Renal Regeneration Research Articles

Extracellular Vesicles: Cell-Derived Biomarkers of Glomerular and Tubular Injury.

Extracellular vesicles (EVs) are important mediators of intercellular communication. Since EVs are also released during pathological conditions, there has been considerable interest in their potential as sensitive biomarkers of cellular stress and/or injury. In the context of kidney disease, urinary EVs are promising indicators of glomerular and tubular damage. In the present review we discuss the role of urinary EVs in kidney health and disease. Our focus is to explore urinary large EVs (lEVs, often referred to as microparticles or microvesicles) as direct and noninvasive early biomarkers of renal injury. In this regard, studies have been demonstrating altered levels of urinary lEVs, especially podocyte-derived lEVs, preceding the decrease of renal function assessed by classical markers. In addition, we discuss the role of small EVs (sEVs, often referred to as exosomes) and their contents in kidney pathophysiology. Even though results concerning the production of sEVs during diseased conditions are varied, there has been a consensus on the importance of urinary sEV content assessment in kidney disease. These mediators, including EV-released miRNAs and mRNAs, are responsible for EV-mediated signaling in the regulation of renal cellular homeostasis, pathogenesis and regeneration. Finally, steps necessary for the validation of EVs as reliable markers will be discussed.

Scaffold-supported extracellular matrices preserved by magnesium hydroxide nanoparticles for renal tissue regeneration.

Fibroblast-derived extracellular matrix (fECM)-supported scaffolds made up of poly(lactic-co-glycolic acid) were prepared with the enhanced preservation of ECM components by composites with magnesium hydroxide nanoparticles (MH NPs), and were applied for the renal tissue regeneration. MH NP utilization resulted in an increased ECM protein amount, decreased scaffold degradation, and surface hydrophilic modification. These effects were correlated with the improved adhesion and viability of renal proximal tubule epithelial cells on the scaffold. In vivo experiments demonstrated effects of fECM and MH NPs on renal regeneration. The number of glomeruli was the largest in the ECM scaffold with MH NPs as compared to the pristine scaffold and ECM scaffold without MH NPs. Quantitative PCR analysis exhibited less inflammation (IL-1β, TNF-α, and IL-6) and fibrosis-related (vimentin, collagen I, and α-SMA) markers, whereas opposite results were found in regeneration-related markers (Pax2, vWf, Wt1, and Emx2). The concentration of renal function-related molecules, creatinine and blood urea nitrogen diminished in the ECM scaffold with MH NPs. All results indicate that MH NPs utilization for the renal regenerative scaffold is effective for in vitro and in vivo environments and is, therefore, a good model for regeneration of kidneys and other tissues, and organs.

Nephroprotective Potential Effect of Quercttin in Renal Ischemia Reperfusion Injury in Rat Model (Role of Akt/m TOR Pathway)

Ischemia reperfusion is determined by a limitation of blood supply to the organs and subsequent blood restoration and reoxygenation. Renal ischemia reperfusion injury (IRI) is a potential element in the pathogenesis of acute kidney injury arising from oxidative stress, inflammation and apoptosis of renal tubular cells. The mammalian target of rapamycin (mTOR) pathway activates after IRI and contributes to renal repair and regeneration. Quercetin is a flavonoid compound that presents in many fruits and vegetables. Quercetin is widely used for its anti-inflammatory and anti-oxidant effects. The present study aimed to investigate the potential protective effect of quercetin on renal IRI in rat model by regulation of Akt/mTOR pathway. At the end of experiment, the serum levels of urea and creatinine and renal tissue levels regarding p-mTOR, p-Akt, IL-1I², caspase-3, and F2-isoprostane were recognized to be significantly (p value<0.05) elevated in control group when compared with sham group. Histopathologic alanalysis of the renal tissues recognized a severe renal injury in control group and there was a significant role of quercetin in ameliorating this injury by minimizing the serum levels of urea and creatinine, tissue levels of IL-1I², caspase-3, F2-isoprostane except for p-mTOR and p-AKt levels which were significantly (p value<0.05) higher in comparison with that of control group. In addition, treatment of quercetin significantly (p<0.05) reversed the histopathologic severity scores of renal tissue damage. From the overall results, we concluded that quercetin significantly diminished renal ischemia reperfusion injury in the rat model through Akt/mTOR pathway by its effect as anti-oxidant, anti-inflammatory and anti-apoptotic. How to Cite this Article Pubmed Style Rusul F. Hasan, Murooj L. Altimimi, Hayder M. Alaridy, Najah R. Hadi. Potential Effect of Quercttin in Renal Ischemia Reperfusion Injury in Rat Model (Role of Akt/m TOR SRP. 2020; 11(1): 315-325. doi:10.5530/srp.2020.1.41 Web Style Rusul F. Hasan, Murooj L. Altimimi, Hayder M. Alaridy, Najah R. Hadi. Potential Effect of Quercttin in Renal Ischemia Reperfusion Injury in Rat Model (Role of Akt/m TOR http://www.sysrevpharm.org/?mno=83862 [Access: March 29, 2021]. doi:10.5530/srp.2020.1.41 AMA (American Medical Association) Style Rusul F. Hasan, Murooj L. Altimimi, Hayder M. Alaridy, Najah R. Hadi. Potential Effect of Quercttin in Renal Ischemia Reperfusion Injury in Rat Model (Role of Akt/m TOR SRP. 2020; 11(1): 315-325. doi:10.5530/srp.2020.1.41 Vancouver/ICMJE Style Rusul F. Hasan, Murooj L. Altimimi, Hayder M. Alaridy, Najah R. Hadi. Potential Effect of Quercttin in Renal Ischemia Reperfusion Injury in Rat Model (Role of Akt/m TOR SRP. (2020), [cited March 29, 2021]; 11(1): 315-325. doi:10.5530/srp.2020.1.41 Harvard Style Rusul F. Hasan, Murooj L. Altimimi, Hayder M. Alaridy, Najah R. Hadi (2020) Potential Effect of Quercttin in Renal Ischemia Reperfusion Injury in Rat Model (Role of Akt/m TOR SRP, 11 (1), 315-325. doi:10.5530/srp.2020.1.41 Turabian Style Rusul F. Hasan, Murooj L. Altimimi, Hayder M. Alaridy, Najah R. Hadi. 2020. Potential Effect of Quercttin in Renal Ischemia Reperfusion Injury in Rat Model (Role of Akt/m TOR Systematic Reviews in Pharmacy, 11 (1), 315-325. doi:10.5530/srp.2020.1.41 Chicago Style Rusul F. Hasan, Murooj L. Altimimi, Hayder M. Alaridy, Najah R. Hadi. Nephroprotective Potential Effect of Quercttin in Renal Ischemia Reperfusion Injury in Rat Model (Role of Akt/m TOR Pathway). Systematic Reviews in Pharmacy 11 (2020), 315-325. doi:10.5530/srp.2020.1.41 MLA (The Modern Language Association) Style Rusul F. Hasan, Murooj L. Altimimi, Hayder M. Alaridy, Najah R. Hadi. Nephroprotective Potential Effect of Quercttin in Renal Ischemia Reperfusion Injury in Rat Model (Role of Akt/m TOR Pathway). Systematic Reviews in Pharmacy 11.1 (2020), 315-325. Print. doi:10.5530/srp.2020.1.41 APA (American Psychological Association) Style Rusul F. Hasan, Murooj L. Altimimi, Hayder M. Alaridy, Najah R. Hadi (2020) Potential Effect of Quercttin in Renal Ischemia Reperfusion Injury in Rat Model (Role of Akt/m TOR Systematic Reviews in Pharmacy, 11 (1), 315-325. doi:10.5530/srp.2020.1.41

Proceedings of the 2019 National Toxicology Program Satellite Symposium.

The 2019 annual National Toxicology Program Satellite Symposium, entitled "Pathology Potpourri," was held in Raleigh, North Carolina, at the Society of Toxicologic Pathology's 38th annual meeting. The goal of this symposium was to present and discuss challenging diagnostic pathology and/or nomenclature issues. This article presents summaries of the speakers' talks along with select images that were used by the audience for voting and discussion. Various lesions and topics covered during the symposium included aging mouse lesions from various strains, as well as the following lesions from various rat strains: rete testis sperm granuloma/fibrosis, ovarian cystadenocarcinoma, retro-orbital schwannoma, periductal cholangiofibrosis of the liver and pancreas, pars distalis hypertrophy, chronic progressive nephropathy, and renal tubule regeneration. Other cases included polyovular follicles in young beagle dogs and a fungal blood smear contaminant. One series of cases challenged the audience to consider how immunohistochemistry may improve the diagnosis of some tumors. Interesting retinal lesions from a rhesus macaque emphasized the difficulty in determining the etiology of any particular retinal lesion due to the retina's similar response to vascular injury. Finally, a series of lesions from the International Harmonization of Nomenclature and Diagnostic Criteria Non-Rodent Fish Working Group were presented.

Ultrasonographic measurement of the renal resistive index in the cynomolgus monkey (Macaca fascicularis) under conscious and ketamine-immobilized conditions.

Measurement of the renal resistive index (RRI) is one of the standard diagnostic procedures for assessing kidney disability clinically. This method is expected to be used for the same purpose in many kinds of animals, including monkeys utilized in conventional toxicology studies. To establish a practical RRI measurement procedure in cynomolgus monkeys (Macaca fascicularis), RRI was measured by ultrasonography in the spine position in conscious and ketamine-immobilized monkeys. The RRI of conscious monkeys and ketamine-immobilized monkeys could be measured consistently without excessive abdominal or thoracic movement. Consequently, the variability of the RRI in conscious monkeys was comparable to that in ketamine-anesthetized monkeys. No sex difference in RRI was noted between the two conditions. The mean values and SD of the RRI of 48 healthy monkeys (n=24/sex) were 0.55 ± 0.07 and 0.50 ± 0.05, under conscious and ketamine-immobilized conditions, respectively. The RRI of ketamine-immobilized monkeys was significantly lower than that of conscious monkeys, correlating with the decreased blood pressure and heart rate. In a monkey model of cisplatin-induced acute renal injury, which was characterized histopathologically by minimal to mild renal tubular necrosis and regeneration, the RRI was increased beyond the cut off value (mean + 2SD, 0.68) associated with the progression of renal pathogenesis. The present results suggest that ultrasonographic measurement of the RRI in conscious monkeys would be a useful tool in conventional toxicology studies evaluating drug-induced renal injury.

Kidney organoids: accurate models or fortunate accidents.

There are now many reports of human kidney organoids generated via the directed differentiation of human pluripotent stem cells (PSCs) based on an existing understanding of mammalian kidney organogenesis. Such kidney organoids potentially represent tractable tools for the study of normal human development and disease with improvements in scale, structure, and functional maturation potentially providing future options for renal regeneration. The utility of such organotypic models, however, will ultimately be determined by their developmental accuracy. While initially inferred from mouse models, recent transcriptional analyses of human fetal kidney have provided greater insight into nephrogenesis. In this review, we discuss how well human kidney organoids model the human fetal kidney and how the remaining differences challenge their utility.

Upregulation of CD133 and CD44 as Markers of Resident Renal Progenitor Cells Following BM-MSCs Transfusion for Renal Regeneration

Upregulation of CD133 and CD44 as Markers of Resident Renal Progenitor Cells Following BM-MSCs Transfusion for Renal Regeneration

Renal Regeneration: Stem Cell-Based Therapies to Battle Kidney Disease

While the worldwide prevalence of kidney disease is increasing rapidly, the current therapeutic repertoire for these patients is often limited to dialysis and organ transplantation. However, advances in developmental and stem cell biology have highlighted the potential of stem cells for the development of novel renal regeneration therapies. While there are currently no approved stem cell-based treatments for kidney disease, various types of stem cells have been shown to facilitate regeneration of kidney tissue in preclinical models of both acute and chronic kidney injury. This review summarises the current status of stem cell-based therapies to battle kidney disease. In addition, future directions for the clinical translation of stem cell research towards development of novel renal regeneration therapies are discussed.

Anti-CD45RB Antibody Therapy Attenuates Renal Ischemia-Reperfusion Injury by Inducing Regulatory B Cells.

Regulatory B cells are a newly discovered B cell subset that suppresses immune responses. Recent studies found that both anti-CD45RB and anti-Tim-1 treatments regulate immune responses by inducing regulatory B cells; however, the role of these cells in renal ischemia-reperfusion injury (IRI) is unknown. Using mouse models, including T cell-deficient (RAG1 knockout and TCRα knockout) mice and B cell-deficient (μMT) mice, we investigated the effects of regulatory B cells and anti-CD45RB on IRI and the mechanisms underlying these effects. Adoptive transfer of regulatory B cells before or after IRI attenuated renal IRI. Anti-CD45RB treatment with or without anti-Tim-1 before IRI increased renal infiltration of CD19+Tim-1+ regulatory B and regulatory T cells. Anti-CD45RB decreased serum creatinine levels, pathologic injury score, tubular apoptosis, and proinflammatory cytokines levels, whereas IL-10 levels increased. Following IRI, anti-CD45RB with or without anti-Tim-1 also induced regulatory B cells, improving renal function and tubular regeneration. In RAG1 knockout mice with B cell transfer, TCRα knockout mice, and wild-type mice with T cell depletion, anti-CD45RB increased regulatory B cells and attenuated IRI. However, anti-CD45RB did not attenuate IRI in RAG1 knockout mice with T cell transfer or μMT mice and induced only mild improvement in wild-type mice with B cell depletion. Furthermore, B cell-deficient mice receiving B cells from IL-10 knockout mice (but not from wild-type mice) did not show renal protection against IRI when treated with anti-CD45RB. Anti-CD45RB treatment attenuated acute renal injury and facilitated renal recovery after IRI through induction of IL-10+ regulatory B cells, pointing to anti-CD45RB as a potential therapeutic strategy in renal IRI.

Dual roles of hydrogen peroxide in promoting zebrafish renal repair and regeneration

Acute renal injury (AKI) is a serious disorder of renal failure or renal damage that occurs within hours or days. At present, there is no approved pharmaceutical treatment for AKI. Zebrafish is an excellent model for studying the repair of AKI because of its remarkable ability to repair kidney injury. Using zebrafish AKI model inducing by gentamicin, we found that hydrogen peroxide (H2O2) plays dual roles during the period of AKI recovery including renal repair and kidney regeneration. In the repair stage of AKI, H2O2 was produced in proximal and distal segments of renal tubules. By inhibiting H2O2 generation using Duox Vivo-Morpholino or chemical inhibitor, it was observed of severe damage of renal tubules, and extensive cell apoptosis. In the stage of regeneration, we found that H2O2 was highly generated in renal interstitium. Inhibiting production of H2O2 could significantly down-regulate the ability of kidney regeneration, which was associated with the failure of proliferation of renal progenitor cells. Therefore, H2O2 acts as a protective factor in renal repair and an initial signal of kidney regeneration, indicating the key roles of H2O2 in promoting recovery of AKI in zebrafish.

Changes in acute kidney injury epidemiology in critically ill patients: a population-based cohort study in Korea

BackgroundAlthough no specific treatment facilitates renal tubular regeneration in acute kidney injury (AKI), the rapid increase in aging populations with more comorbidities and advances in critical care management are expected to change the epidemiology of AKI. However, few recent studies dissected the current epidemiologic characteristics of critically ill patients with AKI. We investigated recent epidemiologic changes in severe AKI in critically ill patients.MethodsAll adult admissions to intensive care units (ICUs) in Korea from 2008 to 2015 were screened using the national health insurance review and assessment database, and 1,744,235 patients were included. Clinical characteristics and changes in AKI incidence and mortality rate were analyzed.ResultsThe incidence of AKI increased from 7.4% in 2008 to 8.3% in 2015 (p for trend < 0.001). Age-standardized AKI rate was 7018.6 per 100,000 person-years. In-hospital mortality significantly decreased from 39.1% in 2008 to 37.2% in 2015 (p for trend < 0.001) with 2427.6 deaths per 100,000 person-years. Patients with AKI showed higher in-hospital mortality, prolonged ICU length of stay, and higher total cost. Multivariable analysis showed increased risk of in-hospital mortality (adjusted odds ratio [OR] 3.74), mechanical ventilation (OR 2.87), ECMO (OR 6.99), and vasopressor requirement (OR 2.75) in patients with AKI.ConclusionsRecent advances in medical management for AKI have improved in-hospital mortality of critically ill patients with AKI despite increases in the elderly population and AKI incidence.

Controlled Delivery of Stem Cell-Derived Trophic Factors Accelerates Kidney Repair After Renal Ischemia-Reperfusion Injury in Rats.

Renal disease is a worldwide health issue. Besides transplantation, current therapies revolve around dialysis, which only delays disease progression but cannot replace other renal functions, such as synthesizing erythropoietin. To address these limitations, cell‐based approaches have been proposed to restore damaged kidneys as an alternative to current therapies. Recent studies have shown that stem cell‐derived secretomes can enhance tissue regeneration. However, many growth factors undergo rapid degradation when they are injected into the body in a soluble form. Efficient delivery and controlled release of secreting factors at the sites of injury would improve the efficacy in tissue regeneration. Herein, we developed a gel‐based delivery system for controlled delivery of trophic factors in the conditioned medium (CM) secreted from human placental stem cells (HPSCs) and evaluated the effect of trophic factors on renal regeneration. CM treatment significantly enhanced cell proliferation and survival in vitro. Platelet‐rich plasma (PRP) was used as a delivery vehicle for CM. Analysis of the release kinetics demonstrated that CM delivery through the PRP gel resulted in a controlled release of the factors both in vitro and in vivo. In an acute kidney injury model in rats, functional and structural analysis showed that CM delivery using the PRP gel system into the injured kidney minimized renal tissue damage, leading to a more rapid functional recovery when compared with saline, CM, or vehicle only injection groups. These results suggest that controlled delivery of HPSC‐derived trophic factors may provide efficient repair of renal tissue injury. stem cells translational medicine 2019;8:959&970

Gcm1 is involved in cell proliferation and fibrosis during kidney regeneration after ischemia\u2013reperfusion injury

In acute kidney injury (AKI), the S3 segment of the proximal tubule is particularly damaged, as it is most vulnerable to ischemia. However, this region is also involved in renal tubular regeneration. To deeply understand the mechanism of the repair process after ischemic injury in AKI, we focused on glial cells missing 1 (Gcm1), which is one of the genes expressed in the S3 segment. Gcm1 is essential for the development of the placenta, and Gcm1 knockout (KO) is embryonically lethal. Thus, the function of Gcm1 in the kidney has not been analyzed yet. We analyzed the function of Gcm1 in the kidney by specifically knocking out Gcm1 in the kidney. We created an ischemia–reperfusion injury (IRI) model to observe the repair process after AKI. We found that Gcm1 expression was transiently increased during the recovery phase of IRI. In Gcm1 conditional KO mice, during the recovery phase of IRI, tubular cell proliferation reduced and transforming growth factor-β1 expression was downregulated resulting in a reduction in fibrosis. In vitro, Gcm1 overexpression promoted cell proliferation and upregulated TGF-β1 expression. These findings indicate that Gcm1 is involved in the mechanisms of fibrosis and cell proliferation after ischemic injury of the kidney.

Renal Regenerative Potential of Extracellular Vesicles Derived from miRNA-Engineered Mesenchymal Stromal Cells

Extracellular vesicles (EVs) derived from mesenchymal stromal cells (MSCs) possess pro-regenerative potential in different animal models with renal injury. EVs contain different molecules, including proteins, lipids and nucleic acids. Among the shuttled molecules, miRNAs have a relevant role in the pro-regenerative effects of EVs and are a promising target for therapeutic interventions. The aim of this study was to increase the content of specific miRNAs in EVs that are known to be involved in the pro-regenerative effect of EVs, and to assess the capacity of modified EVs to contribute to renal regeneration in in vivo models with acute kidney injuries. To this purpose, MSCs were transiently transfected with specific miRNA mimics by electroporation. Molecular analyses showed that, after transfection, MSCs and derived EVs were efficiently enriched in the selected miRNAs. In vitro and in vivo experiments indicated that EVs engineered with miRNAs maintained their pro-regenerative effects. Of relevance, engineered EVs were more effective than EVs derived from naïve MSCs when used at suboptimal doses. This suggests the potential use of a low amount of EVs (82.5 × 106) to obtain the renal regenerative effect.

Eruca sativa and Raphanus sativus oils Enhance Hepatic and Renal Tissues Regeneration in White Mice

Regeneration is a process of tissue repairing in the body, and according to this process the cells of the body are divided into three types; labile, stable and permanent cells. &#x0D; Objectives: The aims of this study are to evaluate the ability of two herbal seed oils (Eruca sativa and Raphanus sativus) to enhance regeneration and repair in the liver and kidney in the irradiated mice. And to investigate which herbal oil is more effective. &#x0D; Method: Four groups of mice were used in this study. The first three groups were exposed to radiation while the fourth was used as a control. After irradiation the first and second groups were treated with local Eruca sativa and Raphanus sativus oils respectively. While the third group used as a control. Then histopathological investigation was done. &#x0D; Results: Histopathological examination in irradiated groups exhibited that both seed oils could induce regeneration in both hepatic and renal tissues but the activity of Raphanus sativus oil was more effective than Eruca sativa especially in renal tissue. Meanwhile, poor regeneration process appeared in the third group (control).&#x0D; Conclusion: Both local herbal oils had ability to enhance regeneration in the examined tissues but R. sativus seed oil exerted more activity than E. sativa seed oil.

High-throughput screens for agonists of bone morphogenetic protein (BMP) signaling identify potent benzoxazole compounds

Bone morphogenetic protein (BMP) signaling is critical in renal development and disease. In animal models of chronic kidney disease (CKD), re-activation of BMP signaling is reported to be protective by promoting renal repair and regeneration. Clinical use of recombinant BMPs, however, requires harmful doses to achieve efficacy and is costly because of BMPs' complex synthesis. Therefore, alternative strategies are needed to harness the beneficial effects of BMP signaling in CKD. Key aspects of the BMP signaling pathway can be regulated by both extracellular and intracellular molecules. In particular, secreted proteins like noggin and chordin inhibit BMP activity, whereas kielin/chordin-like proteins (KCP) enhance it and attenuate kidney fibrosis or CKD. Clinical development of KCP, however, is precluded by its size and complexity. Therefore, we propose an alternative strategy to enhance BMP signaling by using small molecules, which are simpler to synthesize and more cost-effective. To address our objective, here we developed a small-molecule high-throughput screen (HTS) with human renal cells having an integrated luciferase construct highly responsive to BMPs. We demonstrate the activity of a potent benzoxazole compound, sb4, that rapidly stimulated BMP signaling in these cells. Activation of BMP signaling by sb4 increased the phosphorylation of key second messengers (SMAD-1/5/9) and also increased expression of direct target genes (inhibitors of DNA binding, Id1 and Id3) in canonical BMP signaling. Our results underscore the feasibility of utilizing HTS to identify compounds that mimic key downstream events of BMP signaling in renal cells and have yielded a lead BMP agonist.

Histological characteristics of Acute Tubular Injury during Delayed Graft Function predict renal function after renal transplantation.

Acute Tubular Injury (ATI) is the leading cause of Delayed Graft Function (DGF) after renal transplantation (RTX). Biopsies taken 1 week after RTX often show extensive tubular damage, which in most cases resolves due to the high regenerative capacity of the kidney. Not much is known about the relation between histological parameters of renal damage and regeneration immediately after RTX and renal outcome in patients with DGF. We retrospectively evaluated 94 patients with DGF due to ATI only. Biopsies were scored for morphological characteristics of renal damage (edema, casts, vacuolization, and dilatation) by three independent blinded observers. The regenerative potential was quantified by tubular cells expressing markers of proliferation (Ki67) and dedifferentiation (CD133). Parameters were related to renal function after recovery (CKD‐EPI 3, 6, and 12 months posttransplantation). Quantification of morphological characteristics was reproducible among observers (Kendall's W ≥ 0.56). In a linear mixed model, edema and casts significantly associated with eGFR within the first year independently of clinical characteristics. Combined with donor age, edema and casts outperformed the Nyberg score, a well–validated clinical score to predict eGFR within the first year after transplantation (R 2 = 0.29 vs. R 2 = 0.14). Although the number of Ki67+ cells correlated to the extent of acute damage, neither CD133 nor Ki67 correlated with renal functional recovery. In conclusion, the morphological characteristics of ATI immediately after RTX correlate with graft function after DGF. Despite the crucial role of regeneration in recovery after ATI, we did not find a correlation between dedifferentiation marker CD133 or proliferation marker Ki67 and renal recovery after DGF.

Recent advances in renal regeneration.

Regeneration of a functional kidney from pluripotent stem cells (PSCs) is challenging because of its complex structure. Kidneys are derived from embryonic metanephros, which are composed of three progenitor cells: nephron progenitors, ureteric bud, and stromal progenitors. Nephron progenitors and ureteric bud have been induced successfully from PSCs as a result of the understanding of their detailed developmental process through cell-lineage tracing analysis. Moreover, these induced progenitors can be used to reconstruct the three-dimensional (3D) structure of kidneys in vitro, including glomeruli with podocytes, renal tubules, and the branching ureters. Induction of the remaining renal progenitors (that is, stromal progenitors from PSCs and the further maturation of reconstructed kidneys) needs to be studied extensively to regenerate functional and sophisticated kidneys from PSCs. In addition to the proper induction of renal progenitors, new bioengineering methods such as decellularization and 3D bioprinting and the recent advancements in the regeneration of kidneys in other species are promising leads for regenerating the complex spatial arrangement of kidneys, including the vascular network and urinary excretion pathway in humans.

Potentiating Renal Regeneration Using Mesenchymal Stem Cells.

The potential of a mesenchymal stem cell (MSC) therapy to accelerate the repair of ischemically damaged human kidneys during 24 hours of warm perfusion was evaluated. The hypothesis was that by administering MSC directly to the renal tissue, there would be an improved opportunity for cellular repair mediated by intrarenal paracrine effects. Studies were performed using the exsanguinous metabolic support (EMS) tissue-engineering platform. Five pairs of human kidney allografts from donation after circulatory death donors were studied. One human kidney was EMS perfused for 24 hours (control), whereas its paired kidney was EMS perfused with MSC (1 × 10). The kidneys were evaluated for DNA synthesis, cytokine/chemokine synthesis, cytoskeletal regeneration, and mitosis. Treatment with MSC resulted in reduced inflammatory cytokines synthesized by the kidneys. Mesenchymal stem cell treatment led to a significant increase in the synthesis of adenosine triphosphate and growth factors resulting in normalization of metabolism and the cytoskeleton. Toluidine Blue staining of MSC-treated kidneys demonstrated a significant increase in the number of renal cells undergoing mitosis (26%) compared with EMS perfusion alone. To our knowledge, our work is the first to have demonstrated actual renal regeneration while ischemically damaged human kidneys are perfused ex vivo for 24 hours. The observed regeneration entails: increased synthesis of adenosine triphosphate, a reduced inflammatory response, increased synthesis of growth factors, normalization of the cytoskeleton and mitosis. The ability to regenerate renal tissue ex vivo sufficiently to result in immediate function could revolutionize transplantation by solving the chronic organ shortage.

A Bioinspired Scaffold with Anti-Inflammatory Magnesium Hydroxide and Decellularized Extracellular Matrix for Renal Tissue Regeneration.

Kidney diseases are a worldwide public health issue. Renal tissue regeneration using functional scaffolds with biomaterials has attracted a great deal of attention due to limited donor organ availability. Here, we developed a bioinspired scaffold that can efficiently induce renal tissue regeneration. The bioinspired scaffold was designed with poly(lactide-co-glycolide) (PLGA), magnesium hydroxide (Mg(OH)2), and decellularized renal extracellular matrix (ECM). The Mg(OH)2 inhibited materials-induced inflammatory reactions by neutralizing the acidic microenvironment formed by degradation products of PLGA, and the acellular ECM helped restore the biological function of kidney tissues. When the PLGA/ECM/Mg(OH)2 scaffold was implanted in a partially nephrectomized mouse model, it led to the regeneration of renal glomerular tissue with a low inflammatory response. Finally, the PLGA/ECM/Mg(OH)2 scaffold was able to restore renal function more effectively than the control groups. These results suggest that the bioinspired scaffold can be used as an advanced scaffold platform for renal disease treatment.