• CD34 cells
• acute kidney injury
• cell therapy
• chronic kidney diseases
• kidney diseases
• mesenchimal stem cells

• acute kidney injury
• drug delivery
• local renal treatment
• mesenchymal stem cells
• renal decapsulation

• Animals
• Humans
• Acute Kidney Injury/drug therapy
• Acute Kidney Injury/surgery
• Drug Delivery Systems/methods
• Kidney
• Translational Research, Biomedical

• Pregnancy
• Adult
• Female
• Humans
• Mesenchymal Stem Cells
• Stem Cells
• Placenta
• Cell Differentiation/physiology
• Body Fluids

• R03 AI165170 NIAID NIH HHS
• R21 AI152832 NIAID NIH HHS
• R21 DK071791 NIDDK NIH HHS
• R21 EY035833 NEI NIH HHS

• Biomarker
• Non-communicable diseases
• Therapeutic targets
• miR-17-92
• miRNA

• Humans
• Cardiovascular Diseases/genetics
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Diabetes Mellitus/genetics
• Biomarkers
• Kidney Diseases

• acute kidney injury
• cell-free therapeutics
• chronic kidney disease
• clinical application
• extracellular vesicles
• kidney disease
• mechanism of action
• mesenchymal stromal/stem cells
• renoprotection
• transplantation

• CP19/00027 Instituto de Salud Carlos III
• PI21/00204 Instituto de Salud Carlos III
• MV22/00017 Instituto de Salud Carlos III

• Cell therapy
• Kidney disease
• Regenerative medicine
• Stem cell

• Humans
• Disease Progression
• Kidney Failure, Chronic
• Quality of Life
• Renal Dialysis
• Renal Insufficiency, Chronic/therapy
• Renal Insufficiency, Chronic/complications
• Translational Science, Biomedical

• CD34 positive cells
• endothelial progenitor cells
• exosome
• regenerative medicine
• vasculogenesis

• Chronic kidney disease
• Critical limb ischemia
• Endothelial progenitor cells
• Rejuvenation

This experimental study was designed as a preclinical study for testing the hypothesis that intrarenal arterial (IRA) transfusion of human umbilical cord-derived mesenchymal stem cells (HUCDMSCs) therapy preserved the residual renal function of diabetic kidney disease (DKD) in rat [induction by 5/6 nephrectomy of left kidney and right nephrectomy, followed by intraperitoneal administration of aminoguanidine (180 mg/kg) and streptozotocin (30 mg/kg)].

Animals (n = 24) were categorized into group 1 (sham-operated control), group 2 (DKD), group 3 [DKD + HUCDMSCs (2.1 × 10⁵/IRA injection at day 28 after CKD induction)] and group 4 [(DKD + HUCDMSCs (6.3 × 10⁵/IRA injection)].

By day 60 after DKD induction, the kidneys were harvested and the result showed that the creatinine level, ratio of urine protein/urine creatinine and kidney injury score were lowest in group 1, highest in group 2 and significantly lower in group 4 than in group 3 (all p < 0.0001). The protein expressions of apoptotic (cleaved caspase-3/cleaved PARP/mitochondrial Bax), fibrotic (TGF-ß/p-Smad3), autophagic (ratio of LC3B-II/LC3B-I, Atg5/Beclin-1), oxidative stress (NOX-1/NOX-2/oxidized protein/p22phox), mitochondrial/DNA-damaged (cytosolic-cytochrome-C/DRP1/γ-H2AX) and inflammatory (MMP-9/TNF-α/p-NF-κB) biomarkers exhibited an identical pattern, whereas the protein expressions of angiogenesis factors (CD31/vWF/vascularity) exhibited an opposite pattern of creatinine level among the groups (all p < 0.0001). Histopathological findings demonstrated the renal tubular-damaged (KIM-1)/kidney fibrosis area/oxidative stress (8-OHdG + cells) expressed an identical pattern, whereas the podocyte components (ZO-1/synaptopodin/podocin) exhibited an opposite pattern of creatinine level among the groups (all p < 0.0001). No tumorigenesis or immune rejection event was identified.

IRA injection of xenogeneic MSCs was safe and effectively protected the residual renal function and architectural integrity in DKD rat.

• Diabetic CKD
• Renal function
• Xenogeneic mesenchymal stem cell

Chronic kidney disease (CKD) in clinical is defined as a gradual loss of kidney function for more than 3 months. The pathologic course of CKD is characterized by extensive renal fibrosis; thus, preventing renal fibrosis is vital for the treatment of CKD. It has been reported that microRNA (miR)-374a-5p was under-expressed in renal venous blood samples from patients with CKD. In addition, it exhibited anti-apoptotic effects in renal tissues suggesting that miR-374a-5p may play an important role in CKD. However, it is not clear whether miR-374a-5p could be delivered to renal cells by exosomes and exerts anti-renal fibrosis effects. To mimic renal fibrosis in vitro, human renal tubular epithelial cell lines (HK-2 cells) were treated by transforming growth factor-β (TGF-β) 1. Reverse transcription-quantitative polymerase-chain reaction (RT-qPCR) or Western blot was carried out to evaluate the mechanism by which miR-374a-5p regulated the development of renal fibrosis. Next, exosomes were isolated using with ultracentrifugation method, and the relationship between miR-374a-5p and MAPK6 was evaluated using dual-Luciferase a reporter assay system. The results indicated TGF-β1 significantly down-regulated the expression of miR-374a-5p in HK-2 cells and miR-374a-5p agomir remarkably inhibited the progression of fibrosis in vitro. In addition, exosomal miR-374a-5p could be internalized by HK-2 cells and obviously enhanced the level of miR-374a-5p in HK-2 cells. Furthermore, exosomal miR-374a-5p prevented the progression of renal fibrosis in vivo by regulating MAPK6/MK5/YAP axis. In conclusion, exosomal miR-374a-5p inhibited the progression of renal fibrosis by regulating MAPK6/MK5/YAP axis.

• MAPK6
• Renal fibrosis
• exosomes
• mesenchymal stem cells (MSC)
• miR-374a-5p

• Adipose-derived mesenchymal stem cells
• Cellular prior protein
• Melatonin
• Oxidative stress
• Valsartan

Kidney diseases are a prevalent health problem around the world. Multidrug therapy used in the current routine treatment for kidney diseases can only delay disease progression. None of these drugs or treatments can reverse the progression to an end-stage of the disease. Therefore, it is crucial to explore novel therapeutics to improve patients’ quality of life and possibly cure, reverse, or alleviate the kidney disease. Stem cells have promising potentials as a form of regenerative medicine for kidney diseases due to their unlimited replication and their ability to differentiate into kidney cells in vitro. Mounting evidences from the administration of stem cells in an experimental kidney disease model suggested that stem cell-based therapy has therapeutic or renoprotective effects to attenuate kidney damage while improving the function and structure of both glomerular and tubular compartments. This review summarises the current stem cell-based therapeutic approaches to treat kidney diseases, including the various cell sources, animal models or in vitro studies. The challenges of progressing from proof-of-principle in the laboratory to widespread clinical application and the human clinical trial outcomes reported to date are also highlighted. The success of cell-based therapy could widen the scope of regenerative medicine in the future.

• Stem cells
• Kidney regeneration
• Kidney disease
• Mesenchymal stem cells
• Embryonic stem cells
• Induced pluripotent stem cells

• Dilated cardiomyopathy
• Double overexpression of microRNAs
• Inflammation
• Mitochondrial damage
• Oxidative stress

This study tested the hypothesis that therapy with double overexpression of miR‐19a‐3p and miR‐20a‐5p (miR^DOE) to human inducible pluripotent stem cell–derived mesenchymal stem cells (iPS‐MSCs) was superior to iPS‐MSCs alone for preserving renal function in rat with pre‐existing chronic kidney disease (CKD), followed by ischaemia‐reperfusion (IR) injury. In vitro study demonstrated that the protein expressions of oxidative stress (NOX‐1/NOX‐2/NOX4/oxidized protein/p22phox), inflammatory downstream signalling (TLR2&4/MyD88/TRAF6/IKK‐ß/p‐NFκB/IL‐1ß/IL‐6/MMP‐9) and cell apoptosis/death signalling (cleaved caspase‐3/mitochondrial Bax/p‐ERKs/p‐JNK/p‐p38) at time‐points of 24‐hour/48‐hour cell cultures were significantly increased in p‐Cresol‐treated NRK‐52E cells than in the control that was significantly reversed by miR‐19a‐3p‐transfected iPS‐MSC (all P < .001). Animals were categorized into group 1 (sham‐operated control), group 2 (CKD‐IR), group 3 (CKD‐IR + oligo‐miR^DOE of iPS‐MSCs/6.0 ×10⁵/intra‐renal artery transfusion/3 hours after IR procedure), group 4 (CKD‐IR + iPS‐MSCs) and group 5 (CKD‐IR + miR^DOE of iPS‐MSCs/6.0 ×10^5/intra‐renal artery transfusion/3 hour after IR procedure). By day 35, the creatinine/BUN levels were lowest in group 1, highest in group 2 and significantly lower in group 5 than in groups 3 and 4 (all P < .0001) but they showed no difference between the latter two groups. The protein expressions of oxidative stress, inflammatory downstream signalling and cell apoptosis/death signalling exhibited an identical pattern of creatinine level among the five groups (all P < .00001). Also, the microscopic findings demonstrated that the kidney injury score/fibrotic area/number of inflammatory cells (CD14+/CD68+) exhibited an identical pattern of creatine level (all P < .0001). The miR^DOE of iPS‐MSCs was superior to iPS‐MSCs for preserving the residual kidney function and architecture in CKD‐IR rat.

• chronic kidney disease
• fibrosis
• iPS-MSCs
• inflammation
• ischaemia-reperfusion injury
• microRNAs
• oxidative stress

• Angiogenesis
• Anti-inflammation
• End-stage renal disease
• Endothelial progenitor cells
• Quality and quantity culture

• Cells, Cultured
• Endothelial Progenitor Cells
• Humans
• Kidney Failure, Chronic
• Leukocytes, Mononuclear
• Macrophages

• Denudation of carotid artery endothelium
• adventitia
• inflammation
• oxidative stress
• stenosis
• uremic toxic substances

• Acute myocardial infarction
• G9a inhibitor
• apoptosis
• fibrosis
• histone methyltransferase
• inflammation
• oxidative stress

• CKD
• SGLT2 antagonists
• Therapeutic target
• chronic kidney disease
• epithelial to mesenchymal transition
• inflammation
• microbiota
• oxidative stress
• renal fibrosis

MicroRNAs control gene expression by post-transcriptional inhibition. Dysregulation of the expressions of miR-199a/214 cluster has been linked to cardiovascular diseases. This study aimed at identifying potential microRNAs related to vascular senescence.

Seven candidate microRNAs (miR-19a, −20a, −26b, −106b, − 126, − 214, and − 374) related to cell proliferation were tested for their expressions under CoCl₂-induced hypoxia in vascular smooth muscle cells (VSMCs). After identification of miR-214 as the candidate microRNA, telomere integrity impairment and cell cycle arrest were examined in VSMCs by using miR-214 mimic, AntagomiR, and negative controls. To investigate the clinical significance of miR-214 in vascular diseases, its plasma level from patients with carotid artery stenosis (CAS) was assessed by quantitative reverse transcriptase polymerase chain reaction (qRT-PCR).

CoCl₂ treatment for 48 h suppressed cell proliferation and angiogenesis as well as enhanced cell senescence in VSMCs. Besides, miR-214 level was elevated in both intracellular and exosome samples of VSMCs after CoCl₂ treatment. Manipulating miR-214 in VSMCs demonstrated that miR-214 not only inhibited angiogenic and proliferative capacities but also promoted senescence through the suppression of quaking. Additionally, circulating miR-214 level was upregulated in CAS patients with high low-density lipoprotein cholesterol (LDL-C) value.

Our findings suggested that miR-214 plays a role in the modulation of VSMC angiogenesis, proliferation, and senescence with its plasma level being increased in CAS patients with elevated LDL-C value, implying that it may be a vascular senescence marker and a potential therapeutic target for vascular diseases.

• Proliferation
• Senescence
• Vascular smooth muscle cells
• microRNA-214

This was a randomized, open‐label, controlled phase II clinical trial to investigate the safety, efficacy, and outcomes of intrarenal artery infusion of autologous peripheral‐blood‐derived CD34+ cells for patients with chronic kidney disease (CKD; ie, stage III or IV).

Between October 2016 and July 2018, 52 consecutive patients with CKD at stage III or IV were randomly allocated into a treatment group (TG; 2.5 × 10⁷ cells for each intrarenal artery; n = 26) and a control group (CG; standardized pharmacotherapy only; n = 26). The primary endpoints included safety and change of creatinine level/creatinine clearance. The secondary endpoints were 12‐month combined unfavorable clinical outcomes (defined as dialysis or death), improvement in proteinuria, and CD34+ cell‐related adverse events.

All patients were uneventfully discharged after CD34+ cell therapy. The baseline endothelial progenitor cell (EPC) populations did not differ between TG and CG (P > .5). Flow cytometric analysis showed increases in circulating EPC (ie, CD34+KDR+CD45^dim/ CD34+CD133+CD45^dim/CD31+CD133+CD45^dim/CD34+CD133+KDR+/CD133+) and hematopoietic stem cell (CD34+) populations after granulocyte‐colony stimulating factor treatment (all P < .001). Besides, Matrigel assay of angiogenesis was also significantly enhanced (all P < .001). Renal‐venous blood samplings (ie, at 0, 5, 10, and 30 minutes after CD34+ cell infusion) demonstrated significant progressive increases in EPC level (P for trend <.001) among the TG patients. One‐year combined unfavorable clinical outcomes were significantly lower in TG than those in CG (0% [0] vs 13.3% [4], P = .038). By 12 months after CD34+ cell therapy, circulating creatinine level, ratio of urine protein to urine creatinine, and creatinine clearance showed no difference between TG and CG (all P > .1).

CD34+ cell therapy was safe and improved 1‐year outcome.

• CD34+ cell therapy
• angiogenesis
• chronic kidney disease
• circulating endothelial progenitor cells

• Cytokine therapy
• acute kidney injury
• chronic kidney disease
• kidney organoids
• mechanism

This study traced intravenously administered induced pluripotent stem cell (iPSC)‐derived mesenchymal stem cells (MSC) and assessed the impact of iPSC‐MSC on preserving renal function in SD rat after 5/6 nephrectomy. The results of in vitro study showed that FeraTrack™Direct contrast particles (ie intracellular magnetic labelling) in the iPSC‐MSC (ie iPS‐MSC^SPIONs) were clearly identified by Prussian blue stain. Adult‐male SD rats (n = 40) were categorized into group 1 (SC), group 2 [SC + iPS‐MSC^SPIONs (1.0 × 10⁶cells)/intravenous administration post‐day‐14 CKD procedure], group 3 (CKD), group 4 [CKD + iPS‐MSC^SPIONs (0.5 × 10⁶cells)] and group 5 [CKD + iPS‐MSC^SPIONs (1.0 × 10⁶cells)]. By day‐15 after CKD induction, abdominal MRI demonstrated that iPS‐MSC^SPIONs were only in the CKD parenchyma of groups 4 and 5. By day 60, the creatinine level/ratio of urine protein to urine creatinine/kidney injury score (by haematoxylin and eosin stain)/fibrotic area (Masson's trichrome stain)/IF microscopic finding of kidney injury molecule‐1 expression was lowest in groups 1 and 2, highest in group 3, and significantly higher in group 4 than in group 5, whereas IF microscopic findings of podocyte components (ZO‐1/synaptopodin) and protein levels of anti‐apoptosis ((Bad/Bcl‐xL/Bcl‐2) exhibited an opposite pattern to creatinine level among the five groups (all P < .0001). The protein expressions of cell‐proliferation signals (PI3K/p‐Akt/m‐TOR, p‐ERK1/2, FOXO1/GSK3β/p90RSK), apoptotic/DNA‐damage (Bax/caspases8‐10/cytosolic‐mitochondria) and inflammatory (TNF‐α/TNFR1/TRAF2/NF‐κB) biomarkers displayed an identical pattern to creatinine level among the five groups (all P < .0001). The iPS‐MSC^SPIONs that were identified only in CKD parenchyma effectively protected the kidney against CKD injury.

• apoptosis
• chronic kidney disease
• induced pluripotent stem cells-derived mesenchymal stem cells
• inflammation
• magnetic characterization of iron oxide
• nanoparticles

• molecular biology
• prognostic markers
• hepatology

• Acute-On-Chronic Liver Failure/blood
• Acute-On-Chronic Liver Failure/genetics
• Acute-On-Chronic Liver Failure/mortality
• Acute-On-Chronic Liver Failure/pathology
• Biomarkers/blood
• Case-Control Studies
• Female
• Humans
• Liver Cirrhosis/blood
• Liver Cirrhosis/genetics
• Liver Cirrhosis/mortality
• Liver Cirrhosis/pathology
• Male
• MicroRNAs/genetics
• Middle Aged
• Organ Dysfunction Scores
• Prognosis
• ROC Curve
• Severity of Illness Index
• Survival Rate

• biomarker
• coronary angiography
• estimated glomerular filtration rate
• microRNA

• fibrosis
• hydrogel
• kidney
• stem cell

• CD34+ cell therapy
• Old ischemic stroke
• angiogenesis
• neuro-psychological assessment [clinical trial No.: ISRCTN14654908]
• neurological function

This study was aimed at testing the association between the therapeutic efficacy of CD34⁺ cell treatment in patients with end-stage diffuse coronary artery disease as reflected in angiographic grading and results of directed in vivo angiogenesis assay (DIVAA) on their isolated peripheral blood mononuclear cell- (PBMC-) derived endothelial progenitor cells (EPCs).

Angiographic grades (0: <5%; 1: 5–35%; 2: 35–75%; 3: >75%) which presented the improvement of vessel density pre- and post-CD34⁺ treatment were given to 30 patients with end-stage diffuse coronary artery disease having received CD34⁺ cell treatment. The patients were categorized into low-score group (angiographic grade 0 or 1, n = 12) and high-score group (angiographic grade 2 or 3, n = 18). The percentages of circulating EPCs with KDR⁺/CD34⁺/CD45⁻, CD133⁺/CD34⁺/CD45⁻, and CD34⁺ were determined in each patient using flow cytometry. PBMC-derived EPCs from all patients were subjected to DIVAA through a 14-day implantation in nude mice. The DIVAA ratio (i.e., mean fluorescent units in angioreactors with EPCs/mean fluorescent units in angioreactors without EPCs) was obtained for each animal with implanted EPCs from each patient.

The number of EPCs showed no significant difference among the two groups. The DIVAA ratio in the high-score group was significantly higher than that in the low-score group (p = 0.0178). Logistic regression revealed a significant association between the DIVAA ratio and angiographic grading (OR 3.12, 95% CI: 1.14–8.55, p = 0.027). The area under the ROC curve (AUC) was 0.8519 (p = 0.0013). We proposed that DIVAA may be a reliable tool for assessing coronary vascularization after CD34⁺ cell treatment.

• atherosclerosis
• cluster
• hyperhomocysteinemia
• microRNAs

• adipose-derived mesenchymal stem cell
• chronic kidney disease
• exendin-4
• inflammation
• sepsis syndrome