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Giannuzzi F, Picerno A, Maiullari S, Montenegro F, Cicirelli A, Stasi A, De Palma G, Di Lorenzo VF, Pertosa GB, Pontrelli P, Rossini M, Gallo N, Salvatore L, Di Leo V, Errede M, Tamma R, Ribatti D, Gesualdo L, Sallustio F. Unveiling spontaneous renal tubule-like structures from human adult renal progenitor cell spheroids derived from urine. Stem Cells Transl Med 2025; 14:szaf002. [PMID: 40156847 PMCID: PMC11954590 DOI: 10.1093/stcltm/szaf002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2024] [Accepted: 01/05/2025] [Indexed: 04/01/2025] Open
Abstract
The rapidly developing field of renal spheroids and organoids has emerged as a valuable tool for modeling nephrotoxicity, kidney disorders, and kidney development. However, existing studies have relied on intricate and sophisticated differentiation protocols to generate organoids and tubuloids, necessitating the external administration of multiple growth factors within precise timeframes. In our study, we demonstrated that human adult renal progenitor cells (ARPCs) isolated from the urine of both healthy subjects and patients can form spheroids that naturally generated very long tubule-like structures. Importantly, the generation of these tubule-like structures is driven solely by ARPCs, without the need for the external use of chemokines or growth factors to artificially induce this process. These tubule-like structures exhibit the expression of structural and functional renal tubule markers and bear, in some cases, striking structural similarities to various nephron regions, including the distal convoluted tubule, the loop of Henle, and proximal convoluted tubules. Furthermore, ARPC spheroids express markers typical of pluripotent cells, such as stage-specific embryonic antigen 4 (SSEA4), secrete elevated levels of renin, and exhibit angiogenic properties. Notably, ARPCs isolated from the urine of patients with IgA nephropathy form spheroids capable of recapitulating the characteristic IgA1 deposition observed in this disease. These findings represent significant advancements in the field, opening up new avenues for regenerative medicine in the study of kidney development, mechanisms underlying renal disorders, and the development of regenerative therapies for kidney-related ailments.
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Affiliation(s)
- Francesca Giannuzzi
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro,”70124 Bari, Italy
| | - Angela Picerno
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro,”70124 Bari, Italy
| | - Silvia Maiullari
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro,”70124 Bari, Italy
| | - Francesca Montenegro
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro,”70124 Bari, Italy
| | - Antonella Cicirelli
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro,”70124 Bari, Italy
| | - Alessandra Stasi
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro,”70124 Bari, Italy
| | - Giuseppe De Palma
- Institutional BioBank, Experimental Oncology and Biobank Management Unit, IRCCS Istituto Tumori “Giovanni Paolo II,”70124 Bari, Italia
| | | | - Giovanni Battista Pertosa
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro,”70124 Bari, Italy
| | - Paola Pontrelli
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro,”70124 Bari, Italy
| | - Michele Rossini
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro,”70124 Bari, Italy
| | - Nunzia Gallo
- Department of Engineering for Innovation, University of Salento, 73100 Lecce, Italy
- Typeone Biomaterials Srl, 73021 Calimera, Lecce, Italy
| | - Luca Salvatore
- Department of Engineering for Innovation, University of Salento, 73100 Lecce, Italy
- Typeone Biomaterials Srl, 73021 Calimera, Lecce, Italy
| | - Vincenzo Di Leo
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro,”70124 Bari, Italy
| | - Mariella Errede
- Department of Translational Biomedicine and Neuroscience “DiBraiN,” University of Bari “Aldo Moro,”70124 Bari, Italy
| | - Roberto Tamma
- Department of Translational Biomedicine and Neuroscience “DiBraiN,” University of Bari “Aldo Moro,”70124 Bari, Italy
| | - Domenico Ribatti
- Department of Translational Biomedicine and Neuroscience “DiBraiN,” University of Bari “Aldo Moro,”70124 Bari, Italy
| | - Loreto Gesualdo
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro,”70124 Bari, Italy
| | - Fabio Sallustio
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari “Aldo Moro,”70124 Bari, Italy
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Montenegro F, Giannuzzi F, Picerno A, Cicirelli A, Stea ED, Di Leo V, Sallustio F. How Stem and Progenitor Cells Can Affect Renal Diseases. Cells 2024; 13:1460. [PMID: 39273032 PMCID: PMC11393889 DOI: 10.3390/cells13171460] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Revised: 08/26/2024] [Accepted: 08/27/2024] [Indexed: 09/15/2024] Open
Abstract
Stem and progenitor cells have been observed to contribute to regenerative processes in acute renal failure and chronic kidney disease. Recent research has delved into the intricate mechanisms by which stem and progenitor cells exert their influence on kidney diseases. Understanding how these cells integrate with the existing renal architecture and their response to injury could pave the way for innovative treatment strategies aimed at promoting kidney repair and regeneration. Overall, the role of stem and progenitor cells in kidney diseases is multifaceted, with their ability to contribute to tissue regeneration, immune modulation, and the maintenance of renal homeostasis. Here, we review the studies that we have available today about the involvement of stem and progenitor cells both in regenerative therapies and in the causes of renal diseases, as well as in natural healing mechanisms, taking into account the main kidney disorders, such as IgA nephropathy, lupus nephritis, diabetic nephropathy, C3 glomerulopathy, focal segmental glomerulosclerosis, idiopathic membranous nephropathy, anti-glomerular basement membrane glomerulonephritis, and ANCA-associated crescentic glomerulonephritis. Moreover, based on the comprehensive data available in the framework of the specific kidney diseases on stem cells and renal progenitors, we hypothesize a possible role of adult renal progenitors in exacerbating or recovering the illness.
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Affiliation(s)
- Francesca Montenegro
- Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy; (F.M.); (F.G.); (A.P.); (A.C.); (V.D.L.)
| | - Francesca Giannuzzi
- Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy; (F.M.); (F.G.); (A.P.); (A.C.); (V.D.L.)
| | - Angela Picerno
- Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy; (F.M.); (F.G.); (A.P.); (A.C.); (V.D.L.)
| | - Antonella Cicirelli
- Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy; (F.M.); (F.G.); (A.P.); (A.C.); (V.D.L.)
| | - Emma Diletta Stea
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy;
| | - Vincenzo Di Leo
- Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124 Bari, Italy; (F.M.); (F.G.); (A.P.); (A.C.); (V.D.L.)
| | - Fabio Sallustio
- Department of Precision and Regenerative Medicine and Ionian Area, University of Bari Aldo Moro, 70124 Bari, Italy;
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Myszczyszyn A, Popp O, Kunz S, Sporbert A, Jung S, Penning LC, Fendler A, Mertins P, Birchmeier W. Mice with renal-specific alterations of stem cell-associated signaling develop symptoms of chronic kidney disease but surprisingly no tumors. PLoS One 2024; 19:e0282938. [PMID: 38512983 PMCID: PMC10957084 DOI: 10.1371/journal.pone.0282938] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2023] [Accepted: 01/13/2024] [Indexed: 03/23/2024] Open
Abstract
Previously, we found that Wnt and Notch signaling govern stem cells of clear cell kidney cancer (ccRCC) in patients. To mimic stem cell responses in the normal kidney in vitro in a marker-unbiased fashion, we have established tubular organoids (tubuloids) from total single adult mouse kidney epithelial cells in Matrigel and serum-free conditions. Deep proteomic and phosphoproteomic analyses revealed that tubuloids resembled renewal of adult kidney tubular epithelia, since tubuloid cells displayed activity of Wnt and Notch signaling, long-term proliferation and expression of markers of proximal and distal nephron lineages. In our wish to model stem cell-derived human ccRCC, we have generated two types of genetic double kidney mutants in mice: Wnt-β-catenin-GOF together with Notch-GOF and Wnt-β-catenin-GOF together with a most common alteration in ccRCC, Vhl-LOF. An inducible Pax8-rtTA-LC1-Cre was used to drive recombination specifically in adult kidney epithelial cells. We confirmed mutagenesis of β-catenin, Notch and Vhl alleles on DNA, protein and mRNA target gene levels. Surprisingly, we observed symptoms of chronic kidney disease (CKD) in mutant mice, but no increased proliferation and tumorigenesis. Thus, the responses of kidney stem cells in the tubuloid and genetic systems produced different phenotypes, i.e. enhanced renewal versus CKD.
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Affiliation(s)
- Adam Myszczyszyn
- Cancer Research Program, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Oliver Popp
- Proteomics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Severine Kunz
- Electron Microscopy, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Anje Sporbert
- Advanced Light Microscopy, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Simone Jung
- Cancer Research Program, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Louis C. Penning
- Faculty of Veterinary Medicine, Utrecht University, Utrecht, The Netherlands
| | - Annika Fendler
- Cancer Research Program, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Philipp Mertins
- Proteomics, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
| | - Walter Birchmeier
- Cancer Research Program, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany
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Zhang Y, Xu L, Guo C, Li X, Tian Y, Liao L, Dong J. High CD133 expression in proximal tubular cells in diabetic kidney disease: good or bad? J Transl Med 2024; 22:159. [PMID: 38365731 PMCID: PMC10870558 DOI: 10.1186/s12967-024-04950-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2023] [Accepted: 02/03/2024] [Indexed: 02/18/2024] Open
Abstract
BACKGROUND Proximal tubular cells (PTCs) play a critical role in the progression of diabetic kidney disease (DKD). As one of important progenitor markers, CD133 was reported to indicate the regeneration of dedifferentiated PTCs in acute kidney disease. However, its role in chronic DKD is unclear. Therefore, we aimed to investigate the expression patterns and elucidate its functional significance of CD133 in DKD. METHODS Data mining was employed to illustrate the expression and molecular function of CD133 in PTCs in human DKD. Subsequently, rat models representing various stages of DKD progression were established. The expression of CD133 was confirmed in DKD rats, as well as in human PTCs (HK-2 cells) and rat PTCs (NRK-52E cells) exposed to high glucose. The immunofluorescence and flow cytometry techniques were utilized to determine the expression patterns of CD133, utilizing proliferative and injury indicators. After overexpression or knockdown of CD133 in HK-2 cells, the cell proliferation and apoptosis were detected by EdU assay, real-time cell analysis and flow analysis. Additionally, the evaluation of epithelial, progenitor cell, and apoptotic indices was performed through western blot and quantitative RT-PCR analyses. RESULTS The expression of CD133 was notably elevated in both human and rat PTCs in DKD, and this expression increased as DKD progressed. CD133 was found to be co-expressed with CD24, KIM-1, SOX9, and PCNA, suggesting that CD133+ cells were damaged and associated with proliferation. In terms of functionality, the knockdown of CD133 resulted in a significant reduction in proliferation and an increase in apoptosis in HK-2 cells compared to the high glucose stimulus group. Conversely, the overexpression of CD133 significantly mitigated high glucose-induced cell apoptosis, but had no impact on cellular proliferation. Furthermore, the Nephroseq database provided additional evidence to support the correlation between CD133 expression and the progression of DKD. Analysis of single-cell RNA-sequencing data revealed that CD133+ PTCs potentially play a role in the advancement of DKD through multiple mechanisms, including heat damage, cell microtubule stabilization, cell growth inhibition and tumor necrosis factor-mediated signaling pathway. CONCLUSION Our study demonstrates that the upregulation of CD133 is linked to cellular proliferation and protects PTC from apoptosis in DKD and high glucose induced PTC injury. We propose that heightened CD133 expression may facilitate cellular self-protective responses during the initial stages of high glucose exposure. However, its sustained increase is associated with the pathological progression of DKD. In conclusion, CD133 exhibits dual roles in the advancement of DKD, necessitating further investigation.
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Affiliation(s)
- Yuhan Zhang
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China
- Department of Endocrinology, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, 250021, Shandong, China
- Shandong Key Laboratory of Endocrinology and Lipid Metabolism, Jinan, 250021, Shandong, China
| | - Lusi Xu
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China
| | - Congcong Guo
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China
| | - Xianzhi Li
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China
| | - Yutian Tian
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China
| | - Lin Liao
- Department of Endocrinology and Metabology, The First Affiliated Hospital of Shandong First Medical University & Shandong Provincial Qianfoshan Hospital, Jinan, 250014, China.
| | - Jianjun Dong
- Division of Endocrinology, Department of Internal Medicine, Qilu Hospital of Shandong University, Jinan, 250012, China.
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Pergolizzi S, Fumia A, D'Angelo R, Mangano A, Lombardo GP, Giliberti A, Messina E, Alesci A, Lauriano ER. Expression and function of toll-like receptor 2 in vertebrate. Acta Histochem 2023; 125:152028. [PMID: 37075649 DOI: 10.1016/j.acthis.2023.152028] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2023] [Revised: 04/13/2023] [Accepted: 04/13/2023] [Indexed: 04/21/2023]
Abstract
Toll-like receptors (TLRs) are essential for identifying and detecting pathogen-associated molecular patterns (PAMPs) produced by a variety of pathogens, including viruses and bacteria. Since TLR2 is the only TLR capable of creating functional heterodimers with more than two other TLR types, it is very important for vertebrate immunity. TLR2 not only broadens the variety of PAMPs that it can recognize but has also the potential to diversify the subsequent signaling cascades. TLR2 is ubiquitous, which is consistent with the wide variety of tasks and functions it serves. Immune cells, endothelial cells, and epithelial cells have all been found to express TLR2. This review aims to gather currently available information about the preservation of this intriguing immunological molecule in the phylum of vertebrates.
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Affiliation(s)
- Simona Pergolizzi
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Angelo Fumia
- Department of Clinical and Experimental Medicine, University of Messina, Padiglione C, A. O. U. Policlinico "G. Martino", 98124 Messina, Italy
| | - Roberta D'Angelo
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Angelica Mangano
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Giorgia Pia Lombardo
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Angelo Giliberti
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Emmanuele Messina
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, 98166 Messina, Italy
| | - Alessio Alesci
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, 98166 Messina, Italy.
| | - Eugenia Rita Lauriano
- Department of Chemical, Biological, Pharmaceutical, and Environmental Sciences, University of Messina, 98166 Messina, Italy
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Giannuzzi F, Maiullari S, Gesualdo L, Sallustio F. The Mission of Long Non-Coding RNAs in Human Adult Renal Stem/Progenitor Cells and Renal Diseases. Cells 2023; 12:1115. [PMID: 37190024 PMCID: PMC10137190 DOI: 10.3390/cells12081115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 03/29/2023] [Accepted: 04/06/2023] [Indexed: 05/17/2023] Open
Abstract
Long non-coding RNAs (lncRNAs) are a large, heterogeneous class of transcripts and key regulators of gene expression at both the transcriptional and post-transcriptional levels in different cellular contexts and biological processes. Understanding the potential mechanisms of action of lncRNAs and their role in disease onset and development may open up new possibilities for therapeutic approaches in the future. LncRNAs also play an important role in renal pathogenesis. However, little is known about lncRNAs that are expressed in the healthy kidney and that are involved in renal cell homeostasis and development, and even less is known about lncRNAs involved in human adult renal stem/progenitor cells (ARPC) homeostasis. Here we give a thorough overview of the biogenesis, degradation, and functions of lncRNAs and highlight our current understanding of their functional roles in kidney diseases. We also discuss how lncRNAs regulate stem cell biology, focusing finally on their role in human adult renal stem/progenitor cells, in which the lncRNA HOTAIR prevents them from becoming senescent and supports these cells to secrete high quantities of α-Klotho, an anti-aging protein capable of influencing the surrounding tissues and therefore modulating the renal aging.
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Affiliation(s)
- Francesca Giannuzzi
- Department of Interdisciplinary Medicine (DIM), University of Bari Aldo Moro, 70124 Bari, Italy
| | - Silvia Maiullari
- Department of Interdisciplinary Medicine (DIM), University of Bari Aldo Moro, 70124 Bari, Italy
| | - Loreto Gesualdo
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy
- MIRROR—Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Fabio Sallustio
- Department of Precision and Regenerative Medicine and Ionian Area (DiMePRe-J), University of Bari Aldo Moro, 70124 Bari, Italy
- MIRROR—Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
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The "3Ds" of Growing Kidney Organoids: Advances in Nephron Development, Disease Modeling, and Drug Screening. Cells 2023; 12:cells12040549. [PMID: 36831216 PMCID: PMC9954122 DOI: 10.3390/cells12040549] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2023] [Revised: 02/03/2023] [Accepted: 02/07/2023] [Indexed: 02/11/2023] Open
Abstract
A kidney organoid is a three-dimensional (3D) cellular aggregate grown from stem cells in vitro that undergoes self-organization, recapitulating aspects of normal renal development to produce nephron structures that resemble the native kidney organ. These miniature kidney-like structures can also be derived from primary patient cells and thus provide simplified context to observe how mutations in kidney-disease-associated genes affect organogenesis and physiological function. In the past several years, advances in kidney organoid technologies have achieved the formation of renal organoids with enhanced numbers of specialized cell types, less heterogeneity, and more architectural complexity. Microfluidic bioreactor culture devices, single-cell transcriptomics, and bioinformatic analyses have accelerated the development of more sophisticated renal organoids and tailored them to become increasingly amenable to high-throughput experimentation. However, many significant challenges remain in realizing the use of kidney organoids for renal replacement therapies. This review presents an overview of the renal organoid field and selected highlights of recent cutting-edge kidney organoid research with a focus on embryonic development, modeling renal disease, and personalized drug screening.
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Scattered Tubular Cells Markers in Macula Densa of Normal Human Adult Kidney. Int J Mol Sci 2022; 23:ijms231810504. [PMID: 36142420 PMCID: PMC9500602 DOI: 10.3390/ijms231810504] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2022] [Revised: 08/29/2022] [Accepted: 09/08/2022] [Indexed: 11/28/2022] Open
Abstract
Background: The scattered tubular cells (STCs) are a population of resident progenitor tubular cells with expansion, self-renewal and epithelial differentiation abilities. Although these cells are localized within the proximal (PTs) and distal (DTs) tubules in a normal adult kidney, their presence has never been demonstrated in human macula densa (MD). The purpose of the present study is to describe the presence of STCs in MD using specific markers such as prominin-1 (CD133), cytokeratin 7 (KRT7) and vimentin (VIM). Methods: We analyzed two sets of three consecutive serial sections for each sample. The first sections of each set were immunostained for nNOS to identify MD, the second sections were immune-stained for CD133 (specific STCs marker) while the third sections were analyzed for KRT7 (another STCs specific marker) and VIM (that stains the basal pole of the STCs) in the first and second sets, respectively, in order to study the co-expression of KRT7 and VIM with the CD133 marker. Results: CD133 was localized in some MD cells and in the adjacent DT cells. Moreover, CD133 was detected in the parietal epithelial cells of Bowman’s capsule and in some proximal tubules (PT). KRT7-positive cells were identified in MD and adjacent DT cells, while KRT7 positivity was mostly confined in both DT and collecting ducts (CD) in the other areas of the renal parenchyma. CD133 and KRT7 were co-expressed in some MD and adjacent DT cells. Some of the latter cells were positive both for CD133 and VIM. CD133 was always localized in the apical part of the cells, whereas the VIM expression was evident only in the cellular basal pole. Although some cells of MD expressed VIM or CD133, none of them co-expressed VIM and CD133. Conclusions: The presence of STCs was demonstrated in human adult MD, suggesting that this structure has expansion, self-renewal and epithelial differentiation abilities, similar to all other parts of renal tubules.
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Picerno A, Giannuzzi F, Curci C, De Palma G, Di Chiano MG, Simone S, Franzin R, Gallone A, Di Lorenzo VF, Stasi A, Pertosa GB, Sabbà C, Gesualdo L, Sallustio F. The long non-coding RNA HOTAIR controls the self-renewal, cell senescence, and secretion of antiaging protein α-Klotho in human adult renal progenitor cells. Stem Cells 2022; 40:963-975. [PMID: 35922038 DOI: 10.1093/stmcls/sxac054] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 07/06/2022] [Indexed: 11/13/2022]
Abstract
The long non-coding RNAs (lncRNA) play an important role in several biological processes including some renal diseases. Nevertheless, little is known on lncRNA that are expressed in healthy kidney and involved in renal cell homeostasis and development, and even less is known about lncRNA involved in the maintenance of human adult renal stem/progenitor cells (ARPCs) that have been shown to be very important for renal homeostasis and repair processes. Through a whole genome transcriptome screening, we found that the HOTAIR lncRNA is highly expressed in renal progenitors and potentially involved in cell cycle and senescence biological processes. By CRISPR/Cas9 genome editing, we generated HOTAIR knock-out ARPC lines and established a key role of this lncRNA in ARPC self-renewal properties by sustaining their proliferative capacity and limiting the apoptotic process. Intriguingly, the HOTAIR knock-out led to the ARPC senescence and to a significant decrease of the CD133 stem cell marker expression, that is an inverse marker of ARPC senescence and can regulate renal tubular repair after the damage. Furthermore, we found that ARPCs expressed high levels of the α-Klotho anti-aging protein and especially 2.6-fold higher levels compared to that secreted by renal proximal tubular cells (RPTECs). Finally, we showed that HOTAIR exerts its function through the epigenetic silencing of the cell cycle inhibitor p15 inducing the trimethylation of the histone H3K27. Altogether, these results shed new light on the mechanisms of regulation of these important renal cells and may support the future development of precision therapies for kidney diseases.
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Affiliation(s)
- Angela Picerno
- Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124, Bari, Italy
| | - Francesca Giannuzzi
- Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124, Bari, Italy
| | - Claudia Curci
- Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari "Aldo Moro", 70124, Bari, Italy
| | - Giuseppe De Palma
- MIRROR-Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Maria Giovanna Di Chiano
- Institutional BioBank, Experimental Oncology and Biobank Management Unit, IRCCS Istituto Tumori "Giovanni Paolo II", Bari, Italia
| | - Simona Simone
- Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari "Aldo Moro", 70124, Bari, Italy
| | - Rossana Franzin
- Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari "Aldo Moro", 70124, Bari, Italy.,MIRROR-Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Anna Gallone
- MIRROR-Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy.,Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, 70124, Bari, Italy
| | | | - Alessandra Stasi
- Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari "Aldo Moro", 70124, Bari, Italy.,MIRROR-Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Giovanni Battista Pertosa
- Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari "Aldo Moro", 70124, Bari, Italy.,MIRROR-Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Carlo Sabbà
- Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124, Bari, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari "Aldo Moro", 70124, Bari, Italy.,MIRROR-Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
| | - Fabio Sallustio
- Department of Interdisciplinary Medicine, University of Bari Aldo Moro, 70124, Bari, Italy.,MIRROR-Medical Institute for Regeneration, Repairing and Organ Replacement, Interdepartmental Center, University of Bari Aldo Moro, 70124 Bari, Italy
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10
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Picerno A, Castellano G, Curci C, Kopaczka K, Stasi A, Pertosa GB, Sabbà C, Gesualdo L, Gramignoli R, Sallustio F. The Icarus Flight of Perinatal Stem and Renal Progenitor Cells Within Immune System. Front Immunol 2022; 13:840146. [PMID: 35355984 PMCID: PMC8959820 DOI: 10.3389/fimmu.2022.840146] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2021] [Accepted: 02/11/2022] [Indexed: 12/02/2022] Open
Abstract
Our immune system actively fights bacteria and viruses, and it must strike a delicate balance between over- and under-reaction, just like Daedalus and Icarus in Greek mythology, who could not escape their imprisonment by flying too high or too low. Both human amniotic epithelial and mesenchymal stromal cells and the conditioned medium generated from their culture exert multiple immunosuppressive activities. They have strong immunomodulatory properties that are influenced by the types and intensity of inflammatory stimuli present in the microenvironment. Notably, very recently, the immunomodulatory activity of human adult renal stem/progenitor cells (ARPCs) has been discovered. ARPCs cause a decrease in Tregs and CD3+ CD4- CD8- (DN) T cells in the early stages of inflammation, encouraging inflammation, and an increase in the late stages of inflammation, favoring inflammation quenching. If the inflammatory trigger continues, however, ARPCs cause a further increase in DN T cells to avoid the development of a harmful inflammatory state. As in the flight of Daedalus and Icarus, who could not fly too high or too low to not destroy their wings by the heat of the sun or the humidity of the sea, in response to an inflammatory environment, stem cells seem to behave by paying attention to regulating T cells in the balance between immune tolerance and autoimmunity. Recognizing the existence of both suppressive and stimulatory properties, and the mechanisms that underpin the duality of immune reaction, will aid in the development of active immunotherapeutic approaches that manipulate the immune system to achieve therapeutic benefit.
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Affiliation(s)
- Angela Picerno
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis and Renal Transplant Unit, Department of Clinical Sciences and Community Health, University of Milan, Milan, Italy
| | - Claudia Curci
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation (DETO), University of Bari Aldo Moro, Bari, Italy
| | - Katarzyna Kopaczka
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Alessandra Stasi
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation (DETO), University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Battista Pertosa
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation (DETO), University of Bari Aldo Moro, Bari, Italy
| | - Carlo Sabbà
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation (DETO), University of Bari Aldo Moro, Bari, Italy
| | - Roberto Gramignoli
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Fabio Sallustio
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, Bari, Italy
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11
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Sallustio F, Picerno A, Tatullo M, Rampino A, Rengo C, Valletta A, Torretta S, Falcone RM. Toll-Like Receptors in Stem/Progenitor Cells. Handb Exp Pharmacol 2022; 276:175-212. [PMID: 34595583 DOI: 10.1007/164_2021_539] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Abstract
One of the bridges that control the cross-talk between the innate and adaptive immune systems is toll-like receptors (TLRs). TLRs interact with molecules shared and maintained by the source pathogens, but also with endogenous molecules derived from injured tissues (damage/danger-associated molecular patterns - DAMPs). This is likely why some kinds of stem/progenitor cells (SCs) have been found to express TLRs. The role of TLRs in regulating basal motility, proliferation, processes of differentiation, self-renewal, and immunomodulation has been demonstrated in these cells. In this book chapter, we will discuss the many different functions assumed by the TLRs in SCs, pointing out that, depending on the context and the type of ligands they perceive, they may have different effects. In addition, the role of TLR in SC's response to specific tissue damage and in reparative processes will be addressed, as well as how the discovery of molecules mediating TLR signaling's differential function may be decisive for the development of new therapeutic strategies. Given the available studies on TLRs in SCs, the significance of TLRs in sensing an injury to stem/progenitor cells and evaluating their action and reparative activity, which depends on the circumstances, will be discussed here. It could also be possible that SCs used in therapy could theoretically be exposed to TLR ligands, which could modulate their in vivo therapeutic potential. In this context, we need to better understand the mechanisms of action of TLRs on SCs and learn how to regulate these receptors and their downstream pathways in a precise way in order to modulate SC proliferation, survival, migration, and differentiation in the pathological environment. In this way, cell therapy may be strengthened and made safer in the future.
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Affiliation(s)
- Fabio Sallustio
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro", Bari, Italy.
| | - Angela Picerno
- Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari "Aldo Moro", Bari, Italy
| | - Marco Tatullo
- Department of Basic Medical Sciences, Neurosciences and Sense Organs-University of Bari "Aldo Moro", Bari, Italy
| | - Antonio Rampino
- Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy
| | - Carlo Rengo
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy
| | - Alessandra Valletta
- Department of Neurosciences, Reproductive and Odontostomatological Sciences, University of Naples Federico II, Naples, Italy
| | - Silvia Torretta
- Group of Psychiatric Neuroscience, Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari Aldo Moro, Bari, Italy
| | - Rosa Maria Falcone
- Department of Biomedical Sciences and Human Oncology, University of Bari Aldo Moro, Bari, Italy
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12
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Gallo N, Natali ML, Curci C, Picerno A, Gallone A, Vulpi M, Vitarelli A, Ditonno P, Cascione M, Sallustio F, Rinaldi R, Sannino A, Salvatore L. Analysis of the Physico-Chemical, Mechanical and Biological Properties of Crosslinked Type-I Collagen from Horse Tendon: Towards the Development of Ideal Scaffolding Material for Urethral Regeneration. MATERIALS (BASEL, SWITZERLAND) 2021; 14:7648. [PMID: 34947245 PMCID: PMC8707771 DOI: 10.3390/ma14247648] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/04/2021] [Revised: 12/05/2021] [Accepted: 12/09/2021] [Indexed: 11/19/2022]
Abstract
Urethral stenosis is a pathological condition that consists in the narrowing of the urethral lumen because of the formation of scar tissue. Unfortunately, none of the current surgical approaches represent an optimal solution because of the high stricture recurrence rate. In this context, we preliminarily explored the potential of an insoluble type-I collagen from horse tendon as scaffolding material for the development of innovative devices for the regeneration of injured urethral tracts. Non-porous collagen-based substrates were produced and optimized, in terms of crosslinking density of the macromolecular structure, to either provide mechanical properties compliant with the urinary tract physiological stress and better sustain tissue regeneration. The effect of the adopted crosslinking strategy on the protein integrity and on the substrate physical-chemical, mechanical and biological properties was investigated in comparison with a decellularized matrix from porcine small intestinal submucosa (SIS patch), an extensively used xenograft licensed for clinical use in urology. The optimized production protocols allowed the preservation of the type I collagen native structure and the realization of a substrate with appealing end-use properties. The biological response, preliminarily investigated by immunofluorescence experiments on human adult renal stem/progenitor cells until 28 days, showed the formation of a stem-cell monolayer within 14 days and the onset of spheroids within 28 days. These results suggested the great potential of the collagen-based material for the development of scaffolds for urethral plate regeneration and for in vitro cellular studies.
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Affiliation(s)
- Nunzia Gallo
- Department of Engineering for Innovation, University of Salento, 73100 Lecce, Italy; (M.L.N.); (A.S.); (L.S.)
| | - Maria Lucia Natali
- Department of Engineering for Innovation, University of Salento, 73100 Lecce, Italy; (M.L.N.); (A.S.); (L.S.)
- Typeone Biomaterials, Via Vittorio Veneto 64/C, 73036 Muro Leccese, Italy
| | - Claudia Curci
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari “Aldo Moro”, 70124 Bari, Italy; (C.C.); (A.G.)
| | - Angela Picerno
- Nephrology Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Anna Gallone
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari “Aldo Moro”, 70124 Bari, Italy; (C.C.); (A.G.)
| | - Marco Vulpi
- Urology and Andrology Unit, Department of Emergency and Organ Transplant, University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.V.); (A.V.); (P.D.)
| | - Antonio Vitarelli
- Urology and Andrology Unit, Department of Emergency and Organ Transplant, University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.V.); (A.V.); (P.D.)
| | - Pasquale Ditonno
- Urology and Andrology Unit, Department of Emergency and Organ Transplant, University of Bari “Aldo Moro”, 70124 Bari, Italy; (M.V.); (A.V.); (P.D.)
| | - Mariafrancesca Cascione
- Department of Mathematics and Physics “Ennio De Giorgi”, University of Salento, 73100 Lecce, Italy; (M.C.); (R.R.)
| | - Fabio Sallustio
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Rosaria Rinaldi
- Department of Mathematics and Physics “Ennio De Giorgi”, University of Salento, 73100 Lecce, Italy; (M.C.); (R.R.)
| | - Alessandro Sannino
- Department of Engineering for Innovation, University of Salento, 73100 Lecce, Italy; (M.L.N.); (A.S.); (L.S.)
| | - Luca Salvatore
- Department of Engineering for Innovation, University of Salento, 73100 Lecce, Italy; (M.L.N.); (A.S.); (L.S.)
- Typeone Biomaterials, Via Vittorio Veneto 64/C, 73036 Muro Leccese, Italy
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13
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Agarwal S, Sudhini YR, Polat OK, Reiser J, Altintas MM. Renal cell markers: lighthouses for managing renal diseases. Am J Physiol Renal Physiol 2021; 321:F715-F739. [PMID: 34632812 DOI: 10.1152/ajprenal.00182.2021] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Kidneys, one of the vital organs in our body, are responsible for maintaining whole body homeostasis. The complexity of renal function (e.g., filtration, reabsorption, fluid and electrolyte regulation, and urine production) demands diversity not only at the level of cell types but also in their overall distribution and structural framework within the kidney. To gain an in depth molecular-level understanding of the renal system, it is imperative to discern the components of kidney and the types of cells residing in each of the subregions. Recent developments in labeling, tracing, and imaging techniques have enabled us to mark, monitor, and identify these cells in vivo with high efficiency in a minimally invasive manner. In this review, we summarize different cell types, specific markers that are uniquely associated with those cell types, and their distribution in the kidney, which altogether make kidneys so special and different. Cellular sorting based on the presence of certain proteins on the cell surface allowed for the assignment of multiple markers for each cell type. However, different studies using different techniques have found contradictions in cell type-specific markers. Thus, the term "cell marker" might be imprecise and suboptimal, leading to uncertainty when interpreting the data. Therefore, we strongly believe that there is an unmet need to define the best cell markers for a cell type. Although the compendium of renal-selective marker proteins presented in this review is a resource that may be useful to researchers, we acknowledge that the list may not be necessarily exhaustive.
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Affiliation(s)
- Shivangi Agarwal
- Department of Internal Medicine, Rush University, Chicago, Illinois
| | | | - Onur K Polat
- Department of Internal Medicine, Rush University, Chicago, Illinois
| | - Jochen Reiser
- Department of Internal Medicine, Rush University, Chicago, Illinois
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14
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Peired AJ, Lazzeri E, Guzzi F, Anders HJ, Romagnani P. From kidney injury to kidney cancer. Kidney Int 2021; 100:55-66. [PMID: 33794229 DOI: 10.1016/j.kint.2021.03.011] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2020] [Revised: 02/04/2021] [Accepted: 02/17/2021] [Indexed: 02/07/2023]
Abstract
Epidemiologic studies document strong associations between acute or chronic kidney injury and kidney tumors. However, whether these associations are linked by causation, and in which direction, is unclear. Accumulating data from basic and clinical research now shed light on this issue and prompt us to propose a new pathophysiological concept with immanent implications in the management of patients with kidney disease and patients with kidney tumors. As a central paradigm, this review proposes the mechanisms of kidney damage and repair that are active during acute kidney injury but also during persistent injuries in chronic kidney disease as triggers of DNA damage, promoting the expansion of (pre-)malignant cell clones. As renal progenitors have been identified by different studies as the cell of origin for several benign and malignant kidney tumors, we discuss how the different types of kidney tumors relate to renal progenitors at specific sites of injury and to germline or somatic mutations in distinct signaling pathways. We explain how known risk factors for kidney cancer rather represent risk factors for kidney injury as an upstream cause of cancer. Finally, we propose a new role for nephrologists in kidney cancer (i.e., the primary and secondary prevention and treatment of kidney injury to reduce incidence, prevalence, and recurrence of kidney cancer).
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Affiliation(s)
- Anna Julie Peired
- Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies, University of Florence, Florence, Italy; Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy
| | - Elena Lazzeri
- Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies, University of Florence, Florence, Italy; Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy
| | - Francesco Guzzi
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy
| | - Hans-Joachim Anders
- Division of Nephrology, Medizinische Klinik and Poliklinik IV, Ludwig Maximilian University Klinikum, Munich, Germany
| | - Paola Romagnani
- Excellence Centre for Research, Transfer and High Education for the Development of DE NOVO Therapies, University of Florence, Florence, Italy; Department of Experimental and Clinical Biomedical Sciences "Mario Serio," University of Florence, Florence, Italy; Nephrology and Dialysis Unit, Meyer Children's University Hospital, Florence, Italy.
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15
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Liu H, Liu C, Qu Y. The effect and molecular mechanism of hypoxia on proliferation and apoptosis of CD133+ renal stem cells. Bosn J Basic Med Sci 2021; 21:313-322. [PMID: 32767964 PMCID: PMC8112556 DOI: 10.17305/bjbms.2020.4887] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2020] [Accepted: 07/30/2020] [Indexed: 11/24/2022] Open
Abstract
Congenital hydronephrosis caused by ureteropelvic junction obstruction (UPJO) eventually leads to renal interstitial fibrosis and atrophy, after a series of pathophysiological problems. Renal repair after injury depends on renal stem cells. This study aimed to determine the expression of renal stem cell marker CD133 in children of different ages and the regulatory effect of stem cell microenvironment. Renal stem cells from children of different ages were identified and screened out by flow cytometry in the study. Children with hydronephrosis were divided into neonates, infants, preschool age, school age, and adolescents groups. A hypoxic cell model prepared with CoCl2 was developed to detect the effect of hypoxia on the proliferation and apoptosis of renal stem cells. The effect and molecular mechanism of hypoxia-inducible factor 1-alpha (HIF-1α) on the proliferation and apoptosis of renal stem cells were also explored. Both hypoxia and HIF-1α significantly promoted the proliferation of renal stem cells and inhibited cell apoptosis. HIF-1α could bind to the promoter region of proliferating cell nuclear antigen (PCNA) and PROM1 (CD133) to mediate their transcription and expression. The content of CD133+ renal stem cells was the highest in the neonatal group and it decreased with the increase of age. Taken together, this study clarified the effect of age on the content of human renal stem cells and determined the regulatory mechanism of hypoxia on renal stem cells. We expect our results to provide a research basis for the treatment and clinical application of renal stem cells.
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Affiliation(s)
- Hong Liu
- Department of Pediatric General Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Cui Liu
- Department of Pediatric General Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
| | - Yan Qu
- Department of Pediatric General Thoracic Surgery, Affiliated Hospital of Zunyi Medical University, Zunyi, China
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16
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Ludes PO, de Roquetaillade C, Chousterman BG, Pottecher J, Mebazaa A. Role of Damage-Associated Molecular Patterns in Septic Acute Kidney Injury, From Injury to Recovery. Front Immunol 2021; 12:606622. [PMID: 33732235 PMCID: PMC7957065 DOI: 10.3389/fimmu.2021.606622] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Accepted: 02/02/2021] [Indexed: 12/12/2022] Open
Abstract
Damage-associated molecular patterns (DAMPs) are a group of immunostimulatory molecules, which take part in inflammatory response after tissue injury. Kidney-specific DAMPs include Tamm-Horsfall glycoprotein, crystals, and uromodulin, released by tubular damage for example. Non-kidney-specific DAMPs include intracellular particles such as nucleus [histones, high-mobility group box 1 protein (HMGB1)] and cytosol parts. DAMPs trigger innate immunity by activating the NRLP3 inflammasome, G-protein coupled class receptors or the Toll-like receptor. Tubular necrosis leads to acute kidney injury (AKI) in either septic, ischemic or toxic conditions. Tubular necrosis releases DAMPs such as histones and HMGB1 and increases vascular permeability, which perpetuates shock and hypoperfusion via Toll Like Receptors. In acute tubular necrosis, intracellular abundance of NADPH may explain a chain reaction where necrosis spreads from cell to cell. The nature AKI in intensive care units does not have preclinical models that meet a variation of blood perfusion or a variation of glomerular filtration within hours before catecholamine infusion. However, the dampening of several DAMPs in AKI could provide organ protection. Research should be focused on the numerous pathophysiological pathways to identify the relative contribution to renal dysfunction. The therapeutic perspectives could be strategies to suppress side effect of DAMPs and to promote renal function regeneration.
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Affiliation(s)
- Pierre-Olivier Ludes
- Department of Anesthesiology and Intensive Care, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France.,EA 3072, Mitochondrie Stress Oxydant et Protection Musculaire, Faculté de Médecine, FRU 6702, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Charles de Roquetaillade
- Department of Anesthesiology and Critical Care, Hôpital Lariboisière, DMU Parabol, APHP.Nord, Paris, France.,Inserm U942 MASCOT, Université de Paris, Paris, France
| | - Benjamin Glenn Chousterman
- Department of Anesthesiology and Critical Care, Hôpital Lariboisière, DMU Parabol, APHP.Nord, Paris, France.,Inserm U942 MASCOT, Université de Paris, Paris, France
| | - Julien Pottecher
- Department of Anesthesiology and Intensive Care, Hautepierre Hospital, Strasbourg University Hospital, Strasbourg, France.,EA 3072, Mitochondrie Stress Oxydant et Protection Musculaire, Faculté de Médecine, FRU 6702, Fédération de Médecine Translationnelle de Strasbourg (FMTS), Strasbourg, France
| | - Alexandre Mebazaa
- Department of Anesthesiology and Critical Care, Hôpital Lariboisière, DMU Parabol, APHP.Nord, Paris, France.,Inserm U942 MASCOT, Université de Paris, Paris, France
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17
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Molecular Mechanisms of Renal Progenitor Regulation: How Many Pieces in the Puzzle? Cells 2021; 10:cells10010059. [PMID: 33401654 PMCID: PMC7823786 DOI: 10.3390/cells10010059] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2020] [Revised: 12/26/2020] [Accepted: 12/29/2020] [Indexed: 12/12/2022] Open
Abstract
Kidneys of mice, rats and humans possess progenitors that maintain daily homeostasis and take part in endogenous regenerative processes following injury, owing to their capacity to proliferate and differentiate. In the glomerular and tubular compartments of the nephron, consistent studies demonstrated that well-characterized, distinct populations of progenitor cells, localized in the parietal epithelium of Bowman capsule and scattered in the proximal and distal tubules, could generate segment-specific cells in physiological conditions and following tissue injury. However, defective or abnormal regenerative responses of these progenitors can contribute to pathologic conditions. The molecular characteristics of renal progenitors have been extensively studied, revealing that numerous classical and evolutionarily conserved pathways, such as Notch or Wnt/β-catenin, play a major role in cell regulation. Others, such as retinoic acid, renin-angiotensin-aldosterone system, TLR2 (Toll-like receptor 2) and leptin, are also important in this process. In this review, we summarize the plethora of molecular mechanisms directing renal progenitor responses during homeostasis and following kidney injury. Finally, we will explore how single-cell RNA sequencing could bring the characterization of renal progenitors to the next level, while knowing their molecular signature is gaining relevance in the clinic.
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18
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Curci C, Picerno A, Chaoul N, Stasi A, De Palma G, Franzin R, Pontrelli P, Castellano G, Pertosa GB, Macchia L, Di Lorenzo VF, Sabbà C, Gallone A, Gesualdo L, Sallustio F. Adult Renal Stem/Progenitor Cells Can Modulate T Regulatory Cells and Double Negative T Cells. Int J Mol Sci 2020; 22:274. [PMID: 33383950 PMCID: PMC7795073 DOI: 10.3390/ijms22010274] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/20/2020] [Revised: 12/22/2020] [Accepted: 12/25/2020] [Indexed: 01/22/2023] Open
Abstract
Adult Renal Stem/Progenitor Cells (ARPCs) have been recently identified in the human kidney and several studies show their active role in kidney repair processes during acute or chronic injury. However, little is known about their immunomodulatory properties and their capacity to regulate specific T cell subpopulations. We co-cultured ARPCs activated by triggering Toll-Like Receptor 2 (TLR2) with human peripheral blood mononuclear cells for 5 days and 15 days and studied their immunomodulatory capacity on T cell subpopulations. We found that activated-ARPCs were able to decrease T cell proliferation but did not affect CD8+ and CD4+ T cells. Instead, Tregs and CD3+ CD4- CD8- double-negative (DN) T cells decreased after 5 days and increased after 15 days of co-culture. In addition, we found that PAI1, MCP1, GM-CSF, and CXCL1 were significantly expressed by TLR2-activated ARPCs alone and were up-regulated in T cells co-cultured with activated ARPCs. The exogenous cocktail of cytokines was able to reproduce the immunomodulatory effects of the co-culture with activated ARPCs. These data showed that ARPCs can regulate immune response by inducing Tregs and DN T cells cell modulation, which are involved in the balance between immune tolerance and autoimmunity.
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Affiliation(s)
- Claudia Curci
- Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari “Aldo Moro”, 70124 Bari, Italy; (C.C.); (A.P.); (A.S.); (R.F.); (P.P.); (G.B.P.); (L.G.)
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Angela Picerno
- Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari “Aldo Moro”, 70124 Bari, Italy; (C.C.); (A.P.); (A.S.); (R.F.); (P.P.); (G.B.P.); (L.G.)
| | - Nada Chaoul
- Allergology Unit, DETO, University of Bari “Aldo Moro”, 70124 Bari, Italy; (N.C.); (L.M.)
| | - Alessandra Stasi
- Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari “Aldo Moro”, 70124 Bari, Italy; (C.C.); (A.P.); (A.S.); (R.F.); (P.P.); (G.B.P.); (L.G.)
| | - Giuseppe De Palma
- Institutional BioBank, Experimental Oncology and Biobank Management Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, 70124 Bari, Italy;
| | - Rossana Franzin
- Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari “Aldo Moro”, 70124 Bari, Italy; (C.C.); (A.P.); (A.S.); (R.F.); (P.P.); (G.B.P.); (L.G.)
| | - Paola Pontrelli
- Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari “Aldo Moro”, 70124 Bari, Italy; (C.C.); (A.P.); (A.S.); (R.F.); (P.P.); (G.B.P.); (L.G.)
| | - Giuseppe Castellano
- Nephrology, Dialysis and Transplantation Unit, Department of Medical and Surgical Science, University of Foggia, 71122 Foggia, Italy;
| | - Giovanni B. Pertosa
- Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari “Aldo Moro”, 70124 Bari, Italy; (C.C.); (A.P.); (A.S.); (R.F.); (P.P.); (G.B.P.); (L.G.)
| | - Luigi Macchia
- Allergology Unit, DETO, University of Bari “Aldo Moro”, 70124 Bari, Italy; (N.C.); (L.M.)
| | | | - Carlo Sabbà
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Anna Gallone
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari “Aldo Moro”, 70124 Bari, Italy;
| | - Loreto Gesualdo
- Nephrology, Dialysis and Transplantation Unit, DETO, University of Bari “Aldo Moro”, 70124 Bari, Italy; (C.C.); (A.P.); (A.S.); (R.F.); (P.P.); (G.B.P.); (L.G.)
| | - Fabio Sallustio
- Department of Interdisciplinary Medicine, University of Bari “Aldo Moro”, 70124 Bari, Italy;
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19
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Tsuji K, Kitamura S, Sang Y, Fukushima K, Wada J. Adult kidney stem/progenitor cells contribute to regeneration through the secretion of trophic factors. Stem Cell Res 2020; 46:101865. [PMID: 32505897 DOI: 10.1016/j.scr.2020.101865] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/01/2019] [Revised: 05/12/2020] [Accepted: 05/22/2020] [Indexed: 12/20/2022] Open
Abstract
Adult kidney stem cells are known to have important roles in renal regeneration after acute kidney injury. Although trophic factors from tissue stem cells have been reported to promote the regeneration of other organs, there is limited number of evidence of this phenomenon in the kidneys. Here, we explored the effects of secreted factors from kidney stem cells. We intraperitoneally administered culture supernatant obtained from adult rat kidney stem/progenitor cells into rat kidney ischemia/reperfusion injury models, and the treatment significantly ameliorated renal tubulointerstitial injury, suppressed tubular cell apoptosis, diminished inflammation and promoted the proliferation of both residual renal cells and immature cells. In vitro, treatment with culture supernatant from kidney stem cells significantly promoted cell proliferation and suppressed cisplatin-induced cell apoptosis in both normal rat kidney cells and kidney stem cells. In addition, treatment with culture supernatant increased the expression of nestin in normal rat kidney cells, suggesting the dedifferentiation of tubular cells into stem-like cells. Analysis of the culture supernatant revealed that it contained a variety of growth factors. Taken together, the results suggest that these factors together lead to renal regeneration. In conclusion, adult kidney stem cells contribute to renal regeneration indirectly through the secretion of regenerative factors.
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Affiliation(s)
- Kenji Tsuji
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
| | - Shinji Kitamura
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
| | - Yizhen Sang
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan
| | - Kazuhiko Fukushima
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
| | - Jun Wada
- Department of Nephrology, Rheumatology, Endocrinology and Metabolism, Okayama University Graduate School of Medicine, Dentistry, and Pharmaceutical Sciences, Okayama, Japan.
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20
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Zhou F, Reed-Maldonado AB, Tan Y, Yuan H, Peng D, Banie L, Wang G, Hou J, Lin G, Lue TF. Development of Male External Urethral Sphincter and Tissue-Resident Stem/Progenitor Cells in Rats. Stem Cells Dev 2020; 29:133-143. [PMID: 31822215 PMCID: PMC6987740 DOI: 10.1089/scd.2019.0241] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2019] [Accepted: 12/09/2019] [Indexed: 12/14/2022] Open
Abstract
Stress urinary incontinence (SUI) after prostate surgery is primarily caused by urethral sphincter damage. There are few effective therapeutic approaches for male SUI due to both insufficient study of the structure of the external urethral sphincter (EUS) and incomplete understanding of the resident EUS stem/progenitor cells. The goals of this study were to localize and to determine the distribution of tissue-resident stem/progenitor cells in the male EUS throughout EUS development and to understand the anatomic temporal patterns of the EUS. Newborn Sprague Dawley rats were intraperitoneally injected with the thymidine analogue, 5-ethynyl-2-deoxyuridine (EdU), and the EUS was harvested at five time points (1, 2, 3, 4, and 8 weeks postinjection). The tissue was then processed for EdU staining and immunofluorescence staining for stem cell markers Ki67 and proliferating cell nuclear antigen. We counted the EdU+ label-retaining cells (LRCs) at each time point and colocalized with each stem cell marker, also we isolated and cultured the cells in vitro. The results revealed that the number of EdU+ LRCs in each EUS cross-section decreased over time and that the LRCs were located immediately under the basal membrane of laminin, densely adherent to the muscle fibers. In addition, the thickness of the striated muscle layer developed much faster than the smooth muscle layer during EUS development. By 4 weeks, the structure of the EUS layers was well differentiated. The EUS resident stem/progenitor cells were isolated with MACS® MicroBeads system, and myogenesis was confirmed. In this study, we defined both the time-course development of the EUS and the distribution of resident stem/progenitor cells. This information is crucial for forthcoming studies regarding male micturition and for development of novel therapeutic approaches for postoperative male SUI.
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Affiliation(s)
- Feng Zhou
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
- Department of Urology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
| | - Amanda B. Reed-Maldonado
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
- Department of Urology, Tripler Army Medical Center, Honolulu, Hawaii
| | - Yan Tan
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
| | - Huixing Yuan
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
| | - Dongyi Peng
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
| | - Lia Banie
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
| | - Guifang Wang
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
| | - Jianquan Hou
- Department of Urology, The First Affiliated Hospital of Soochow University, Soochow University, Suzhou, China
| | - Guiting Lin
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
| | - Tom F. Lue
- Knuppe Molecular Urology Laboratory, Department of Urology, School of Medicine, University of California, San Francisco, California
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21
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Andrianova NV, Buyan MI, Zorova LD, Pevzner IB, Popkov VA, Babenko VA, Silachev DN, Plotnikov EY, Zorov DB. Kidney Cells Regeneration: Dedifferentiation of Tubular Epithelium, Resident Stem Cells and Possible Niches for Renal Progenitors. Int J Mol Sci 2019; 20:ijms20246326. [PMID: 31847447 PMCID: PMC6941132 DOI: 10.3390/ijms20246326] [Citation(s) in RCA: 27] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2019] [Revised: 12/10/2019] [Accepted: 12/12/2019] [Indexed: 12/11/2022] Open
Abstract
A kidney is an organ with relatively low basal cellular regenerative potential. However, renal cells have a pronounced ability to proliferate after injury, which undermines that the kidney cells are able to regenerate under induced conditions. The majority of studies explain yielded regeneration either by the dedifferentiation of the mature tubular epithelium or by the presence of a resident pool of progenitor cells in the kidney tissue. Whether cells responsible for the regeneration of the kidney initially have progenitor properties or if they obtain a “progenitor phenotype” during dedifferentiation after an injury, still stays the open question. The major stumbling block in resolving the issue is the lack of specific methods for distinguishing between dedifferentiated cells and resident progenitor cells. Transgenic animals, single-cell transcriptomics, and other recent approaches could be powerful tools to solve this problem. This review examines the main mechanisms of kidney regeneration: dedifferentiation of epithelial cells and activation of progenitor cells with special attention to potential niches of kidney progenitor cells. We attempted to give a detailed description of the most controversial topics in this field and ways to resolve these issues.
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Affiliation(s)
- Nadezda V. Andrianova
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119992 Moscow, Russia
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Marina I. Buyan
- Faculty of Bioengineering and Bioinformatics, Lomonosov Moscow State University, 119992 Moscow, Russia
| | - Ljubava D. Zorova
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Irina B. Pevzner
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Vasily A. Popkov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Valentina A. Babenko
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Denis N. Silachev
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
| | - Egor Y. Plotnikov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
- Sechenov First Moscow State Medical University, Institute of Molecular Medicine, 119991 Moscow, Russia
- Correspondence: (E.Y.P.); (D.B.Z.); Tel.: +7-495-939-5944 (E.Y.P.)
| | - Dmitry B. Zorov
- A.N. Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University, 119992 Moscow, Russia
- V.I. Kulakov National Medical Research Center of Obstetrics, Gynecology and Perinatology, 117997 Moscow, Russia
- Correspondence: (E.Y.P.); (D.B.Z.); Tel.: +7-495-939-5944 (E.Y.P.)
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22
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Sallustio F, Stasi A, Curci C, Divella C, Picerno A, Franzin R, De Palma G, Rutigliano M, Lucarelli G, Battaglia M, Staffieri F, Crovace A, Pertosa GB, Castellano G, Gallone A, Gesualdo L. Renal progenitor cells revert LPS-induced endothelial-to-mesenchymal transition by secreting CXCL6, SAA4, and BPIFA2 antiseptic peptides. FASEB J 2019; 33:10753-10766. [PMID: 31268775 DOI: 10.1096/fj.201900351r] [Citation(s) in RCA: 36] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Endothelial dysfunction is a hallmark of LPS-induced acute kidney injury (AKI). Endothelial cells (ECs) acquired a fibroblast-like phenotype and contributed to myofibroblast generation through the endothelial-to-mesenchymal transition (EndMT) process. Of note, human adult renal stem/progenitor cells (ARPCs) enhance the tubular regenerative mechanism during AKI but little is known about their effects on ECs. Following LPS exposure, ECs proliferated, decreased EC markers CD31 and vascular endothelial cadherin, and up-regulated myofibroblast markers, collagen I, and vimentin. The coculture with ARPCs normalized the EC proliferation rate and abrogated the LPS-induced EndMT. The gene expression analysis showed that most of the genes modulated in LPS-stimulated ARPCs belong to cell activation and defense response pathways. We showed that the ARPC-specific antifibrotic effect is exerted by the secretion of CXCL6, SAA4, and BPIFA2 produced after the anaphylatoxin stimulation. Next, we investigated the molecular signaling that underlies the ARPC protective mechanism and found that renal progenitors diverge from differentiated tubular cells and ECs in myeloid differentiation primary response 88-independent pathway activation. Finally, in a swine model of LPS-induced AKI, we observed that activated ARPCs secreted CXCL6, SAA4, and BPIFA2 as a defense response. These data open new perspectives on the treatment of both sepsis- and endotoxemia-induced AKI, suggesting an underestimated role of ARPCs in preventing endothelial dysfunction and novel strategies to protect the endothelial compartment and promote kidney repair.-Sallustio, F., Stasi, A., Curci, C., Divella, C., Picerno, A., Franzin, R., De Palma, G., Rutigliano, M., Lucarelli, G., Battaglia, M., Staffieri, F., Crovace, A., Pertosa, G. B., Castellano, G., Gallone, A., Gesualdo, L. Renal progenitor cells revert LPS-induced endothelial-to-mesenchymal transition by secreting CXCL6, SAA4, and BPIFA2 antiseptic peptides.
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Affiliation(s)
- Fabio Sallustio
- Department of Basic Medical Sciences, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy
- Nephrology, Dialysis, and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Alessandra Stasi
- Nephrology, Dialysis, and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Claudia Curci
- Department of Basic Medical Sciences, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy
- Nephrology, Dialysis, and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Chiara Divella
- Nephrology, Dialysis, and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Angela Picerno
- Nephrology, Dialysis, and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Rossana Franzin
- Nephrology, Dialysis, and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppe De Palma
- Institutional Biobank, Experimental Oncology and Biobank Management Unit, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Istituto Tumori Bari Giovanni Paolo II, Bari, Italy
| | - Monica Rutigliano
- Urology, Andrology, and Renal Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppe Lucarelli
- Urology, Andrology, and Renal Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Michele Battaglia
- Urology, Andrology, and Renal Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Francesco Staffieri
- Veterinary Surgery Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Antonio Crovace
- Veterinary Surgery Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giovanni Battista Pertosa
- Nephrology, Dialysis, and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Giuseppe Castellano
- Nephrology, Dialysis, and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
| | - Anna Gallone
- Department of Basic Medical Sciences, Neuroscience, and Sense Organs, University of Bari Aldo Moro, Bari, Italy
| | - Loreto Gesualdo
- Nephrology, Dialysis, and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari Aldo Moro, Bari, Italy
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23
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Gaidukov L, Wroblewska L, Teague B, Nelson T, Zhang X, Liu Y, Jagtap K, Mamo S, Tseng WA, Lowe A, Das J, Bandara K, Baijuraj S, Summers NM, Lu TK, Zhang L, Weiss R. A multi-landing pad DNA integration platform for mammalian cell engineering. Nucleic Acids Res 2019; 46:4072-4086. [PMID: 29617873 PMCID: PMC5934685 DOI: 10.1093/nar/gky216] [Citation(s) in RCA: 108] [Impact Index Per Article: 18.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 03/14/2018] [Indexed: 12/11/2022] Open
Abstract
Engineering mammalian cell lines that stably express many transgenes requires the precise insertion of large amounts of heterologous DNA into well-characterized genomic loci, but current methods are limited. To facilitate reliable large-scale engineering of CHO cells, we identified 21 novel genomic sites that supported stable long-term expression of transgenes, and then constructed cell lines containing one, two or three 'landing pad' recombination sites at selected loci. By using a highly efficient BxB1 recombinase along with different selection markers at each site, we directed recombinase-mediated insertion of heterologous DNA to selected sites, including targeting all three with a single transfection. We used this method to controllably integrate up to nine copies of a monoclonal antibody, representing about 100 kb of heterologous DNA in 21 transcriptional units. Because the integration was targeted to pre-validated loci, recombinant protein expression remained stable for weeks and additional copies of the antibody cassette in the integrated payload resulted in a linear increase in antibody expression. Overall, this multi-copy site-specific integration platform allows for controllable and reproducible insertion of large amounts of DNA into stable genomic sites, which has broad applications for mammalian synthetic biology, recombinant protein production and biomanufacturing.
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Affiliation(s)
- Leonid Gaidukov
- Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | | | - Brian Teague
- Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Tom Nelson
- Cell Line Development, Biotherapeutics Pharmaceutical Science, Pfizer Inc, Andover, MA 01810, USA
| | - Xin Zhang
- Biomedicine Design, Pfizer Inc, Cambridge, MA 02139, USA
| | - Yan Liu
- Biomedicine Design, Pfizer Inc, Cambridge, MA 02139, USA
| | - Kalpana Jagtap
- Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Selamawit Mamo
- Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Wen Allen Tseng
- Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Alexis Lowe
- Biomedicine Design, Pfizer Inc, Cambridge, MA 02139, USA
| | - Jishnu Das
- Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.,Ragon Institute of MGH, MIT & Harvard, Cambridge, MA 02139, USA
| | - Kalpanie Bandara
- Cell Line Development, Biotherapeutics Pharmaceutical Science, Pfizer Inc, Andover, MA 01810, USA
| | - Swetha Baijuraj
- Cell Line Development, Biotherapeutics Pharmaceutical Science, Pfizer Inc, Andover, MA 01810, USA
| | - Nevin M Summers
- Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
| | - Timothy K Lu
- Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.,Research Laboratory of Electronics, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
| | - Lin Zhang
- Cell Line Development, Biotherapeutics Pharmaceutical Science, Pfizer Inc, Andover, MA 01810, USA
| | - Ron Weiss
- Synthetic Biology Center, Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA 02139, USA
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24
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Portone A, Sciancalepore AG, Melle G, Netti GS, Greco G, Persano L, Gesualdo L, Pisignano D. Quasi-3D morphology and modulation of focal adhesions of human adult stem cells through combinatorial concave elastomeric surfaces with varied stiffness. SOFT MATTER 2019; 15:5154-5162. [PMID: 31192342 DOI: 10.1039/c9sm00481e] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/09/2023]
Abstract
In vivo cell niches are complex architectures that provide a wide range of biochemical and mechanical stimuli to control cell behavior and fate. With the aim to provide in vitro microenvironments mimicking physiological niches, microstructured substrates have been exploited to support cell adhesion and to control cell shape as well as three dimensional morphology. At variance with previous methods, we propose a simple and rapid protein subtractive soft lithographic method to obtain microstructured polydimethylsiloxane substrates for studying stem cell adhesion and growth. The shape of adult renal stem cells and nuclei is found to depend predominantly on micropatterning of elastomeric surfaces and only weakly on the substrate mechanical properties. Differently, focal adhesions in their shape and density but not in their alignment mainly depend on the elastomer stiffness almost regardless of microscale topography. Local surface topography with concave microgeometry enhancing adhesion drives stem cells in a quasi-three dimensional configuration where stiffness might significantly steer mechanosensing as highlighted by focal adhesion properties.
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Affiliation(s)
- A Portone
- NEST, Istituto Nanoscienze-CNR and Scuola Normale Superiore, Piazza S. Silvestro 12, I-56127 Pisa, Italy.
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25
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Sallustio F, Curci C, Stasi A, De Palma G, Divella C, Gramignoli R, Castellano G, Gallone A, Gesualdo L. Role of Toll-Like Receptors in Actuating Stem/Progenitor Cell Repair Mechanisms: Different Functions in Different Cells. Stem Cells Int 2019; 2019:6795845. [PMID: 31089331 PMCID: PMC6476106 DOI: 10.1155/2019/6795845] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2018] [Accepted: 12/19/2018] [Indexed: 02/07/2023] Open
Abstract
Toll-like receptors (TLRs) represent one of the bridges that regulate the cross-talk between the innate and adaptive immune systems. TLRs interact with molecules shared and preserved by the pathogens of origin but also with endogenous molecules (damage/danger-associated molecular patterns (DAMPs)) that derive from injured tissues. This is probably why TLRs have been found to be expressed on several kinds of stem/progenitor cells (SCs). In these cells, the role of TLRs in the regulation of the basal motility, proliferation, differentiation processes, self-renewal, and immunomodulation has been demonstrated. In this review, we analyze the many different functions that the TLRs assume in SCs, pointing out that they can have different effects, depending on the background and on the kind of ligands that they recognize. Moreover, we discuss the TLR involvement in the response of SC to specific tissue damage and in the reparative processes, as well as how the identification of molecules mediating the differential function of TLR signaling could be decisive for the development of new therapeutic strategies. Considering the available studies on TLRs in SCs, here we address the importance of TLRs in sensing an injury by stem/progenitor cells and in determining their behavior and reparative activity, which is dependent on the conditions. Therefore, it could be conceivable that SCs employed in therapy could be potentially exposed to TLR ligands, which might modulate their therapeutic potential in vivo. In this context, to modulate SC proliferation, survival, migration, and differentiation in the pathological environment, we need to better understand the mechanisms of action of TLRs on SCs and learn how to control these receptors and their downstream pathways in a precise way. In this manner, in the future, cell therapy could be improved and made safer.
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Affiliation(s)
- Fabio Sallustio
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari “Aldo Moro”, Bari 70124, Italy
- Nephrology Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Claudia Curci
- Nephrology Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Alessandra Stasi
- Nephrology Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Giuseppe De Palma
- Nephrology Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
- Institutional Biobank, Experimental Oncology and Biobank Management Unit, IRCCS Istituto Tumori “Giovanni Paolo II”, Bari, Italy
| | - Chiara Divella
- Nephrology Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Roberto Gramignoli
- Department of Laboratory Medicine, Division of Pathology, Karolinska Institutet, SE-171 76 Stockholm, Sweden
| | - Giuseppe Castellano
- Nephrology Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Anna Gallone
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari “Aldo Moro”, Bari 70124, Italy
| | - Loreto Gesualdo
- Nephrology Unit, Department of Emergency and Organ Transplantation, University of Bari “Aldo Moro”, Bari 70124, Italy
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26
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Sallustio F, Gesualdo L, Pisignano D. The Heterogeneity of Renal Stem Cells and Their Interaction with Bio- and Nano-materials. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2019; 1123:195-216. [PMID: 31016602 DOI: 10.1007/978-3-030-11096-3_12] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Abstract
For a long time, the kidney has been considered incapable of regeneration. Instead, in recent years, studies have supported the existence of heterogeneity of renal stem/progenitor cells with the ability to regenerate both glomerular and tubular epithelial cells. Indeed, several studies evidence that renal progenitor cells, releasing chemokines, growth factors, microvesicles, and transcription factors through paracrine mechanisms, can induce tissue regeneration and block pathological processes of the kidney. In this chapter the potentiality of the kidney regenerative processes is considered and reviewed, and the main classes of stem/progenitor cells that might contribute to the renal tissue renewal is analyzed. Moreover, we evaluate the role of biomaterials in the regulation of cellular functions, specifically addressing renal stem/progenitor cells. Materials can be synthesized and tailored in order to recreate a finely structured microenvironment (by nanostructures, nanofibers, bioactive compounds, etc.) with which the cells can interact actively. For instance, by patterning substrates in regions that alternately promote or prevent protein adsorption, cell adhesion and spreading processes can be controlled in space. We illustrate the potentiality of nanotechnologies and engineered biomaterials in affecting and enhancing the behavior of renal stem/progenitor cells. Although there are still many challenges for the translation of novel therapeutics, advances in biomaterials and nanomedicine have the potential to drastically change the clinical and therapeutic landscape, even in combination with stem cell biology.
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Affiliation(s)
- Fabio Sallustio
- Department of Basic Medical Sciences, Neuroscience and Sense Organs, University of Bari "Aldo Moro", Bari, Italy.
- Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy.
| | - Loreto Gesualdo
- Department of Emergency and Organ Transplantation, University of Bari "Aldo Moro", Bari, Italy
| | - Dario Pisignano
- Dipartimento di Fisica 'E. Fermi', University of Pisa, Pisa, Italy
- NEST CNR-Istituto Nanoscienze Piazza S. Silvestro 12, Pisa, Italy
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27
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Brossa A, Papadimitriou E, Collino F, Incarnato D, Oliviero S, Camussi G, Bussolati B. Role of CD133 Molecule in Wnt Response and Renal Repair. Stem Cells Transl Med 2018; 7:283-294. [PMID: 29431914 PMCID: PMC5827750 DOI: 10.1002/sctm.17-0158] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 12/06/2017] [Indexed: 02/06/2023] Open
Abstract
Renal repair after injury is dependent on clonal expansion of proliferation-competent cells. In the human kidney, the expression of CD133 characterizes a population of resident scattered cells with resistance to damage and ability to proliferate. However, the biological function of the CD133 molecule is unknown. By RNA sequencing, we found that cells undergoing cisplatin damage lost the CD133 signature and acquired metanephric mesenchymal and regenerative genes such as SNAIL1, KLF4, SOX9, and WNT3. CD133 was reacquired in the recovery phase. In CD133-Kd cells, lack of CD133 limited cell proliferation after injury and was specifically correlated with deregulation of Wnt signaling and E-cadherin pathway. By immunoprecipitation, CD133 appeared to form a complex with E-cadherin and β-catenin. In parallel, CD133-Kd cells showed lower β-catenin levels in basal condition and after Wnt pathway activation and reduced TCF/LEF promoter activation in respect to CD133+ cells. Finally, the lack of CD133 impaired generation of nephrospheres while favoring senescence. These data indicate that CD133 may act as a permissive factor for β-catenin signaling, preventing its degradation in the cytoplasm. Therefore, CD133 itself appears to play a functional role in renal tubular repair through maintenance of proliferative response and control of senescence. Stem Cells Translational Medicine 2018;7:283-294.
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Affiliation(s)
- Alessia Brossa
- Department of Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Torino, Italy
| | - Elli Papadimitriou
- Department of Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Torino, Italy
| | - Federica Collino
- Institute of Biophysics Carlos Chagas Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
| | - Danny Incarnato
- Italian Institute for Genomic Medicine (IIGM), Torino, Italy.,Dipartimento di Scienze della Vita e Biologia dei Sistemi, University of Turin, Torino, Italy
| | - Salvatore Oliviero
- Italian Institute for Genomic Medicine (IIGM), Torino, Italy.,Dipartimento di Scienze della Vita e Biologia dei Sistemi, University of Turin, Torino, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Turin, Torino, Italy
| | - Benedetta Bussolati
- Department of Biotechnology and Health Sciences, Molecular Biotechnology Center, University of Turin, Torino, Italy
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28
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Sallustio F, Curci C, Aloisi A, Toma CC, Marulli E, Serino G, Cox SN, De Palma G, Stasi A, Divella C, Rinaldi R, Schena FP. Inhibin-A and Decorin Secreted by Human Adult Renal Stem/Progenitor Cells Through the TLR2 Engagement Induce Renal Tubular Cell Regeneration. Sci Rep 2017; 7:8225. [PMID: 28811645 PMCID: PMC5557965 DOI: 10.1038/s41598-017-08474-0] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2017] [Accepted: 05/26/2017] [Indexed: 01/08/2023] Open
Abstract
Acute kidney injury (AKI) is a public health problem worldwide. Several therapeutic strategies have been made to accelerate recovery and improve renal survival. Recent studies have shown that human adult renal progenitor cells (ARPCs) participate in kidney repair processes, and may be used as a possible treatment to promote regeneration in acute kidney injury. Here, we show that human tubular ARPCs (tARPCs) protect physically injured or chemically damaged renal proximal tubular epithelial cells (RPTECs) by preventing cisplatin-induced apoptosis and enhancing proliferation of survived cells. tARPCs without toll-like receptor 2 (TLR2) expression or TLR2 blocking completely abrogated this regenerative effect. Only tARPCs, and not glomerular ARPCs, were able to induce tubular cell regeneration process and it occurred only after damage detection. Moreover, we have found that ARPCs secreted inhibin-A and decorin following the RPTEC damage and that these secreted factors were directly involved in cell regeneration process. Polysaccharide synthetic vesicles containing these molecules were constructed and co-cultured with cisplatin damaged RPTECs. These synthetic vesicles were not only incorporated into the cells, but they were also able to induce a substantial increase in cell number and viability. The findings of this study increase the knowledge of renal repair processes and may be the first step in the development of new specific therapeutic strategies for renal repair.
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Affiliation(s)
- Fabio Sallustio
- University of Bari, Department of Emergency and Organ Transplantation, Piazza G. Cesare 11, 70124, Bari, Italy.,C.A.R.S.O. Consortium, Strada Prov. le Valenzano-Casamassima Km 3, 70100, Valenzano (Ba), Italy
| | - Claudia Curci
- University of Bari, Department of Emergency and Organ Transplantation, Piazza G. Cesare 11, 70124, Bari, Italy.,C.A.R.S.O. Consortium, Strada Prov. le Valenzano-Casamassima Km 3, 70100, Valenzano (Ba), Italy.,Schena Foundation, Strada Prov. le Valenzano-Casamassima Km 3, 70100, Valenzano (Ba), Italy
| | - Alessandra Aloisi
- Consiglio Nazionale delle Ricerche (CNR), Institute of Nanoscience, Via Arnesano 16, 73100, Lecce, Italy.,Institute of Microelectronics and Microsystems (C.N.R.- I.M.M.), via Monteroni, Campus Ecotekne, 73100, Lecce, Italy
| | - Chiara Cristina Toma
- Consiglio Nazionale delle Ricerche (CNR), Institute of Nanoscience, Via Arnesano 16, 73100, Lecce, Italy.,University of Salento, Mathematics and Physics "E. De Giorgi" Department, University of Salento, 73100, Lecce, Italy
| | - Elisabetta Marulli
- Consiglio Nazionale delle Ricerche (CNR), Institute of Nanoscience, Via Arnesano 16, 73100, Lecce, Italy.,University of Salento, Mathematics and Physics "E. De Giorgi" Department, University of Salento, 73100, Lecce, Italy
| | - Grazia Serino
- National Institute of Gastroenterology "S. de Bellis", Research Hospital, Castellana Grotte, Bari, 70013, Italy
| | - Sharon Natasha Cox
- C.A.R.S.O. Consortium, Strada Prov. le Valenzano-Casamassima Km 3, 70100, Valenzano (Ba), Italy.,Schena Foundation, Strada Prov. le Valenzano-Casamassima Km 3, 70100, Valenzano (Ba), Italy
| | - Giuseppe De Palma
- University of Bari, Department of Emergency and Organ Transplantation, Piazza G. Cesare 11, 70124, Bari, Italy.,C.A.R.S.O. Consortium, Strada Prov. le Valenzano-Casamassima Km 3, 70100, Valenzano (Ba), Italy.,Schena Foundation, Strada Prov. le Valenzano-Casamassima Km 3, 70100, Valenzano (Ba), Italy
| | - Alessandra Stasi
- University of Bari, Department of Emergency and Organ Transplantation, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Chiara Divella
- University of Bari, Department of Emergency and Organ Transplantation, Piazza G. Cesare 11, 70124, Bari, Italy
| | - Rosaria Rinaldi
- Consiglio Nazionale delle Ricerche (CNR), Institute of Nanoscience, Via Arnesano 16, 73100, Lecce, Italy.,University of Salento, Mathematics and Physics "E. De Giorgi" Department, University of Salento, 73100, Lecce, Italy
| | - Francesco Paolo Schena
- University of Bari, Department of Emergency and Organ Transplantation, Piazza G. Cesare 11, 70124, Bari, Italy. .,C.A.R.S.O. Consortium, Strada Prov. le Valenzano-Casamassima Km 3, 70100, Valenzano (Ba), Italy. .,Schena Foundation, Strada Prov. le Valenzano-Casamassima Km 3, 70100, Valenzano (Ba), Italy.
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29
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Abstract
Over a decade ago, it was proposed that the regulation of tubular repair in the kidney might involve the recapitulation of developmental pathways. Although the kidney cannot generate new nephrons after birth, suggesting a low level of regenerative competence, the tubular epithelial cells of the nephrons can proliferate to repair the damage after AKI. However, the debate continues over whether this repair involves a persistent progenitor population or any mature epithelial cell remaining after injury. Recent reports have highlighted the expression of Sox9, a transcription factor critical for normal kidney development, during postnatal epithelial repair in the kidney. Indeed, the proliferative response of the epithelium involves expression of several pathways previously described as being involved in kidney development. In some instances, these pathways are also apparently involved in the maladaptive responses observed after repeated injury. Whether development and repair in the kidney are the same processes or we are misinterpreting the similar expression of genes under different circumstances remains unknown. Here, we review the evidence for this link, concluding that such parallels in expression may more correctly represent the use of the same pathways in a distinct context, likely triggered by similar stressors.
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Affiliation(s)
- Melissa Helen Little
- Murdoch Children's Research Institute, Melbourne, Australia; and .,Department of Pediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
| | - Pamela Kairath
- Murdoch Children's Research Institute, Melbourne, Australia; and.,Department of Pediatrics, Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne, Melbourne, Australia
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30
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Myszczyszyn A, Czarnecka AM, Matak D, Szymanski L, Lian F, Kornakiewicz A, Bartnik E, Kukwa W, Kieda C, Szczylik C. The Role of Hypoxia and Cancer Stem Cells in Renal Cell Carcinoma Pathogenesis. Stem Cell Rev Rep 2016. [PMID: 26210994 PMCID: PMC4653234 DOI: 10.1007/s12015-015-9611-y] [Citation(s) in RCA: 68] [Impact Index Per Article: 7.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
The cancer stem cell (CSC) model has recently been approached also in renal cell carcinoma (RCC). A few populations of putative renal tumor-initiating cells (TICs) were identified, but they are indifferently understood; however, the first and most thoroughly investigated are CD105-positive CSCs. The article presents a detailed comparison of all renal CSC-like populations identified by now as well as their presumable origin. Hypoxic activation of hypoxia-inducible factors (HIFs) contributes to tumor aggressiveness by multiple molecular pathways, including the governance of immature stem cell-like phenotype and related epithelial-to-mesenchymal transition (EMT)/de-differentiation, and, as a result, poor prognosis. Due to intrinsic von Hippel-Lindau protein (pVHL) loss of function, clear-cell RCC (ccRCC) develops unique pathological intra-cellular pseudo-hypoxic phenotype with a constant HIF activation, regardless of oxygen level. Despite satisfactory evidence concerning pseudo-hypoxia importance in RCC biology, its influence on putative renal CSC-like largely remains unknown. Thus, the article discusses a current knowledge of HIF-1α/2α signaling pathways in the promotion of undifferentiated tumor phenotype in general, including some experimental findings specific for pseudo-hypoxic ccRCC, mostly dependent from HIF-2α oncogenic functions. Existing gaps in understanding both putative renal CSCs and their potential connection with hypoxia need to be filled in order to propose breakthrough strategies for RCC treatment.
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Affiliation(s)
- Adam Myszczyszyn
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland
| | - Anna M Czarnecka
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland.
| | - Damian Matak
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland.,School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland
| | - Lukasz Szymanski
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland.,Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland
| | - Fei Lian
- Emory School of Medicine, Atlanta, GA, USA
| | - Anna Kornakiewicz
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland.,School of Molecular Medicine, Medical University of Warsaw, Warsaw, Poland.,Department of General Surgery and Transplantology, Medical University of Warsaw, Warsaw, Poland
| | - Ewa Bartnik
- Institute of Genetics and Biotechnology, Faculty of Biology, University of Warsaw, Warsaw, Poland.,Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland
| | - Wojciech Kukwa
- Department of Otolaryngology, Czerniakowski Hospital, Medical University of Warsaw, Warsaw, Poland
| | - Claudine Kieda
- Centre de Biophysique Moléculaire, CNRS UPR 4301, Orléans, France
| | - Cezary Szczylik
- Department of Oncology with Laboratory of Molecular Oncology, Military Institute of Medicine, Szaserow 128, 04-141, Warsaw, Poland
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31
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The Immune System in Tissue Environments Regaining Homeostasis after Injury: Is "Inflammation" Always Inflammation? Mediators Inflamm 2016; 2016:2856213. [PMID: 27597803 PMCID: PMC4997018 DOI: 10.1155/2016/2856213] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2016] [Revised: 07/08/2016] [Accepted: 07/19/2016] [Indexed: 12/31/2022] Open
Abstract
Inflammation is a response to infections or tissue injuries. Inflammation was once defined by clinical signs, later by the presence of leukocytes, and nowadays by expression of "proinflammatory" cytokines and chemokines. But leukocytes and cytokines often have rather anti-inflammatory, proregenerative, and homeostatic effects. Is there a need to redefine "inflammation"? In this review, we discuss the functions of "inflammatory" mediators/regulators of the innate immune system that determine tissue environments to fulfill the need of the tissue while regaining homeostasis after injury.
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32
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Sciancalepore AG, Portone A, Moffa M, Persano L, De Luca M, Paiano A, Sallustio F, Schena FP, Bucci C, Pisignano D. Micropatterning control of tubular commitment in human adult renal stem cells. Biomaterials 2016; 94:57-69. [PMID: 27105437 DOI: 10.1016/j.biomaterials.2016.03.042] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2016] [Revised: 03/19/2016] [Accepted: 03/28/2016] [Indexed: 12/12/2022]
Abstract
The treatment of renal injury by autologous, patient-specific adult stem cells is still an unmet need. Unsolved issues remain the spatial integration of stem cells into damaged areas of the organ, the commitment in the required cell type and the development of improved bioengineered devices. In this respect, biomaterials and architectures have to be specialized to control stem cell differentiation. Here, we perform an extensive study on micropatterned extracellular matrix proteins, which constitute a simple and non-invasive approach to drive the differentiation of adult renal progenitor/stem cells (ARPCs) from human donors. ARPCs are interfaced with fibronectin (FN) micropatterns, in the absence of exogenous chemicals or cellular reprogramming. We obtain the differentiation towards tubular cells of ARPCs cultured in basal medium conditions, the tubular commitment thus being specifically induced by micropatterned substrates. We characterize the stability of the tubular differentiation as well as the induction of a polarized phenotype in micropatterned ARPCs. Thus, the developed cues, driving the functional commitment of ARPCs, offer a route to recreate the microenvironment of the stem cell niche in vitro, that may serve, in perspective, for the development of ARPC-based bioengineered devices.
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Affiliation(s)
- Anna G Sciancalepore
- Istituto Nanoscienze-CNR, Euromediterranean Center for Nanomaterial Modelling and Technology (ECMT), via Arnesano, 73100 Lecce, Italy; Center for Biomolecular Nanotechnologies @UNILE, Istituto Italiano di Tecnologia, via Barsanti, 73010 Arnesano, Lecce, Italy.
| | - Alberto Portone
- Istituto Nanoscienze-CNR, Euromediterranean Center for Nanomaterial Modelling and Technology (ECMT), via Arnesano, 73100 Lecce, Italy; Dipartimento di Matematica e Fisica "Ennio De Giorgi", Università del Salento, via Arnesano, 73100 Lecce, Italy
| | - Maria Moffa
- Istituto Nanoscienze-CNR, Euromediterranean Center for Nanomaterial Modelling and Technology (ECMT), via Arnesano, 73100 Lecce, Italy; Center for Biomolecular Nanotechnologies @UNILE, Istituto Italiano di Tecnologia, via Barsanti, 73010 Arnesano, Lecce, Italy
| | - Luana Persano
- Istituto Nanoscienze-CNR, Euromediterranean Center for Nanomaterial Modelling and Technology (ECMT), via Arnesano, 73100 Lecce, Italy
| | - Maria De Luca
- Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali (DiSTeBA), Università del Salento, via Provinciale Monteroni, 73100 Lecce, Italy
| | - Aurora Paiano
- Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali (DiSTeBA), Università del Salento, via Provinciale Monteroni, 73100 Lecce, Italy
| | - Fabio Sallustio
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; Centro Addestramento Ricerca Scientifica in Oncologia (C.A.R.S.O.) Consortium, Strada Prov. le Valenzano-Casamassima, 70010 Valenzano, Italy
| | - Francesco P Schena
- Nephrology, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, 70124 Bari, Italy; Centro Addestramento Ricerca Scientifica in Oncologia (C.A.R.S.O.) Consortium, Strada Prov. le Valenzano-Casamassima, 70010 Valenzano, Italy
| | - Cecilia Bucci
- Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali (DiSTeBA), Università del Salento, via Provinciale Monteroni, 73100 Lecce, Italy
| | - Dario Pisignano
- Istituto Nanoscienze-CNR, Euromediterranean Center for Nanomaterial Modelling and Technology (ECMT), via Arnesano, 73100 Lecce, Italy; Center for Biomolecular Nanotechnologies @UNILE, Istituto Italiano di Tecnologia, via Barsanti, 73010 Arnesano, Lecce, Italy; Dipartimento di Matematica e Fisica "Ennio De Giorgi", Università del Salento, via Arnesano, 73100 Lecce, Italy.
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33
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Hansson J, Ericsson AE, Axelson H, Johansson ME. Species diversity regarding the presence of proximal tubular progenitor cells of the kidney. Eur J Histochem 2016; 60:2567. [PMID: 26972712 PMCID: PMC4800248 DOI: 10.4081/ejh.2016.2567] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2015] [Revised: 12/02/2015] [Accepted: 12/20/2015] [Indexed: 11/23/2022] Open
Abstract
The cellular source for tubular regeneration following kidney injury is a matter of dispute, with reports suggesting a stem or progenitor cells as the regeneration source while linage tracing studies in mice seemingly favor the classical theory, where regeneration is performed by randomly surviving cells. We, and others have previously described a scattered cell population localized to the tubules of human kidney, which increases in number following injury. Here we have characterized the species distribution of these proximal tubular progenitor cells (PTPCs) in kidney tissue from chimpanzee, pig, rat and mouse using a set of human PTPC markers. We detected PTPCs in chimpanzee and pig kidneys, but not in mouse tissue. Also, subjecting mice to the unilateral urethral obstruction model, caused clear signs of tubular injury, but failed to induce the PTPC phenotype in renal tubules.
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34
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Sciancalepore AG, Moffa M, Carluccio S, Romano L, Netti GS, Prattichizzo C, Pisignano D. Bioactive Nanofiber Matrices Functionalized with Fibronectin-Mimetic Peptides Driving the Alignment and Tubular Commitment of Adult Renal Stem Cells. MACROMOL CHEM PHYS 2015. [DOI: 10.1002/macp.201500370] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Affiliation(s)
- Anna G. Sciancalepore
- Istituto Nanoscienze-CNR; Euromediterranean Center for Nanomaterial Modelling and Technology (ECMT); Via Arnesano I-73100 Lecce Italy
| | - Maria Moffa
- Istituto Nanoscienze-CNR; Euromediterranean Center for Nanomaterial Modelling and Technology (ECMT); Via Arnesano I-73100 Lecce Italy
| | - Simonetta Carluccio
- Dipartimento di Scienze e Tecnologie Biologiche e Ambientali; Università del Salento; Via provinciale per Monteroni I-73100 Lecce Italy
| | - Luigi Romano
- Dipartimento di Matematica e Fisica “Ennio De Giorgi”; Università del Salentoand Istituto Nanoscienze-CNR; Euromediterranean Center for Nanomaterial Modelling and Technology (ECMT); Via Arnesano I-73100 Lecce Italy
| | - Giuseppe S. Netti
- Clinical Pathology Unit; Department of Medical and Surgical Sciences; University of Foggia; Hospital University “Ospedali Riuniti”; viale Luigi Pinto I-71122 Foggia Italy
| | - Clelia Prattichizzo
- Clinical Pathology Unit; Department of Medical and Surgical Sciences; University of Foggia; Hospital University “Ospedali Riuniti”; viale Luigi Pinto I-71122 Foggia Italy
| | - Dario Pisignano
- Dipartimento di Matematica e Fisica “Ennio De Giorgi”; Università del Salentoand Istituto Nanoscienze-CNR; Euromediterranean Center for Nanomaterial Modelling and Technology (ECMT); Via Arnesano I-73100 Lecce Italy
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Severe Nephrotoxic Nephritis following Conditional and Kidney-Specific Knockdown of Stanniocalcin-1. PLoS One 2015; 10:e0138440. [PMID: 26393521 PMCID: PMC4579070 DOI: 10.1371/journal.pone.0138440] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2015] [Accepted: 08/30/2015] [Indexed: 12/14/2022] Open
Abstract
BACKGROUND Inflammation is the hallmark of nephrotoxic nephritis. Stanniocalcin-1 (STC1), a pro-survival factor, inhibits macrophages, stabilizes endothelial barrier function, and diminishes trans-endothelial migration of leukocytes; consistently, transgenic (Tg) overexpression of STC1 protects from nephrotoxic nephritis. Herein, we sought to determine the phenotype of nephrotoxic nephritis after conditional and kidney-specific knockdown of STC1. METHODS We used Tg mice that, express either STC1 shRNA (70% knockdown of STC1 within 4d) or scrambled shRNA (control) upon delivery of Cre-expressing plasmid to the kidney using ultrasound microbubble technique. Sheep anti-mouse GBM antibody was administered 4d after shRNA activation; and mice were euthanized 10 days later for analysis. RESULTS Serum creatinine, proteinuria, albuminuria and urine output were similar 10 days after anti-GBM delivery in both groups; however, anti-GBM antibody delivery to mice with kidney-specific knockdown of STC1 produced severe nephrotoxic nephritis, characterized by severe tubular necrosis, glomerular hyalinosis/necrosis and massive cast formation, while control mice manifested mild tubular injury and crescentic glomerulonephritis. Surprisingly, the expression of cytokines/chemokines and infiltration with T-cells and macrophages were also diminished in STC1 knockdown kidneys. Staining for sheep anti-mouse GBM antibody, deposition of mouse C3 and IgG in the kidney, and antibody response to sheep IgG were equal. CONCLUSIONS nephrotoxic nephritis after kidney-specific knockdown of STC1 is characterized by severe tubular and glomerular necrosis, possibly due to loss of STC1-mediated pro-survival factors, and we attribute the paucity of inflammation to diminished release of cytokines/chemokines/growth factors from the necrotic epithelium.
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36
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Bussolati B, Camussi G. Therapeutic use of human renal progenitor cells for kidney regeneration. Nat Rev Nephrol 2015; 11:695-706. [PMID: 26241019 DOI: 10.1038/nrneph.2015.126] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
The ability of the human kidney to repair itself is limited. Consequently, repeated injury can trigger a maladaptive response that is characterized by fibrosis and loss of renal function. The transcription patterns that characterize nephrogenesis in fetal renal progenitor cells (RPCs) are only partially activated during renal repair in adults. Nevertheless, evidence suggests that segment-restricted progenitor resident cells support renal healing in adults. In this Review, we discuss the evidence for the existence of functional human RPCs in adults and their role in renal repair, and consider the controversial issue of whether RPCs are a fixed population or arise through phenotypical plasticity of tubular cells that is mediated by the microenvironment. We also discuss the strategies for generating renal progenitor cells from pluripotent stem cells or differentiated cells and their use in therapy. Finally, we examine preclinical data on the therapeutic use of human fetal cells, adult progenitor cells and adult renal cells.
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Affiliation(s)
- Benedetta Bussolati
- Department of Molecular Biotechnology and Health Sciences, University of Torino, Via Nizza 52, Torino 10126, Italy
| | - Giovanni Camussi
- Department of Medical Sciences, University of Torino, Via Nizza 52, Torino 10126, Italy
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37
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Strategies to optimize kidney recovery and preservation in transplantation: specific aspects in pediatric transplantation. Pediatr Nephrol 2015; 30:1243-54. [PMID: 25185880 DOI: 10.1007/s00467-014-2924-2] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2014] [Revised: 07/09/2014] [Accepted: 07/21/2014] [Indexed: 01/08/2023]
Abstract
In renal transplantation, live donor kidney grafts are associated with optimum success rates due to the shorter period of ischemia during the surgical procedure. The current shortage of donor organs for adult patients has caused a shift towards deceased donors, often with co-morbidity factors, whose organs are more sensitive to ischemia-reperfusion injury, which is unavoidable during transplantation. Donor management is pivotal to kidney graft survival through the control of the ischemia-reperfusion sequence, which is known to stimulate numerous deleterious or regenerative pathways. Although the key role of endothelial cells has been established, the complexity of the injury, associated with stimulation of different cell signaling pathways, such as unfolded protein response and cell death, prevents the definition of a unique therapeutic target. Preclinical transplant models in large animals are necessary to establish relationships and kinetics and have already contributed to the improvement of organ preservation. Therapeutic strategies using mesenchymal stem cells to induce allograft tolerance are promising advances in the treatment of the pediatric recipient in terms of reducing/withdrawing immunosuppressive therapy. In this review we focus on the different donor management strategies in kidney graft conditioning and on graft preservation consequences by highlighting the role of endothelial cells. We also propose strategies for preventing ischemia-reperfusion, such as cell therapy.
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38
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Sallustio F, Serino G, Schena FP. Potential Reparative Role of Resident Adult Renal Stem/Progenitor Cells in Acute Kidney Injury. Biores Open Access 2015; 4:326-33. [PMID: 26309808 PMCID: PMC4509615 DOI: 10.1089/biores.2015.0011] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Human kidney is particularly susceptible to ischemia and toxins with consequential tubular necrosis and activation of inflammatory processes. This process can lead to the acute renal injury, and even if the kidney has a great capacity for regeneration after tubular damage, in several circumstances, the normal renal repair program may not be sufficient to achieve a successful regeneration. Resident adult renal stem/progenitor cells could participate in this repair process and have the potentiality to enhance the renal regenerative mechanism. This could be achieved both directly, by means of their capacity to differentiate and integrate into the renal tissues, and by means of paracrine factors able to induce or improve the renal repair or regeneration. Recent genetic fate-tracing studies indicated that tubular damage is instead repaired by proliferative duplication of epithelial cells, acquiring a transient progenitor phenotype and by fate-restricted clonal cell progeny emerging from different nephron segments. In this review, we discuss about the properties and the reparative characteristics of high regenerative CD133(+)/CD24(+) cells, with a view to a future application of these cells for the treatment of acute renal injury.
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Affiliation(s)
- Fabio Sallustio
- Department of Emergency and Organ Transplantation, University of Bari , Bari, Italy . ; C.A.R.S.O. Consortium, Strada Prov. le Valenzano-Casamassima Km 3 , Valenzano, Italy . ; Dipartimento di Scienze e Tecnologie Biologiche ed Ambientali (DiSTeBA), Università del Salento , Lecce-Monteroni, Lecce, Italy
| | - Grazia Serino
- Department of Emergency and Organ Transplantation, University of Bari , Bari, Italy
| | - Francesco Paolo Schena
- C.A.R.S.O. Consortium, Strada Prov. le Valenzano-Casamassima Km 3 , Valenzano, Italy . ; Schena Foundation, Research Center of Renal Diseases , Bari, Italy
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Abstract
The podocyte is a highly differentiated cell located in the outer space of the glomerular basement membrane that deals with many different functions. This phylogenetically preserved cell that is responsible for the virtually absence of proteins in the urine lacks of the capacity to divide under normal conditions. When podocytes receive molecular insults, which normally occur during stress conditions as glomerulonephritis, hyperfiltration or metabolic disturbances, they adapt to the new situation by contracting their actin fibers. This adaptive behavior puts at risk the quality of the plasmatic filtration due to the denudation of the glomerular basement membrane, the potential mesangial inflammation and the appearance of proteinuria; podocytes run the risk of detachment from the basement membrane due to a decrease in the adherence to the surrounding matrix after contraction, a process called foot processes effacement. Podocytes change their shape and under constant mechanical stress they finally detach, rendering the glomerular basement membrane unprotected unless other contiguous podocytes are capable of covering the surface. However, these still anchored podocytes are generally also under the same stress situation and follow the same pathway. Podocyturia refers to the presence of these differentiated cells in the urinary sediment. Noteworthy, the podocytes that are encountered in the urine are viable despite the glomerular hostile environment and the urinary acidity. Podocyturia can precede proteinuria and can aggravate it. Therefore, in diseases that can threaten the glomerular normal environment, the presence and the quantification of urinary podocytes can be of remarkable relevance, as it can herald or accompany the appearance of proteinuria, and could offer another view to the interpretation and clinical approach and outcome of proteinuria. However, its identification needs a wide-spread training among biochemists and technicians, as well as commercially available kits.
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Affiliation(s)
- Hernán Trimarchi
- Nephrology and Kidney Transplant Unit, Department of Medicine, Hospital Británico de Buenos Aires, Buenos Aires, Argentina
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40
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Chung HC, Ko IK, Atala A, Yoo JJ. Cell-based therapy for kidney disease. Korean J Urol 2015; 56:412-21. [PMID: 26078837 PMCID: PMC4462630 DOI: 10.4111/kju.2015.56.6.412] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2015] [Accepted: 05/06/2015] [Indexed: 12/15/2022] Open
Abstract
The prevalence of renal disease continues to increase worldwide. When normal kidney is injured, the damaged renal tissue undergoes pathological and physiological events that lead to acute and chronic kidney diseases, which frequently progress to end stage renal failure. Current treatment of these renal pathologies includes dialysis, which is incapable of restoring full renal function. To address this issue, cell-based therapy has become a potential therapeutic option to treat renal pathologies. Recent development in cell therapy has demonstrated promising therapeutic outcomes, in terms of restoration of renal structure and function impaired by renal disease. This review focuses on the cell therapy approaches for the treatment of kidney diseases, including various cell sources used, as well recent advances made in preclinical and clinical studies.
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Affiliation(s)
- Hyun Chul Chung
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA. ; Department of Urology, Yonsei University Wonju College of Medicine, Wonju, Korea
| | - In Kap Ko
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
| | - Anthony Atala
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
| | - James J Yoo
- Wake Forest Institute for Regenerative Medicine, Wake Forest School of Medicine, Medical Center Boulevard, Winston-Salem, NC, USA
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41
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Trophic Factors from Tissue Stem Cells for Renal Regeneration. Stem Cells Int 2015; 2015:537204. [PMID: 26089918 PMCID: PMC4452108 DOI: 10.1155/2015/537204] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2014] [Revised: 01/09/2015] [Accepted: 01/09/2015] [Indexed: 12/23/2022] Open
Abstract
Stem cell therapies against renal injury have been advancing. The many trials for renal regeneration are reported to be effective in many kinds of renal injury models. Regarding the therapeutic mechanism, it is believed that stem cells contribute to make regeneration via not only direct stem cell differentiation in the injured space but also indirect effect via secreted factors from stem cells. Direct differentiation from stem cells to renal composed cells has been reported. They differentiate to renal composed cells and make functions. However, regarding renal regeneration, stem cells are discussed to secrete many kinds of growth factors, cytokines, and chemokines in paracrine or autocrine manner, which protect against renal injury, too. In addition, it is reported that stem cells have the ability to communicate with nearby cells via microvesicle-related RNA and proteins. Taken together from many reports, many secreted factors from stem cells were needed for renal regeneration orchestrally with harmony. In this review, we focused on the effects and insights of stem cells and regenerative factors from stem cells.
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42
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Diverse Cell Populations Involved in Regeneration of Renal Tubular Epithelium following Acute Kidney Injury. Stem Cells Int 2015; 2015:964849. [PMID: 26089922 PMCID: PMC4452180 DOI: 10.1155/2015/964849] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/05/2014] [Accepted: 12/06/2014] [Indexed: 12/17/2022] Open
Abstract
Renal tubular epithelium has the capacity to regenerate, repair, and reepithelialize in response to a variety of insults. Previous studies with several kidney injury models demonstrated that various growth factors, transcription factors, and extracellular matrices are involved in this process. Surviving tubular cells actively proliferate, migrate, and differentiate in the kidney regeneration process after injury, and some cells express putative stem cell markers or possess stem cell properties. Using fate mapping techniques, bone marrow-derived cells and endothelial progenitor cells have been shown to transdifferentiate into tubular components in vivo or ex vivo. Similarly, it has been demonstrated that, during tubular cell regeneration, several inflammatory cell populations migrate, assemble around tubular cells, and interact with tubular cells during the repair of tubular epithelium. In this review, we describe recent advances in understanding the regeneration mechanisms of renal tubules, particularly the characteristics of various cell populations contributing to tubular regeneration, and highlight the targets for the development of regenerative medicine for treating kidney diseases in humans.
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Ramezani A, Devaney JM, Cohen S, Wing MR, Scott R, Knoblach S, Singhal R, Howard L, Kopp JB, Raj DS. Circulating and urinary microRNA profile in focal segmental glomerulosclerosis: a pilot study. Eur J Clin Invest 2015; 45:394-404. [PMID: 25682967 PMCID: PMC4903079 DOI: 10.1111/eci.12420] [Citation(s) in RCA: 83] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/24/2014] [Accepted: 02/06/2015] [Indexed: 12/22/2022]
Abstract
BACKGROUND MicroRNAs (miRNAs) are noncoding RNA molecules that play important roles in the pathogenesis of various kidney diseases. We investigated whether patients with minimal change disease (MCD) and focal segmental glomerulosclerosis (FSGS) have distinct circulating and urinary miRNA expression profiles that could lead to potential development of noninvasive biomarkers of the disease. MATERIALS AND METHODS Exosome miRNAs were extracted from plasma and urine samples of patients with primary FSGS (n = 16) or MCD (n = 5) and healthy controls (n = 5). Differences in miRNA abundance were examined using Affymetrix GeneChip miRNA 3.0 arrays. QRT-PCR was used to validate the findings from the array. RESULTS Comparison analysis of FSGS versus MCD revealed 126 and 155 differentially expressed miRNAs in plasma and in urine, respectively. Only 38 of these miRNAs were previously cited, whereas the remaining miRNAs have not been described. Comparison analysis showed that a significant number of miRNAs were downregulated in both plasma and urine samples of patients with FSGS compared to those with MCD. Plasma levels of miR-30b, miR-30c, miR-34b, miR-34c and miR-342 and urine levels of mir-1225-5p were upregulated in patients with MCD compared to patients with FSGS and controls (P < 0.001). Urinary levels of mir-1915 and miR-663 were downregulated in patients with FSGS compared to MCD and controls (P < 0.001), whereas the urinary levels of miR-155 were upregulated in patients with FSGS when compared to patients with MCD and controls (P < 0.005). CONCLUSIONS Patients with FSGS and MCD have a unique circulating and urinary miRNA profile. The diagnostic and prognostic potential of miRNAs in FSGS and MCD warrants further studies.
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Affiliation(s)
- Ali Ramezani
- Division of Renal Diseases and Hypertension, The George Washington University School of Medicine, Washington, DC, USA
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Hishikawa K, Takase O, Yoshikawa M, Tsujimura T, Nangaku M, Takato T. Adult stem-like cells in kidney. World J Stem Cells 2015; 7:490-494. [PMID: 25815133 PMCID: PMC4369505 DOI: 10.4252/wjsc.v7.i2.490] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/29/2014] [Revised: 10/31/2014] [Accepted: 12/10/2014] [Indexed: 02/06/2023] Open
Abstract
Human pluripotent cells are promising for treatment for kidney diseases, but the protocols for derivation of kidney cell types are still controversial. Kidney tissue regeneration is well confirmed in several lower vertebrates such as fish, and the repair of nephrons after tubular damages is commonly observed after renal injury. Even in adult mammal kidney, renal progenitor cell or system is reportedly presents suggesting that adult stem-like cells in kidney can be practical clinical targets for kidney diseases. However, it is still unclear if kidney stem cells or stem-like cells exist or not. In general, stemness is defined by several factors such as self-renewal capacity, multi-lineage potency and characteristic gene expression profiles. The definite use of stemness may be obstacle to understand kidney regeneration, and here we describe the recent broad findings of kidney regeneration and the cells that contribute regeneration.
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45
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Castellano G, Cafiero C, Divella C, Sallustio F, Gigante M, Pontrelli P, De Palma G, Rossini M, Grandaliano G, Gesualdo L. Local synthesis of interferon-alpha in lupus nephritis is associated with type I interferons signature and LMP7 induction in renal tubular epithelial cells. Arthritis Res Ther 2015; 17:72. [PMID: 25889472 PMCID: PMC4389585 DOI: 10.1186/s13075-015-0588-3] [Citation(s) in RCA: 51] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2014] [Accepted: 02/25/2015] [Indexed: 12/20/2022] Open
Abstract
INTRODUCTION Type I interferons are pivotal in the activation of autoimmune response in systemic lupus erythematous. However, the pathogenic role of interferon-alpha in patients affected by lupus nephritis remains uncertain. The aim of our study was to investigate the presence of a specific interferon signature in lupus nephritis and the effects of interferon-alpha at renal level. METHODS We performed immunohistochemical analysis for MXA-protein and in situ hybridization to detect interferon-alpha signature and production in human lupus nephritis. Through microarray studies, we analyzed the gene expression profile of renal tubular epithelial cells, stimulated with interferon-alpha. We validated microarray results through real-time polymerase chain reaction, flow cytometry on renal tubular epithelial cells, and through immunohistochemical analysis and confocal microscopy on renal biopsies. RESULTS Type I interferons signature was characterized by MXA-specific staining in renal tubular epithelial cells; in addition, in situ hybridization showed that renal tubular epithelial cells were the major producers of interferon-alpha, indicating a potential autocrine effect. Whole-genome expression profile showed interferon-alpha induced up-regulation of genes involved in innate immunity, protein ubiquitination and switching to immunoproteasome. In accordance with the in vitro data, class IV lupus nephritis showed up-regulation of the immunoproteasome subunit LMP7 in tubular epithelial cells associated with type I interferon signature. CONCLUSIONS Our data indicate that type I interferons might have a pathogenic role in lupus nephritis characterized by an autocrine effect of interferon-alpha on renal tubular epithelial cells. Therefore we hypothesize that inhibition of type I interferons might represent a therapeutic target to prevent tubulo-interstitial damage in patients with lupus nephritis.
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Affiliation(s)
- Giuseppe Castellano
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
| | - Cesira Cafiero
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
| | - Chiara Divella
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
| | | | - Margherita Gigante
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
| | - Paola Pontrelli
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
| | | | - Michele Rossini
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
| | - Giuseppe Grandaliano
- Renal, Dialysis and Transplantation Unit, Department of Medical and Surgical Sciences, University of Foggia, Foggia, Italy.
| | - Loreto Gesualdo
- Renal, Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation, University of Bari, Piazza Giulio Cesare 11, 70124, Bari, Italy.
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Galleggiante V, Rutigliano M, Sallustio F, Ribatti D, Ditonno P, Bettocchi C, Selvaggi FP, Lucarelli G, Battaglia M. CTR2 Identifies a Population of Cancer Cells with Stem Cell-like Features in Patients with Clear Cell Renal Cell Carcinoma. J Urol 2014; 192:1831-41. [PMID: 24972308 DOI: 10.1016/j.juro.2014.06.070] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/17/2014] [Indexed: 12/11/2022]
Affiliation(s)
- Vanessa Galleggiante
- Andrology and Kidney Transplantation Unit, Department of Emergency and Organ Transplantation-Urology, University of Bari, Bari, Italy
| | - Monica Rutigliano
- Andrology and Kidney Transplantation Unit, Department of Emergency and Organ Transplantation-Urology, University of Bari, Bari, Italy
| | - Fabio Sallustio
- Dialysis and Transplantation Unit, Department of Emergency and Organ Transplantation-Nephrology, University of Bari, Bari, Italy
| | - Domenico Ribatti
- Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari, Bari, Italy
| | - Pasquale Ditonno
- Andrology and Kidney Transplantation Unit, Department of Emergency and Organ Transplantation-Urology, University of Bari, Bari, Italy
| | - Carlo Bettocchi
- Andrology and Kidney Transplantation Unit, Department of Emergency and Organ Transplantation-Urology, University of Bari, Bari, Italy
| | - Francesco Paolo Selvaggi
- Andrology and Kidney Transplantation Unit, Department of Emergency and Organ Transplantation-Urology, University of Bari, Bari, Italy
| | - Giuseppe Lucarelli
- Andrology and Kidney Transplantation Unit, Department of Emergency and Organ Transplantation-Urology, University of Bari, Bari, Italy
| | - Michele Battaglia
- Andrology and Kidney Transplantation Unit, Department of Emergency and Organ Transplantation-Urology, University of Bari, Bari, Italy
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47
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Isolation and Characterization of Cancer Stem Cells in Renal Cell Carcinoma. Urologia 2014; 82:46-53. [DOI: 10.5301/uro.5000099] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/29/2014] [Indexed: 12/17/2022]
Abstract
Recently, several studies have investigated the presence of cancer stem cells in kidney cancer, performed characterization, and compared their profile with the normal stem cell counterparts. CD133, alone or in combination with other molecular markers, has been used to isolate normal and cancer stem cells from different sources, including renal carcinoma; however, it is still a matter of debate whether CD133+cells really represent the main tumorigenic population within the heterogeneous pool of cancer cells that characterize this tumor. In this review, we summarize and discuss the current findings related to cancer stem cells isolation in renal cell carcinoma, focusing on controversies about their origin and the identification of a specific marker.
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48
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Anders HJ, Schaefer L. Beyond tissue injury-damage-associated molecular patterns, toll-like receptors, and inflammasomes also drive regeneration and fibrosis. J Am Soc Nephrol 2014; 25:1387-400. [PMID: 24762401 PMCID: PMC4073442 DOI: 10.1681/asn.2014010117] [Citation(s) in RCA: 234] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Tissue injury initiates an inflammatory response through the actions of immunostimulatory molecules referred to as damage-associated molecular patterns (DAMPs). DAMPs encompass a group of heterogenous molecules, including intracellular molecules released during cell necrosis and molecules involved in extracellular matrix remodeling such as hyaluronan, biglycan, and fibronectin. Kidney-specific DAMPs include crystals and uromodulin released by renal tubular damage. DAMPs trigger innate immunity by activating Toll-like receptors, purinergic receptors, or the NLRP3 inflammasome. However, recent evidence revealed that DAMPs also trigger re-epithelialization upon kidney injury and contribute to epithelial-mesenchymal transition and, potentially, to myofibroblast differentiation and proliferation. Thus, these discoveries suggest that DAMPs drive not only immune injury but also kidney regeneration and renal scarring. Here, we review the data from these studies and discuss the increasingly complex connection between DAMPs and kidney diseases.
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Affiliation(s)
- Hans-Joachim Anders
- Nephrological Center, Medizinische Klinik und Poliklinik IV, University of Munich, Munich, Germany; and
| | - Liliana Schaefer
- Pharmazentrum Frankfurt, Institute of General Pharmacology and Toxicology, Goethe-University of Frankfurt/Main, Frankfurt/Main, Germany
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Rangel EB, Gomes SA, Dulce RA, Premer C, Rodrigues CO, Kanashiro-Takeuchi RM, Oskouei B, Carvalho DA, Ruiz P, Reiser J, Hare JM. C-kit(+) cells isolated from developing kidneys are a novel population of stem cells with regenerative potential. Stem Cells 2014; 31:1644-56. [PMID: 23733311 DOI: 10.1002/stem.1412] [Citation(s) in RCA: 31] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2013] [Accepted: 04/02/2013] [Indexed: 12/26/2022]
Abstract
The presence of tissue specific precursor cells is an emerging concept in organ formation and tissue homeostasis. Several progenitors are described in the kidneys. However, their identity as a true stem cell remains elusive. Here, we identify a neonatal kidney-derived c-kit(+) cell population that fulfills all of the criteria as a stem cell. These cells were found in the thick ascending limb of Henle's loop and exhibited clonogenicity, self-renewal, and multipotentiality with differentiation capacity into mesoderm and ectoderm progeny. Additionally, c-kit(+) cells formed spheres in nonadherent conditions when plated at clonal density and expressed markers of stem cells, progenitors, and differentiated cells. Ex vivo expanded c-kit(+) cells integrated into several compartments of the kidney, including tubules, vessels, and glomeruli, and contributed to functional and morphological improvement of the kidney following acute ischemia-reperfusion injury in rats. Together, these findings document a novel neonatal rat kidney c-kit(+) stem cell population that can be isolated, expanded, cloned, differentiated, and used for kidney repair following acute kidney injury. These cells have important biological and therapeutic implications.
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Affiliation(s)
- Erika B Rangel
- Interdisciplinary Stem Cell Institute, São Paulo, São Paulo, Brazil; Sociedade Beneficente Albert Einstein, Albert Einstein Hospital, São Paulo, São Paulo, Brazil; Division of Nephrology, Department of Medicine, Federal University of São Paulo, São Paulo, São Paulo, Brazil
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50
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Abstract
Toll-like receptors (TLRs) and nucleotide-binding oligomerization domain receptors (NLRs) are families of pattern recognition receptors that, together with inflammasomes, sense and respond to highly conserved pathogen motifs and endogenous molecules released upon cell damage or stress. Evidence suggests that TLRs, NLRs and the NACHT, LRR and PYD domains-containing protein 3 (NLRP3) inflammasome have important roles in kidney diseases through regulation of inflammatory and tissue-repair responses to infection and injury. In this Review, we discuss the pathological mechanisms that are related to TLRs, NLRs and NLRP3 in various kidney diseases. In general, these receptors are protective in the host defence against urinary tract infection, but can sustain and self-perpetuate tissue damage in sterile inflammatory and immune-mediated kidney diseases. TLRs, NLRs and NLRP3, therefore, have become promising drug targets to enable specific modulation of kidney inflammation and suppression of immunopathology in kidney disease.
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