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Theranostics 2019; 9(14):4221-4232. doi:10.7150/thno.34050 This issue Cite

Research Paper

Impaired Regeneration Potential in Urinary Stem Cells Diagnosed from the Patients with Diabetic Nephropathy

Geng Xiong^{1,3,4 *}, Weiqing Tang^2*, Deying Zhang^3,4, David He⁴, Guanghui Wei⁴, Antony Atala³, Xing-Jie Liang⁵, Anthony J. Bleyer⁶, Michael E. Bleyer⁶, Jie Yu⁷, Joseph A. Aloi⁸, Jian-Xing Ma⁹, Cristina M. Furdui¹⁰, Yuanyuan Zhang^3✉

1. Department of Pediatric Surgery, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, China
2. The MOH Key Laboratory of Geriatrics, Beijing Hospital, National Center of Gerontology, Beijing, China
3. Wake Forest Institute for Regenerative Medicine, Winston-Salem, NC, USA
4. Department of Urology, Children Hospital of Chongqing Medical University, Chongqing, China
5. Chinese Academy of Sciences (CAS) Key Laboratory for Biomedical Effects of Nanomaterials and Nanosafety, National Center for Nanoscience and Technology of China, Beijing, China
6. Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
7. Department of Obstetrics and Gynecology, Wake Forest School of Medicine, Winston-Salem, NC, USA
8. Department of Endocrinology, Wake Forest School of Medicine, Winston-Salem, NC, USA
9. Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK, USA.
10. Department of Internal Medicine, Section on Molecular Medicine, Wake Forest School of Medicine, Winston-Salem, NC, USA
* Both authors contribute equally in this study

✉ Corresponding author: Yuanyuan Zhang. E-mail: yzhangedu, Tel: 1-336-713-1189

Abstract

Stem cells present in urine possess regenerative capacity to repair kidney injury. However, the unique characteristics of urinary stem cells (USC) from patients with diabetic nephropathy (d-USC) are unknown. The goal of this study was to investigate stemness properties in cell phenotype and regenerative potential of d-USC, compared to USC from healthy individuals.

Methods: Thirty-six urine samples collected from patients (n=12, age range 60-75 years) with diabetic nephropathy (stages 3-4 stage chronic kidney disease [CKD]) were compared with 30 urine samples from healthy age-matched donors (n=10, age range 60-74 years).

Results: There were approximately six times as many cells in urine samples from patients with diabetic nephropathy, including twice as many USC clones as healthy donors. However, approximately 70% of d-USC had weaker regenerative capacity as assessed by cell proliferation, less secretion of paracrine factors, weaker telomerase activity, and lower renal tubular epithelial differentiation potential compared to healthy controls. In addition, the levels of inflammatory factors (IL-1β and Cx43) and apoptotic markers (Caspase-3, and TUNEL) were significantly increased in d-USC compared to USC (p<0.01). Protein levels of autophagy marker (LC3-II) and mTOR signaling molecules (p-mTOR/mTOR, p-Raptor/Raptor and p-S6K1) were significantly lower in patient with diabetic nephropathy (p<0.01). Nevertheless, up to 30% of d-USC possessed similar regenerative capacity as USC from healthy donors.

Conclusions: Regenerative performance of most d-USC was significantly lower than normal controls. Understanding the specific changes in d-USC regeneration capability will help elucidate the pathobiology of diabetic nephropathy and lead to prevent USC from diabetic insults, recover the stemness function and also identify novel biomarkers to predict progression of this chronic kidney disease.

Keywords: diabetic nephropathy, urine, stem cells, renal insufficiency

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