentiation of human parietal epithelial cells toward a podocyte phenotype. J Am Soc Nephrol 26: 1389-1401.
  11. Guan JJ, Niu X, Gong FX, et al. (2014) Biological characteristics of human-urine-derived stem cells: Potential for cell-based therapy in neurology. Tissue Eng Part A 20: 1794-1806.
  12. Lazzeri E, Ronconi E, Angelotti ML, et al. (2015) Human urine-derived renal progenitors for personalized modeling of genetic kidney disorders. J Am Soc Nephrol 26: 1961-1974.
  13. Fu Y, Guan J, Guo S, et al. (2014) Human urine-derived stem cells in combination with polycaprolactone/gelatin nanofibrous membranes enhance wound healing by promoting angiogenesis. J Transl Med 12: 274.
  14. Liu G, Pareta RA, Wu R, et al. (2015) Skeletal myogenic differentiation of urine-derived stem cells, angiogenesis and innervation using hydrogel loaded with growth factors for potential in treatment of urinary incontinence. J Urol 193: E74.
  15. Zhang Y, McNeill E, Tian H, et al. (2008) Urine derived cells are a potential source for urological tissue reconstruction. J Urol 180: 2226-2233.
  16. Bharadwaj S, Liu G, Shi Y, et al. (2011) Characterization of urine-derived stem cells obtained from upper urinary tract for use in cell-based urological tissue engineering. Tissue Eng Part A 17: 2123-2132.
  17. Shi YA, Liu GH, Bharadwaj S, et al. (2012) Urine derived stem cells with high telomerase activity for cell based therapy in urology. J Urol 187: e302.
  18. Ouyang B, Sun X, Han D, et al. (2014) Human urine-derived stem cells alone or genetically-modified with FGF2 Improve type 2 diabetic erectile dysfunction in a rat model. PLoS One 9: e92825.
  19. Tran CNT A, Balog B, Zhang Y, (2015) Paracrine effects of human urine-derived stem cells in treatment of female stress urinary incontinence in a rodent model. Tissue Eng Part A 21: S385.
  20. Chun SY, Kim HT, Lee JS, et al. (2012) Characterization of urine-derived cells from upper urinary tract in patients with bladder cancer. Urology 79: e1-e7.
  21. Zhou J, Wang X, Zhang S, et al. (2013) Generation and characterization of human cryptorchid-specific induced pluripotent stem cells from urine. Stem Cells Dev 22: 717-725.
  22. Afzal MZ, Strande JL (2015) Generation of induced pluripotent stem cells from muscular dystrophy patients: Efficient integration-free reprogramming of urine derived cells. J Vis Exp 2015: 52032.
  23. Gao P, Jiang D, Liu W, et al. (2016) Urine-derived Stem Cells, A New Source of Seed Cells for Tissue Engineering. Curr Stem Cell Res Ther 11: 547-553.
  24. Guan J, Zhang J, Guo S, et al. (2015) Human urine-derived stem cells can be induced into osteogenic lineage by silicate bioceramics via activation of the wnt/β-catenin signaling pathway. Biomaterials 55: 1-11.
  25. Guan J, Zhang J, Li H, et al. (2015) Human urine derived stem cells in combination with β-tcp can be applied for bone regeneration. PLoS One 10: e0125253.
  26. Guan J, Zhang J, Zhu Z, et al. (2015) Bone morphogenetic protein 2 gene transduction enhances the osteogenic potential of human urine-derived stem cells. Stem Cell Res Ther 6: 5.
  27. Jouni M, Si-Tayeb K, Es-Salah-Lamoureux Z, et al. (2015) Toward personalized medicine: Using cardiomyocytes differentiated from urine-derived pluripotent stem cells to recapitulate electrophysiological characteristics of type 2 long qt syndrome. J Am Heart Assoc 4: e002159.
  28. Kang HS, Choi SH, Kim BS, et al. (2015) Advanced properties of urine derived stem cells compared to adipose tissue derived stem cells in terms of cell proliferation, immune modulation and multi differentiation. J Korean Med Sci 30: 1764-1776.
  29. Lee JN, Chun SY, Lee HJ, et al. (2015) Human Urine-derived Stem Cells Seeded Surface Modified Composite Scaffold Grafts for Bladder Reconstruction in a Rat Model. J Korean Med Sci 30: 1754-1763.
  30. Nersesyan A, Kundi M, Fenech M, et al. (2014) Micronucleus assay with urine derived cells (UDC): A review of its application in human studies investigating genotoxin exposure and bladder cancer risk. Mutat Res Rev Mutat Res 762: 37-51.
  31. Wang C, Hei F, Ju Z, et al. (2016) Differentiation of urine-derived human induced pluripotent stem cells to alveolar type II epithelial cells. Cell Reprogram 18: 30-36.
  32. Zhang SZ, Li HF, Ma LX, et al. (2015) Urine-derived induced pluripotent stem cells as a modeling tool for paroxysmal kinesigenic dyskinesia. Biol Open 4: 1744-1752.
  33. Oliveira Arcolino F, Tort Piella A, Papadimitriou E, et al. (2015) Human urine as a noninvasive source of kidney cells. Stem Cells Int 2015: 362562.
  34. Liu G, Pareta RA, Wu R, et al. (2013) Skeletal myogenic differentiation of urine-derived stem cells and angiogenesis using microbeads loaded with growth factors. Biomaterials 34: 1311-1326.
  35. Qin H, Zhu C, An Z, et al. (2014) Silver nanoparticles promote osteogenic differentiation of human urine-derived stem cells at noncytotoxic concentrations. Int J Nanomedicine 9: 2469-2478.

References

  1. Osafune K (2012) Ips cell technology-based research for the treatment of diabetic nephropathy. Semin Nephrol 32: 479-485.
  2. Dong X, Zhang T, Liu Q, et al. (2016) Beneficial effects of urine-derived stem cells on fibrosis and apoptosis of myocardial, glomerular and bladder cells. Mol Cell Endocrinol 427: 21-32.
  3. Griffin TP, Martin WP, Islam N, et al. (2016) The promise of mesenchymal stem cell therapy for diabetic kidney disease. Curr Diab Rep 16: 42.
  4. Jiang ZZ, Liu YM, Niu X, et al. (2016) Exosomes secreted by human urine-derived stem cells could prevent kidney complications from type I diabetes in rats. Stem Cell Res Ther 7: 24.
  5. Eliopoulos N, Stagg J, Lejeune L, et al. (2005) Allogeneic marrow stromal cells are immune rejected by MHC class I- and class II-mismatched recipient mice. Blood 106: 4057-4065.
  6. Bharadwaj S, Liu G, Shi Y, et al. (2013) Multipotential differentiation of human urine-derived stem cells: Potential for therapeutic applications in urology. Stem Cells 31: 1840-1856.
  7. Lang R, Liu G, Shi Y, et al. (2013) Self-renewal and differentiation capacity of urine-derived stem cells after urine preservation for 24 hours. PLoS One 8: E53980.
  8. Wu RP, Liu G, Shi YA, et al. (2014) Human urine-derived stem cells originate from parietal stem cells. J Urol 191: e1-e958.
  9. Shankland SJ, Smeets B, Pippin JW, et al. (2014) The emergence of the glomerular parietal epithelial cell. Nat Rev Nephrol 10: 158-173.
  10. Kietzmann L, Guhr SS, Meyer TN, et al. (2015) MicroRNA-193a regulates the transdifferentiation of human parietal epithelial cells toward a podocyte phenotype. J Am Soc Nephrol 26: 1389-1401.
  11. Guan JJ, Niu X, Gong FX, et al. (2014) Biological characteristics of human-urine-derived stem cells: Potential for cell-based therapy in neurology. Tissue Eng Part A 20: 1794-1806.
  12. Lazzeri E, Ronconi E, Angelotti ML, et al. (2015) Human urine-derived renal progenitors for personalized modeling of genetic kidney disorders. J Am Soc Nephrol 26: 1961-1974.
  13. Fu Y, Guan J, Guo S, et al. (2014) Human urine-derived stem cells in combination with polycaprolactone/gelatin nanofibrous membranes enhance wound healing by promoting angiogenesis. J Transl Med 12: 274.
  14. Liu G, Pareta RA, Wu R, et al. (2015) Skeletal myogenic differentiation of urine-derived stem cells, angiogenesis and innervation using hydrogel loaded with growth factors for potential in treatment of urinary incontinence. J Urol 193: E74.
  15. Zhang Y, McNeill E, Tian H, et al. (2008) Urine derived cells are a potential source for urological tissue reconstruction. J Urol 180: 2226-2233.
  16. Bharadwaj S, Liu G, Shi Y, et al. (2011) Characterization of urine-derived stem cells obtained from upper urinary tract for use in cell-based urological tissue engineering. Tissue Eng Part A 17: 2123-2132.
  17. Shi YA, Liu GH, Bharadwaj S, et al. (2012) Urine derived stem cells with high telomerase activity for cell based therapy in urology. J Urol 187: e302.
  18. Ouyang B, Sun X, Han D, et al. (2014) Human urine-derived stem cells alone or genetically-modified with FGF2 Improve type 2 diabetic erectile dysfunction in a rat model. PLoS One 9: e92825.
  19. Tran CNT A, Balog B, Zhang Y, (2015) Paracrine effects of human urine-derived stem cells in treatment of female stress urinary incontinence in a rodent model. Tissue Eng Part A 21: S385.
  20. Chun SY, Kim HT, Lee JS, et al. (2012) Characterization of urine-derived cells from upper urinary tract in patients with bladder cancer. Urology 79: e1-e7.
  21. Zhou J, Wang X, Zhang S, et al. (2013) Generation and characterization of human cryptorchid-specific induced pluripotent stem cells from urine. Stem Cells Dev 22: 717-725.
  22. Afzal MZ, Strande JL (2015) Generation of induced pluripotent stem cells from muscular dystrophy patients: Efficient integration-free reprogramming of urine derived cells. J Vis Exp 2015: 52032.
  23. Gao P, Jiang D, Liu W, et al. (2016) Urine-derived Stem Cells, A New Source of Seed Cells for Tissue Engineering. Curr Stem Cell Res Ther 11: 547-553.
  24. Guan J, Zhang J, Guo S, et al. (2015) Human urine-derived stem cells can be induced into osteogenic lineage by silicate bioceramics via activation of the wnt/β-catenin signaling pathway. Biomaterials 55: 1-11.
  25. Guan J, Zhang J, Li H, et al. (2015) Human urine derived stem cells in combination with β-tcp can be applied for bone regeneration. PLoS One 10: e0125253.
  26. Guan J, Zhang J, Zhu Z, et al. (2015) Bone morphogenetic protein 2 gene transduction enhances the osteogenic potential of human urine-derived stem cells. Stem Cell Res Ther 6: 5.
  27. Jouni M, Si-Tayeb K, Es-Salah-Lamoureux Z, et al. (2015) Toward personalized medicine: Using cardiomyocytes differentiated from urine-derived pluripotent stem cells to recapitulate electrophysiological characteristics of type 2 long qt syndrome. J Am Heart Assoc 4: e002159.
  28. Kang HS, Choi SH, Kim BS, et al. (2015) Advanced properties of urine derived stem cells compared to adipose tissue derived stem cells in terms of cell proliferation, immune modulation and multi differentiation. J Korean Med Sci 30: 1764-1776.
  29. Lee JN, Chun SY, Lee HJ, et al. (2015) Human Urine-derived Stem Cells Seeded Surface Modified Composite Scaffold Grafts for Bladder Reconstruction in a Rat Model. J Korean Med Sci 30: 1754-1763.
  30. Nersesyan A, Kundi M, Fenech M, et al. (2014) Micronucleus assay with urine derived cells (UDC): A review of its application in human studies investigating genotoxin exposure and bladder cancer risk. Mutat Res Rev Mutat Res 762: 37-51.
  31. Wang C, Hei F, Ju Z, et al. (2016) Differentiation of urine-derived human induced pluripotent stem cells to alveolar type II epithelial cells. Cell Reprogram 18: 30-36.
  32. Zhang SZ, Li HF, Ma LX, et al. (2015) Urine-derived induced pluripotent stem cells as a modeling tool for paroxysmal kinesigenic dyskinesia. Biol Open 4: 1744-1752.
  33. Oliveira Arcolino F, Tort Piella A, Papadimitriou E, et al. (2015) Human urine as a noninvasive source of kidney cells. Stem Cells Int 2015: 362562.
  34. Liu G, Pareta RA, Wu R, et al. (2013) Skeletal myogenic differentiation of urine-derived stem cells and angiogenesis using microbeads loaded with growth factors. Biomaterials 34: 1311-1326.
  35. Qin H, Zhu C, An Z, et al. (2014) Silver nanoparticles promote osteogenic differentiation of human urine-derived stem cells at noncytotoxic concentrations. Int J Nanomedicine 9: 2469-2478.