Human umbilical cord-derived mesenchymal stem cells prevent the progression of early diabetic nephropathy through inhibiting inflammation and fibrosis
Xiang et al. Stem Cell Research & Therapy
(2020) 11:336
https://doi.org/10.1186/s13287-020-01852-y
RESEARCH
Open Access
Human umbilical cord-derived
mesenchymal stem cells prevent the
progression of early diabetic nephropathy
through inhibiting inflammation and
fibrosis
E Xiang1,2, Bing Han2, Quan Zhang2, Wei Rao2, Zhangfan Wang2, Cheng Chang1, Yaqi Zhang1, Chengshu Tu2,
Changyong Li3* and Dongcheng Wu1,2*
Abstract
Background: Diabetic nephropathy (DN) is one of the most serious complications of diabetes and the leading
cause of end-stage chronic kidney disease. Currently, there are no effective drugs for treating DN. Therefore, novel
and effective strategies to ameliorate DN at the early stage should be identified. This study aimed to explore the
effectiveness and underlying mechanisms of human umbilical cord mesenchymal stem cells (UC-MSCs) in DN.
Methods: We identified the basic biological properties and examined the multilineage differentiation potential of
UC-MSCs. Streptozotocin (STZ)-induced DN rats were infused with 2 × 106 UC-MSCs via the tail vein at week 6. After
2 weeks, we measured blood glucose level, levels of renal function parameters in the blood and urine, and cytokine
levels in the kidney and blood, and analyzed renal pathological changes after UC-MSC treatment. We also determined
the colonization of UC-MSCs in the kidney with or without STZ injection. Moreover, in vitro experiments were
performed to analyze cytokine levels of renal tubular epithelial cell lines (NRK-52E, HK2) and human renal glomerular
endothelial cell line (hrGECs).
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* Correspondence: ;
3
Department of Physiology, Wuhan University School of Basic Medical
Sciences, Wuhan, China
1
Department of Biochemistry and Molecular Biology, Wuhan University
School of Basic Medical Sciences, Wuhan, China
Full list of author information is available at the end of the article
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Xiang et al. Stem Cell Research & Therapy
(2020) 11:336
Page 2 of 14
(Continued from previous page)
Results: UC-MSCs significantly ameliorated functional parameters, such as 24-h urinary protein, creatinine clearance
rate, serum creatinine, urea nitrogen, and renal hypertrophy index. Pathological changes in the kidney were manifested
by significant reductions in renal vacuole degeneration, inflammatory cell infiltration, and renal interstitial fibrosis after
UC-MSC treatment. We observed that the number of UC-MSCs recruited to the injured kidneys was increased
compared with the controls. UC-MSCs apparently reduced the levels of pro-inflammatory cytokines (IL-6, IL-1β, and
TNF-α) and pro-fibrotic factor (TGF-β) in the kidney and blood of DN rats. In vitro experiments showed that UC-MSC
conditioned medium and UC-MSC-derived exosomes decreased the production of these cytokines in high glucoseinjured renal tubular epithelial cells, and renal glomerular endothelial cells. Moreover, UC-MSCs secreted large amounts
of growth factors including epidermal growth factor, fibroblast growth factor, hepatocyte growth factor, and vascular
endothelial growth factor.
Conclusion: UC-MSCs can effectively improve the renal function, inhibit inflammation and fibrosis, and prevent its
progression in a model of diabetes-induced chronic renal injury, indicating that UC-MSCs could be a promising
treatment strategy for DN.
Keywords: Diabetic nephropathy, Umbilical cord mesenchymal stem cells, Inflammation, Renal fibrosis
Background
Diabetic nephropathy (DN) is the most detrimental
microvascular complication of diabetes and the leading
cause of chronic kidney disease worldwide. Diabetes is a
progressive disease. Long-term hyperglycemia causes
damage to tissues and organs, resulting in various diabetic complications, such as diabetic retinopathy, diabetic foot, DN, and so on [1]. Among them, DN is a
refractory disease with low awareness, high incidence,
and high disability. The incidence of DN can reach 30 to
40% after 20 years of diabetes, of which 5~10% of
patients will progress to end-stage renal disease, and
epidemiological surveys predict that by 2030, DN will
become the seventh leading cause of death in the world
[2–5]. Risk factors for DN include advanced age, gender,
long disease course, obesity, high salt diet, dyslipidemia,
nephrotoxic substances, acute kidney injury, and excessive protein intake. Hyperglycemia and hypertension are
the most significant risk factors [6, 7]. Compared with
other types of diabetic patients, DN patients have a
higher mortality rate, and most of the deaths are due to
cardiovascular events [8].
The main manifestation of early DN is the appearance
of microalbuminuria. As the disease progresses, a large
amount of proteinuria appears in most patients with DN
and eventually develops into chronic renal failure until
uremia [9]. The main pathological features of DN include
glomerular basement membrane thickening, mesangial expansion, and glomerular sclerosis. Besides, podocyte loss
and apoptosis, interstitial inflammation infiltration, renal
interstitial fibrosis, and renal tubular atrophy sparse capillaries around the tube are also included in the pathological
characteristics of DN [10]. The prevention and treatment
of DN are mainly divided into pre-diabetes prevention (active screening, early detection, and reasonable intervention), early treatment (tight control of blood glucose and
blood pressure) to delay the development of DN and comprehensive treatment of advanced DN (including alternative treatments such as dialysis or kidney transplantation)
to reduce the risk of cardiovascular events and death [11].
Currently, effective therapeutic strategies to counteract
and reverse the progression of DN are lacking; therefore,
it is imperative to develop new strategies for treating DN.
Notably, stem cell therapy has become the most likely
new breakthrough in the treatment of DN due to its
self-renewal capacity, multilineage di (...truncated)
