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Gruppo Romagnani

Laboratory of Nephrology

Coordinator:

Paola Romagnani, MD, Full Professor

Brief Biographical sketch of the Coordinator

Paola Romagnani, MD, PhD, is Full Professor and Chair of Nephrology at the University of Florence, and Head of Nephrology and Dialysis at the Meyer Children’s University Hospital, Florence, Italy.

Main achievements:

1999:              Young Investigator Award of the Hoechst Marion Roussel Foundation

2007:               ERC Starting Grant

2011:               Included in AcademiaNet (www.academia-net.org), the database of outstanding female scientists.

2014:               ERC Consolidator Grant

2014-2019:      Scientific Advisory Board ERA-EDTA

2010-2018:      Member of the Editorial Board of JASN

2020-               Member of the Editorial Board of Kidney International

2020:               ERA-EDTA Award for Outstanding Basic Science Contribution to Nephrology.

2021:               ERC Advanced Grant

Research Team

1) Paola Romagnani, MD, Full Professor, 02/03/1970, paola.romagnani@unifi.it

2) Laura Lasagni, Associate Professor, 24/11/1964, laura.lasagni@unifi.it

3) Elena Lazzeri, Associate Professor, 06/12/1974, elena.lazzeri@unifi.it

4) Augusto Vaglio, MD, Associate Professor, 22/09/1974, augusto.vaglio@unifi.it

5) Anna Julie Peired, Research fellow, 12/09/1977, annajulie.peired@unifi.it

6) Maria Lucia Angelotti, Research Technician, 04/06/1982, marialucia.angelotti@unifi.it

7) Carolina Conte, PhD fellow, 30/03/1990, carolina.conte@unifi.it

8) Benedetta Mazzinghi, Biologist manager, 08/09/1976, benedetta.mazzinghi@meyer.it

9) Giulia Antonelli, PhD fellow, 12/11/1990, giulia.antonelli@unifi.it

10) Maria Elena Melica, PhD fellow, 06/02/1989, mariaelena.melica@unifi.it

11) Letizia De Chiara, Postdoctoral Research Fellow , 24/02/1985, letizia.dechiara@gmail.com

12) Gilda La Regina, Research fellow, 06/01/1991, gilda.laregina@unifi.it

13) Alice Molli, Research fellow, 22/05/1994, alice.molli.94@gmail.com

14) Francesca Becherucci, MD, 27/06/1982, francesca.becherucci@gmail.com

15) Luigi Cirillo, MD, 11/07/1989, luigi.cirillo@unifi.it

16) Gianmarco Lugli, MD, 13/05/1992, gianmarco.lugli@unifi.it

17) Valentina Raglianti, MD, 29/05/1988, valentinaraglianti@gmail.com

 

Current research interest

Kidney diseases and renal regeneration

We have recently discovered that renal progenitor cells (RPCs) have a role in progression or resolution of glomerular and tubular injury, and clarified the mechanisms involved in these processes. This knowledge is the starting point to validate RPC as therapeutic targets to improve kidney regeneration and disease regression. Indeed, the identification of new drugs that can promote kidney regeneration by enhancing activity of RPC is one of the most promising stem-cell based therapeutic option for kidney disorders.

 

Glomerular regeneration:

RPC can generate new podocytes in response to glomerular damage and podocyte regeneration can influence glomerular disease prognosis. Podocyte regeneration can be pharmacologically modulated, which is the starting point for the development of new drugs to treat kidney disorders

 

Lasagni L et al. Stem Cell Reports, 2015

https://www.cell.com/action/showPdf?pii=S2213-6711%2815%2900195-2

 

Romoli S, Angelotti ML et al. Kidney Int, 2018

https://www.kidney-international.org/article/S0085-2538(18)30596-9/pdf

 

Tubular response to injury:

RPC can generate new tubular cells in response to acute kidney injury and undergo clonal amplification to replace lost tubular cells. However, regeneration after acute kidney injury is limited and hypertrophy of differentiated tubular cells is needed to recover kidney function after injury. This is achieved by endoreplication-mediated polyploidization. We are currently studying how to target these different mechanisms od response for therapeutic purposes.

 

Lazzeri E, Angelotti ML et al. Nature Communications, 2018

https://www.nature.com/articles/s41467-018-03753-4.pdf

 

Lazzeri E et al. Trends Mol Med, 2019

https://www.cell.com/action/showPdf?pii=S1471-4914%2819%2930041-3

 

Genetic of kidney diseases

We recently developed a method for culturing RPC from urine of patients affected by renal diseases that opens the perspective of a kidney-personalized medicine. This new strategy allows us to complement the extended genetic diagnosis of kidney disease performed in our Unit thanks to the close collaboration of the Genetic Unit of Meyer Children’s Hospital, providing a unique clinical approach for patients affected by kidney diseases In this perspective, this technique ideally complements state-of-the-art genetic diagnostics through next-generation sequencing strategies and allows to study the clinical expression of the disorder. In addition, patient-specific RPC can be used for screening of new treatment strategies in terms of safety and efficacy.

 

Lazzeri E et al. Journal of the American Society of Nephrology, 2015

https://jasn.asnjournals.org/content/jnephrol/26/8/1961.full.pdf

 

Landini S, Mazzinghi B, Becherucci F et al. Clinical Journal of the American Society of Nephrology 2020

https://cjasn.asnjournals.org/content/clinjasn/15/1/89.full.pdf

 

Kidney cancer

We recently identified acute kidney injury (AKI) as a major risk factor in papillary renal cell carcinoma (pRCC) development in human and mice. This discovery has important implications for patient care. We also demonstrated that Notch1, an AKI-related pathway, plays an important role in pRCC formation. We showed that pRCCs originate from deregulated RPCs that behave as cancer stem cells (CSCs), a cell population resistant to traditional chemo- and radiotherapy treatments, and often responsible for the recurrence of RCC in patients. Therefore, we propose to develop new drugs aimed at CSCs, based on the molecular mechanisms that regulate the properties of stem cells. Full article can be accessed here:

 

Peired AJ et al. Science Translational Medicine, 2020

http://stm.sciencemag.org/cgi/content/full/12/536/eaaw6003?ijkey=SskNkBXFM/kdQ&keytype=ref&siteid=scitransmed

 

Gender-specificity in kidney physiology and diseases

Kidney diseases, including kidney cancer, show a consistent sexual dimorphism in incidence and outcome. We propose that sex hormones regulate the regenerative capacity of RPC, modulating their number and function. We are currently studying how the sex hormone signaling in RPC influences kidney disease and pregnancy complication, such as preeclampsia.

 

Interferon-related kidney disorders

Research is ongoing on Interferon-related kidney disorders, particularly those secondary to type I interferonopathies, viral infections or autoimmune diseases such as systemic lupus erythematosus. We aim to characterize the type I interferon response in the kidney, to explore which cell types and kidney compartments are involved in the different interferon-related disorders and the potential associations between gene mutations leading to type I interferonopathies and  glomerular injury patterns. Understanding the type I response in the kidney may help identify the patients who can benefit from treatments specifically targeting the interferon pathway.

 

Fenaroli P et al., Am J Kidney Dis., 2021

 

Current/recent sources of funding

1) ERC Advanced Investigator Grant-Horizon 2020: “Sexual dimorphIsM in renal PrOgenitors to explain gender-Specificity In kidney physiOlogy aNd diseases SIMPOSION.

2) Fourth ERA PerMed Joint Transnational Call for Proposals 2021. Implementation of personalized management in nephrotic syndrome. PER-NEPH.

3) Bando Ricerca Salute 2018 “Messa a punto di un algoritmo per la diagnosi personalizzata delle malattie renali rare” (NIKE).

4) Ministero dell'Istruzione dell'Università e della Ricerca-PRIN 2017. New strategies for 3D modelling, diagnosis and treatment of acute kidney injury.

5) Associazione Italiana per la Ricerca sul Cancro and Fondazione CR Firenze under IG ID.21821 project—Role of renal progenitors and endocycling tubular cells in the pathogenesis of different renal cell carcinoma subtypes

6) Progetto "Smart" BANDO FAS SALUTE, Sviluppo Toscana. Messa a punto di una strategia innovativa di medicina personalizzata per la diagnosi e la terapia delle malattie renali nei bambini.

7) RENOIR, ERC Consolidator Grant, Horizon 2020, RENal prOgenItoRs as tools to understand kidney pathophysiology and treat renal disorders

8) STELLAR, FP7-HEALTH-2012, Stem-cell based therapy for kidney repair.

9) VITA- Bando NUTRACEUTICA, Regione Toscana, Uso della supplementazione dietetica con vitamina A per promuovere la regressione delle malattie renali croniche.

10) Kidney Connect: A Gateway to European Kidney Research Resources, FP7-Cost Project

11) Kidney Research UK: Miracle in collecting ducts underlie albuminuria-induced kidney fibrosis.

12) Star-trek, FP7, HEALTH-F5, Set up and comparison of multiple stem cell approaches for kidney repair.

13) Italian Ministery of Health “Set up of Stem cell strategies for acute and chronic renal failure”

14) Regione Toscana “Renal stem cells amplification from the urine of patients with glomerular disorders for the set-up of autologous cell therapy of chronic renal injury”

15) RESCARF, ERC-Starting Grant, FP7. Renal stem cells: possible role in kidney pathologies and as new therapeutic tools.

10 best pubblications of the last 5 years

1) Peired AJ, Antonelli G, Angelotti ML, Allinovi M, Guzzi F, Sisti A, Semeraro R, Conte C, Mazzinghi B, Nardi S, Melica ME, De Chiara L, Lazzeri E, Lasagni L, Lottini T, Landini S, Giglio S, Mari A, Di Maida F, Antonelli A, Porpiglia F, Schiavina R, Ficarra V, Facchiano D, Gacci M, Serni S, Carini M, Netto GJ, Roperto RM, Magi A, Christiansen CF, Rotondi M, Liapis H, Anders HJ, Minervini A, Raspollini MR, Romagnani P. Acute kidney injury promotes development of papillary renal cell adenoma and carcinoma from renal progenitor cells. Sci Transl Med. 2020 Mar 25;12(536). pii: eaaw6003. Full text available here: http://stm.sciencemag.org/cgi/content/full/12/536/eaaw6003?ijkey=SskNkBXFM/kdQ&keytype=ref&siteid=scitransmed

2) Landini S, Mazzinghi B, Becherucci F, Allinovi M, Provenzano A, Palazzo V, Ravaglia F, Artuso R, Bosi E, Stagi S, Sansavini G, Guzzi F, Cirillo L, Vaglio A, Murer L, Peruzzi L, Pasini A, Materassi M, Roperto RM, Anders HJ, Rotondi M, Giglio SR, Romagnani P. Reverse Phenotyping after Whole-Exome Sequencing in Steroid-Resistant Nephrotic Syndrome. Clin J Am Soc Nephrol. 2020 Jan 7;15(1):89-100.

3) Melica ME, La Regina G, Parri M, Peired AJ, Romagnani P, Lasagni L. Substrate Stiffness Modulates Renal Progenitor Cell Properties via a ROCK-Mediated Mechanotransduction Mechanism. Cells. 2019 Dec 3;8(12). pii: E1561.

4) Romoli S, Angelotti ML, Antonelli G, Kumar Vr S, Mulay SR, Desai J, Anguiano Gomez L, Thomasova D, Eulberg D, Klussmann S, Melica ME, Conte C, Lombardi D, Lasagni L, Anders HJ, Romagnani P. CXCL12 blockade preferentially regenerates lost podocytes in cortical nephrons by targeting an intrinsic podocyte-progenitor feedback mechanism. Kidney Int. 2018 Dec;94(6):1111-1126.

5) Lazzeri E, Angelotti ML, Peired A, Conte C, Marschner JA, Maggi L, Mazzinghi B, Lombardi D, Melica ME, Nardi S, Ronconi E, Sisti A, Antonelli G, Becherucci F, De Chiara L, Guevara RR, Burger A, Schaefer B, Annunziato F, Anders HJ, Lasagni L, Romagnani P. Endocycle-related tubular cell hypertrophy and progenitor proliferation recover renal function after acute kidney injury. Nat Commun. 2018 Apr 9;9(1):1344.

6) Romagnani P, Giglio S, Angelotti ML, Provenzano A, Becherucci F, Mazzinghi B, Müller S, Amann K, Weidenbusch M, Romoli S, Lazzeri E, Anders HJ. Next generation sequencing and functional analysis of patient urine renal progenitor-derived podocytes to unravel the diagnosis underlying refractory lupus nephritis. Nephrol Dial Transplant. 2016 Sep;31(9):1541-5.

7) Lasagni L, Angelotti ML, Ronconi E, Lombardi D, Nardi S, Peired A, Becherucci F, Mazzinghi B, Sisti A, Romoli S, Burger A, Schaefer B, Buccoliero A, Lazzeri E, Romagnani P. Podocyte Regeneration Driven by Renal Progenitors Determines Glomerular Disease Remission and Can Be Pharmacologically Enhanced. Stem Cell Reports. 2015 Aug 11;5(2):248-63.

8) Romagnani P, Rinkevich Y, Dekel B. The use of lineage tracing to study kidney injury and regeneration. Nat Rev Nephrol. 2015 Jul;11(7):420-31.

9) Giglio S, Provenzano A, Mazzinghi B, Becherucci F, Giunti L, Sansavini G, Ravaglia F, Roperto RM, Farsetti S, Benetti E, Rotondi M, Murer L, Lazzeri E, Lasagni L, Materassi M, Romagnani P. Heterogeneous genetic alterations in sporadic nephrotic syndrome associate with resistance to immunosuppression. J Am Soc Nephrol. 2015 Jan;26(1):230-6.

10) Lazzeri E, Ronconi E, Angelotti ML, Peired A, Mazzinghi B, Becherucci F, Conti S, Sansavini G, Sisti A, Ravaglia F, Lombardi D, Provenzano A, Manonelles A, Cruzado JM, Giglio S, Roperto RM, Materassi M, Lasagni L, Romagnani P. Human Urine-Derived Renal Progenitors for Personalized Modeling of Genetic Kidney Disorders. J Am Soc Nephrol. 2015 Aug;26(8):1961-74.

Previeus research experiences

In her career, she was responsible for other important scientific breakthroughs. In 2001, she clarified the mechanisms involved in the angiostatic effects of chemokines. This study (Romagnani P et al. JCI, 2001), was selected for the cover of the journal and was the subject of a highlight of the Editor. She has then identified and functionally characterized a novel chemokine receptor involved in cell growth control (Lasagni L et al. J Exp Med, 2003). In 2005, she has demonstrated the existence of a previously unrecognized population of circulating stem cells (Romagnani P et al. Circ Res, 2005).

Main scientific contributions

-Establishment of the role of acute kidney injury in the development of papillary renal cell carcinoma

-Identification of the mechanisms at play during kidney recovery following acute kidney injury

-Generation of a unique mouse model for lineage tracing of the renal progenitor system in the mouse.

-Elucidation of the mechanisms of podocyte regeneration driven by renal progenitors.

-Establishment of a method for selection and identification of renal progenitors from the urine of patients affected by kidney disorders.

-Clarification of the mechanisms involved in the angiostatic effects of chemokines

-Identification and functional characterization of a novel chemokine receptor (CXCR3B) involved in cell growth control

-Demonstration of the existence of a previously unrecognized population of circulating stem cells

Collaborations

•          Genetic Unit of Meyer Children’s Hospital, Florence, Italy

•          Benjamin Vervaet, Department of Biomedical Sciences, University of Antwerp, Antwerp, Belgium.

•          Josep M Cruzado, Nephrology Department, L'Hospitalet de Llobregat, Hospital Universitari de Bellvitge, Barcelona, Spain.

•          Hans-Joachim Anders/Basic and Clinical Nephrology/ Nephrologisches Zentrum, Medizinische Klinik und Poliklinik IV, Klinikum der Universität München-Innenstadt, Munich, Germany.

•          Giuseppe Remuzzi/Basic and Clinical Nephrology. Mario Negri Institute for Pharmacological Research, Bergamo, Italy

•          Qihe Xu/Basic researcher, Metabolism/King’s College, London, UK

•          Ton Rabelink/Clinical Researcher, Internal Medicine/LMU Leiden University Medical Center/Ledien, The Netherlands

•          Benjamin Dekel/Basic and Clinical Pediatrics and Nephrology/Tel Aviv University, Tel Aviv, Israel

•          Tobias Huber/Basic Nephrology/University Medical Center Freiburg/Freiburg, Germany

•          Janos Peti-Peterdi/Basic research, Physiology, University of South California, Los Angeles, USA

  • Alessandro Pecci, Department of Internal Medicine, IRCCS Policlinico San Matteo Foundation and University of Pavia, 27100 Pavia, Italy.

Renal progenitor cells (RPC) can be visualized and tracked in vivo by using transgenic mouse models developed in Romagnani’s lab. Left: In the Pax2/Confetti mouse, RPC express four different fluorochromes and appear as cells localized in the parietal epithelium of the Bowman capsule in the glomeruli (G) and as scattered cells along different tubular segments. Right: By using the Pax2/TomRed/GFP mouse as a RPC-specific tracking tool, we could establish that RPC differentiation into podocytes can occur following glomerular injury and critically contributes to disease improvement. Reproduced from Lasagni et al. (2015) Stem Cell Reports 5, 248-263.

Left: Renal progenitor cells, stained in blue with an anticlaudin 1 antibody, migrating from Bowman’s capsule into the glomerular tuft and progressively acquiring the podocyte marker podocin. (Peired et al, 2013). Center: Representative glomeruli with Pax2+ cells (green) in Bowman’s capsule (arrows) in the cortex of a healthy Pax2/TomRed/GFP mouse kidney (Romoli et al, 2018). Right: 3D reconstruction of papillary renal cell carcinoma developing in Pax8/Confetti/NICD1 mouse kidney, showing the monoclonal origin of the lesions. Collagen IV is labeled in cyan (Peired et al, 2020).

                              

Integrated database towards a global view on Kidney Physiopathology

Ultimo aggiornamento

11.01.2022

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