MO060ACUTE KIDNEY INJURY PROMOTES DEVELOPMENT OF A PAPILLARY RENAL CELL ADENOMA-CARCINOMA SEQUENCE FROM RENAL PROGENITORS

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Anna Julie Peired ◽  
Marco Allinovi ◽  
Giulia Antonelli ◽  
Maria Lucia Angelotti ◽  
Francesco Guzzi ◽  
...  
Keyword(s):  
Risk Factors ◽  
Single Cell ◽  
Renal Cell ◽  
Tissue Injury ◽  
Lineage Tracing ◽  
Molecular Signature ◽  
Research Network ◽  
Wild Type ◽  
Renal Progenitors

Abstract Background and Aims Renal cell carcinoma (RCC) accounts for 2% of all cancers, with about 190,000 new cases per year worldwide. Risk factors for RCC include obesity, diabetes, hypertension and genetic factors, but the majority of cancers occur in apparent absence of clear risk factors. Acute tissue injury (AKI) causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. We proposed to verify whether AKI plays a role in RCC development, and to identify the cellular origin of RCC. Method We used the following techniques: 1. observational, retrospective clinical trial to identify a possible association of AKI with RCC. 2. Experimental AKI induction in wild-type mice to study tumor development over 36 weeks. 3. Analysis of TCGA Research Network dataset on human papillary RCC (pRCC) molecular characterization, focusing on AKI-driven pathways. 4. Development of mouse models in which the intracellular domain of Notch 1 (NICD1), a molecule modulated during AKI, is expressed constitutively by all Pax8+ tubular epithelial cells (Pax8/NICD1) or only by Pax2+ renal progenitors (Pax2/NICD1) upon induction in adult mice. The mice were sacrificed at 36 weeks or 4 weeks after AKI. 5. Clonal analysis of tumoral lesions with Confetti reporter. 6. Examination of single cell RNA sequencing (RNAseq) data from pRCC patients. Results We observed that an AKI episode is a major risk factor for pRCC development and recurrence in patients. Wild-type mice subjected to AKI developed pRCC over time in an adenoma-carcinoma sequence, corroborating our human findings. Among AKI-related pathways, Notch1 overexpression in human pRCC associated with worse outcome, prompting us to generate Notch1-overexpressing mice. At 36 weeks o at 4 weeks following AKI, Pax8/NICD1 mice presented a significant decline of renal excretory function as well as type 2 pRCCs. Confetti lineage tracing showed that most of the pRCCs were monoclonal or biclonal, suggesting that they could originate from a local stem cell/progenitor population. Pax2/NICD1 mice presented type 2 pRCCs, and lineage tracing identified single Pax2+ tubular progenitors as the source of pRCCs. Single cell RNAseq analysis confirmed that the molecular signature of the pRCC cell of origin matched the one of human tubular progenitors. Conclusion This study expose the link between AKI and pRCC development in patients, with important clinical implications. In mice, AKI promotes long-term development of type 2 papillary tumors by activating the AKI-associated Notch1 pathway. Additionally, pRCC originates from clonal proliferation of renal progenitors in a classical adenoma-carcinoma sequence leading to invasive pRCC growth and metastatization in mice.

Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells

2020 ◽  
Vol 12 (536) ◽  
pp. eaaw6003 ◽  
Author(s):  
Anna Julie Peired ◽  
Giulia Antonelli ◽  
Maria Lucia Angelotti ◽  
Marco Allinovi ◽  
Francesco Guzzi ◽  
...  
Keyword(s):  
Acute Kidney Injury ◽  
Progenitor Cells ◽  
Renal Cell ◽  
Tissue Injury ◽  
Kidney Injury ◽  
Lineage Tracing ◽  
Cell Of Origin ◽  
Renal Progenitor Cells ◽  
Renal Progenitor

Acute tissue injury causes DNA damage and repair processes involving increased cell mitosis and polyploidization, leading to cell function alterations that may potentially drive cancer development. Here, we show that acute kidney injury (AKI) increased the risk for papillary renal cell carcinoma (pRCC) development and tumor relapse in humans as confirmed by data collected from several single-center and multicentric studies. Lineage tracing of tubular epithelial cells (TECs) after AKI induction and long-term follow-up in mice showed time-dependent onset of clonal papillary tumors in an adenoma-carcinoma sequence. Among AKI-related pathways, NOTCH1 overexpression in human pRCC associated with worse outcome and was specific for type 2 pRCC. Mice overexpressing NOTCH1 in TECs developed papillary adenomas and type 2 pRCCs, and AKI accelerated this process. Lineage tracing in mice identified single renal progenitors as the cell of origin of papillary tumors. Single-cell RNA sequencing showed that human renal progenitor transcriptome showed similarities to PT1, the putative cell of origin of human pRCC. Furthermore, NOTCH1 overexpression in cultured human renal progenitor cells induced tumor-like 3D growth. Thus, AKI can drive tumorigenesis from local tissue progenitor cells. In particular, we find that AKI promotes the development of pRCC from single progenitors through a classical adenoma-carcinoma sequence.

scholarly journals Ventricular, atrial and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak

2020 ◽  
Author(s):  
Kenzo Ivanovitch ◽  
Pablo Soro-Barrio ◽  
Probir Chakravarty ◽  
Rebecca A Jones ◽  
S. Neda Mousavy Gharavy ◽  
...  
Keyword(s):  
Single Cell ◽  
Heart Development ◽  
Primitive Streak ◽  
Outflow Tract ◽  
Lineage Tracing ◽  
Molecular Signature ◽  
Genetic Lineage ◽  
Cardiac Progenitors ◽  
Heart Field ◽  
Genetic Lineage Tracing

AbstractThe heart develops from two sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single cell transcriptomic assay in combination with genetic lineage tracing, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are pre-patterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function and disease.

scholarly journals Ventricular, atrial, and outflow tract heart progenitors arise from spatially and molecularly distinct regions of the primitive streak

PLoS Biology ◽  
2021 ◽  
Vol 19 (5) ◽  
pp. e3001200
Author(s):  
Kenzo Ivanovitch ◽  
Pablo Soro-Barrio ◽  
Probir Chakravarty ◽  
Rebecca A. Jones ◽  
Donald M. Bell ◽  
...  
Keyword(s):  
Single Cell ◽  
Heart Development ◽  
Primitive Streak ◽  
Outflow Tract ◽  
Lineage Tracing ◽  
Molecular Signature ◽  
Genetic Lineage ◽  
Cardiac Progenitors ◽  
Heart Field ◽  
Genetic Lineage Tracing

The heart develops from 2 sources of mesoderm progenitors, the first and second heart field (FHF and SHF). Using a single-cell transcriptomic assay combined with genetic lineage tracing and live imaging, we find the FHF and SHF are subdivided into distinct pools of progenitors in gastrulating mouse embryos at earlier stages than previously thought. Each subpopulation has a distinct origin in the primitive streak. The first progenitors to leave the primitive streak contribute to the left ventricle, shortly after right ventricle progenitor emigrate, followed by the outflow tract and atrial progenitors. Moreover, a subset of atrial progenitors are gradually incorporated in posterior locations of the FHF. Although cells allocated to the outflow tract and atrium leave the primitive streak at a similar stage, they arise from different regions. Outflow tract cells originate from distal locations in the primitive streak while atrial progenitors are positioned more proximally. Moreover, single-cell RNA sequencing demonstrates that the primitive streak cells contributing to the ventricles have a distinct molecular signature from those forming the outflow tract and atrium. We conclude that cardiac progenitors are prepatterned within the primitive streak and this prefigures their allocation to distinct anatomical structures of the heart. Together, our data provide a new molecular and spatial map of mammalian cardiac progenitors that will support future studies of heart development, function, and disease.

scholarly journals Single-Cell RNA Sequencing in Multiple Pathologic Types of Renal Cell Carcinoma Revealed Novel Potential Tumor-Specific Markers

2021 ◽  
Vol 11 ◽  
Author(s):  
Cheng Su ◽  
Yufang Lv ◽  
Wenhao Lu ◽  
Zhenyuan Yu ◽  
Yu Ye ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Single Cell ◽  
Rna Sequencing ◽  
Renal Cell ◽  
Small Sample Size ◽  
Mrna Level ◽  
Small Sample ◽  
Single Cell Rna Sequencing

BackgroundRenal cell carcinoma (RCC) is the most common type of kidney cancer. Studying the pathogenesis of RCC is particularly important, because it could provide a direct guide for clinical treatment. Given that tumor heterogeneity is probably reflected at the mRNA level, the study of mRNA in RCC may reveal some potential tumor-specific markers, especially single-cell RNA sequencing (scRNA-seq).MethodsWe performed an exploratory study on three pathological types of RCC with a small sample size. This study presented clear-cell RCC (ccRCC), type 2 pRCC, and chRCC in a total of 30,263 high-quality single-cell transcriptome information from three pathological types of RCC. In addition, scRNA-seq was performed on normal kidneys. Tumor characteristics were well identified by the comparison between different pathological types of RCC and normal kidneys at the scRNA level.ResultsSome new tumor-specific markers for different pathologic types of RCC, such as SPOCK1, PTGIS, REG1A, CP and SPAG4 were identified and validated. We also discovered that NDUFA4L2 both highly expressed in tumor cells of ccRCC and type 2 pRCC. The presence of two different types of endothelial cells in ccRCC and type 2 pRCC was also identified and verified. An endothelial cell in ccRCC may be associated with fibroblasts and significantly expressed fibroblast markers, such as POSTN and COL3A1. At last, by applying scRNA-seq results, the activation of drug target pathways and sensitivity to drug responses was predicted in different pathological types of RCC.ConclusionsTaken together, these findings considerably enriched the single-cell transcriptomic information for RCC, thereby providing new insights into the diagnosis and treatment of RCC.

scholarly journals Rapid doubling of Alzheimer’s amyloid-β40 and 42 levels in brains of mice exposed to a nickel nanoparticle model of air pollution

F1000Research ◽  
2012 ◽  
Vol 1 ◽  
pp. 70 ◽  
Author(s):  
Soong Ho Kim ◽  
Elysse M Knight ◽  
Eric L Saunders ◽  
Azita K Cuevas ◽  
Marusia Popovech ◽  
...  
Keyword(s):  
Risk Factors ◽  
Air Pollution ◽  
Amyloid Β ◽  
Clinical Importance ◽  
Wild Type ◽  
Physiological Basis ◽  
Nickel Nanoparticle ◽  
Pollution Modeling ◽  
Obesity Hypertension

Background: Over 20 genetic risk factors have been confirmed to associate with elevated risk for Alzheimer’s disease (AD), but the identification of environmental and/or acquired risk factors has been more elusive. At present, recognized acquired risks for AD include traumatic brain injury, hypercholesterolemia, obesity, hypertension, and type 2 diabetes.Methods: Based on reports associating various inhalants with AD pathology, we investigated the possibility that air pollution might contribute to AD risk by exposing wild-type mice to a standard air pollution modeling system employing nickel nanoparticle-enriched atmosphere for 3 hr.Results: Mice exposed to air pollution showed 72-129% increases in brain levels of both amyloid-β peptides Aβ40 and Aβ42, as well as Aβ42/40 (p <0.01).Conclusions: These effects on elevation of brain Aβ exceed those associated with trisomy 21, a known risk for early onset AD pathology, raising the possibility that clinical importance might be attached. Further work is required to establish the molecular and physiological basis for these phenomena. The rapid, dramatic effect, if verified, would suggest that inhalant exposures should be evaluated for their possible roles in contributing to the environmental risk for common forms of AD.

scholarly journals Risk Factors and Bronchopulmonary Dysplasia Severity. Data From the Spanish Bronchopulmonary Dysplasia Research Network

2021 ◽  
Author(s):  
Cristina Ramos-Navarro ◽  
Elena Maderuelo-Rodriguez ◽  
Ana Concheiro-Guisan ◽  
Santiago Perez-Tarazona ◽  
Santiago Rueda-Esteban ◽  
...  
Keyword(s):  
Risk Factors ◽  
Bronchopulmonary Dysplasia ◽  
Total Sample ◽  
Research Network ◽  
Positive Pressure ◽  
Public And Private ◽  
Postnatal Risk Factors ◽  
Type 3 ◽  
The Impact

Abstract GEIDIS is a national based research-net registry of patients with bronchopulmonary dysplasia (BPD) from public and private Spanish hospitals. It was created to provide data on the clinical characterization and follow up of infants with BPD until adulthood. The purpose of this observational study was to analyze the characteristics and the impact of perinatal risk factors on BPD severity. The study included 1,780 patients diagnosed with BPD. Of the total sample, 98.6% were premature (less than 37 weeks) and 89,4% less than 30 weeks of gestation. The median gestational age was 27.1 weeks (25.8–28.5) and median birth weight 890 g (740–1,090 g). 52.3% (n=931) were classified as mild (type 1), 25.1% (n=447) were moderate (type 2), and 22.6% (n=402) severe BPD (type 3). Most pre-and postnatal risk factors for type 2/3 BPD were associated with the length of exposure to mechanical ventilation (MV). Independent prenatal risk factors were male gender, oligohydramnios, and intrauterine growth restriction. Postnatal risk factors included the need for FiO2 of > 0.30 in the delivery room, two or more doses of surfactant administration, nosocomial pneumonia, and the length of exposure to MV. Conclusions: In this national based research-net registry of BPD patients the length of MV is the most important risk factor associated with type 2/3 BPD. Among type 3 BPD patients, those who required an FiO2 > .30 at 36 weeks’ postmenstrual age had a higher morbidity, during hospitalization and at discharge, compared to those with nasal positive pressure but FiO2 < .30.

scholarly journals Single-cell transcriptional analysis reveals naïve helper ILC-like cells in zebrafish

2018 ◽  
Author(s):  
Pedro P. Hernández ◽  
Paulina M. Strzelecka ◽  
Emmanouil I. Athanasiadis ◽  
Ana F. Robalo ◽  
Catherine M. Collins ◽  
...  
Keyword(s):  
Single Cell ◽  
Lymphoid Cells ◽  
Transcriptional Analysis ◽  
Environmental Cues ◽  
Immune Challenge ◽  
Wild Type ◽  
And Function ◽  
Type 3 ◽  
Barrier Tissues

AbstractInnate lymphoid cells (ILCs) are important mediators of the immune response and homeostasis in barrier tissues of mammals. However, the existence and function of ILCs in other vertebrates is poorly understood. Here, we use single-cell RNA sequencing to generate a comprehensive atlas of zebrafish lymphocytes during tissue homeostasis and following immune challenge. We profiled 14,080 individual cells from the gut of wild-type zebrafish, as well as of rag1-deficient fish which lack T and B cells, and discovered diverse populations of helper ILC-like cells. Unexpectedly, fish displayed a rorc-positive, naïve subset that established a Type 3 or Type 2 response only upon immune challenge. Specifically, naïve ILC-like cells expressed il22 and tnfa following exposure to inactivated bacteria, or il13 following exposure to helminth extract. Cytokine-producing ILC-like cells express a specific repertoire of novel immune-type receptors, likely involved in recognition of environmental cues. We identified additional novel markers of zebrafish ILCs and generated a cloud repository for their in-depth exploration.

scholarly journals AFF3 and BACH2 are master regulators of metabolic inflexibility, β/α-cell transition, and dedifferentiation in type 2 diabetes

2019 ◽  
Author(s):  
Jinsook Son ◽  
Hongxu Ding ◽  
Domenico Accii ◽  
Andrea Califano
Keyword(s):  
Type 2 Diabetes ◽  
Single Cell ◽  
Cell Mass ◽  
Lineage Tracing ◽  
Calcium Flux ◽  
Pharmacological Intervention ◽  
Β Cell ◽  
Master Regulators ◽  
Metabolic Inflexibility

ABSTRACTType 2 Diabetes is associated with defective insulin secretion, reduced β-cell mass, and increased glucagon production. Cell lineage-tracing in rodents and human autopsy surveys support the notion of β-cell dedifferentiation as a unifying mechanism for these abnormalities. Yet, mechanistic determinants of human β-cell failure remain elusive. Using regulatory-network-based single-cell analysis of human islets, we identify aberrant, diabetes-enriched transitional states characterized by metabolic inflexibility, α/β-transition, and endocrine progenitor/stem cell features. A coordinated transcription factor hierarchy mediating cell state transition emerged and was validated using barcoded guide-based, single-cell gene transfer and calcium flux measures in primary human islet cells. Specifically, two master regulators and associated epigenetic drivers emerged, one (AFF3) controlling β- to α-like-cell reprogramming, the other (BACH2) transition to a dedifferentiated endocrine progenitor-like cell. The findings provide mechanistic insight into diabetic islet cell dysfunction and suggest actionable pathways for pharmacological intervention.

scholarly journals Molecular Mechanisms of Renal Progenitor Regulation: How Many Pieces in the Puzzle?

Cells ◽  
2021 ◽  
Vol 10 (1) ◽  
pp. 59
Author(s):  
Anna Julie Peired ◽  
Maria Elena Melica ◽  
Alice Molli ◽  
Cosimo Nardi ◽  
Paola Romagnani ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Kidney Injury ◽  
Molecular Signature ◽  
Molecular Characteristics ◽  
Evolutionarily Conserved ◽  
Toll Like Receptor 2 ◽  
Renal Progenitors ◽  
Renal Progenitor

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.

scholarly journals Molecular Mechanisms of Renal Progenitor Regulation: How Many Pieces in the Puzzle?

2020 ◽  
Author(s):  
Anna Julie Peired ◽  
Maria Elena Melica ◽  
Alice Molli ◽  
Cosimo Nardi ◽  
Paola Romagnani ◽  
...  
Keyword(s):  
Molecular Mechanisms ◽  
Tissue Injury ◽  
Kidney Injury ◽  
Molecular Signature ◽  
Molecular Characteristics ◽  
Beta Catenin ◽  
Evolutionarily Conserved ◽  
Toll Like Receptor 2 ◽  
Renal Progenitors ◽  
Renal Progenitor

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/&beta;-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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